To compare the efficacy and safety of radiotherapy before and after CD19 CAR T-cell therapy in patients with R/R DLBCL

To compare the efficacy and safety of radiotherapy before and after CD19 CAR T-cell therapy in patients with R/R DLBCL | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article To compare the efficacy and safety of radiotherapy before and after CD19 CAR T-cell therapy in patients with R/R DLBCL Jingyi Li, Juan Mu, Xin Li, Qing Li, Rui Cui, YIli Jiang, JIa Wang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8589923/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Radiotherapy is an effective salvage treatment after CAR T-cell therapy. However, the differences between the efficacy and side effects of radiotherapy before and after CAR T-cell therapy are still unknown. 14 and 17 patients received radiotherapy 1–7 months before CAR T-cell therapy (R-C group) and 2–3 months after CAR T-cell therapy (C-R group), respectively. The R-C group was categorised into the following subgroups according to the duration of radiotherapy: 1-3-month group and > 3 (> 3-month group. We compared the differences in efficacy and side effects between groups. The ORR and CR were 81.82% and 54.55%, respectively, in the R-C group and 64.71% and 35.29%, respectively, in the C-R group. However, the ORR and CR increased to 64.71% and 64.71%, respectively, in the C-R group after salvage radiotherapy. The peaks of CAR T-cells were higher in the R-C group than in the C-R group and higher in the R-C (1–3 months) group than in the R-C (> 3 months) group. No difference was observed in the grades of CRS and ICANS between the R-C and C-R groups. CAR T-cell therapy followed by radiotherapy improved the CR without significant increase the severe adverse events. Trial registration number : ChiCTR1800019622 , registered date: 21-11-2018 . Chimeric antigen receptor (CAR) Relapsed/refractory Diffuse large B-cell lymphoma Radiotherapy Efficacy Side effects Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an effective and promising salvage therapy for patients with relapsed/refractory (R/R) B-cell lymphoma [ 1 – 4 ]. However, some patients are unresponsive to CD19 CAR T-cell therapy and are at risk of disease relapse [ 5 , 6 ]. Patients with R/R diffuse large B-cell lymphoma (DLBCL) who have adverse factors to CD19 CAR T-cell therapy, including bulky disease, international prognostic index (IPI) score of ≥ 3, and elevated lactate dehydrogenase, have been reported to benefit from combination or bridging therapy with CD19 CAR T-cell infusion [ 7 ]. These therapies include steroids, chemotherapy, targeted treatment, radiotherapy, systemic therapy, and combined modality treatment. Radiotherapy bridging treatment has been reported to improve the survival rate of CD19 CAR T-cell therapy, provided the intensive management of prolonged cytopenia after CAR T-cell therapy is strengthened [ 7 , 8 ]. However, another study reported that progression-free survival (PFS) and overall survival (OS) were similar between the bridging therapy group, no-bridging therapy group, and bridging therapy subgroups [ 9 ]. Additionally, low-dose radiotherapy could be an effective salvage treatment for patients with R/R DLBCL who are unresponsive to CAR-T therapy or experience disease relapse after CAR T-cell treatment [ 10 ]. There was literature outlining the problem of employing different strategies to overcome different obstacles [ 11 ]. Especially, R/R DLBCL patients with CD19-negative tumor cells, diminished CD19 expression, low CD19 expression are all in a higher risk of failure or relapses in CD19 CAR T-cell therapy [ 12 ]. Radiotherapy is an effective treatment strategy for patients with R/R DLBCL [ 13 ] and has been shown to provide tumour-associated antigens for antigen-specific T-cells, enhance cytotoxicity and proliferation of native T-cells and adoptively transferred T-cells [ 14 ]. Another finding suggests that the mechanism of radiotherapy combined with CAR T-cell therapy involves overcoming antigen escape [ 15 ]. Therefore, CAR T-cell therapy in combination with radiotherapy may be more effective than CAR T-cell treatment alone. In this study, we investigated the efficacy and side effects of radiotherapy before and after CAR T-cell therapy in patients with R/R DLBCL. 2. Materials and Methods 2.1Study Participants In this study, 31 patients with R/R DLBCL received anti-CD19-CAR T-cell therapy between January 2019 and June 2021. All 31 patients had at least one bulky disease (maximum diameter of ≥ 7.5 cm), and none of them underwent hematopoietic stem cell transplantation before this study. Because all the 31 patients with R/R DLBCL had at least one bulky disease, they had received anti-CD19 CAR T-cell therapy combined with radiotherapy. In our study, the cutoff date was 30 June 2023. The follow-up period was from the day of CAR T-cell infusion to the cutoff date or the day of death. 2.2 Response Criteria and Study Endpoint The IPI was based on the disease state when patients underwent leukapheresis [ 16 ]. Additionally, the efficacy of anti-CD19 CAR T-cell therapy was evaluated according to the Lugano Revised Criteria [ 17 ] 2 months after the infusion date. In our study, response was evaluated using positron emission tomography-computed tomography or computed tomography. 2.3 Anti-CD19 CAR T-Cell Therapy All 31 patients with R/R DLBCL received anti-CD19 CAR T-cell therapy (trial registration number: ChiCTR1800019622 ), which was approved by the Medical Ethics Committee of the Department of Hematology at the Tianjin First Central Hospital, Tianjin, China (approval number: 2018N105KY). The study protocol was performed in accordance with the guidelines of the Declaration of Helsinki. All patients signed a written informed consent form prior to this therapy. In our study, fludarabine (30 mg/m 2 /day) and cyclophosphamide (400 mg/m 2 /day) for 3 days were selected for lymphodepleting chemotherapy. The infusion dose of CAR T-cells was 2 × 10 6 cells/kg on day 0. 2.4 Grouping Method All 31 patients with R/R DLBCL were categorised into the following groups according to the sequence in which they received radiotherapy and anti-CD19 CAR T-cell therapy: radiotherapy before CAR T-cell therapy (R-C group) and after CAR T-cell therapy (C-R group). The R-C group was further classified into two subgroups according to the interval between radiotherapy and CAR T-cell therapy as follows: radiotherapy for 1–3 (1-3-month group) and > 3 (> 3-month group) months before CAR T-cell therapy. All patients received radiotherapy before the leukapheresis. 2.5 Radiotherapy Fourteen patients with R/R DLBCL (patients 1–14) received radiotherapy 1–7 months before enrolment into our clinical trial (R-C group). The largest lymphoma lesions in the 14 patients with R/R DLBCL were selected for radiotherapy. All 14 patients in R-C group received a radiation dose of 40–45 Gy in 15–20 fractions before leukapheresis. When evaluated before CAR T-cell infusion, all patients in the R-C group achieved stable disease (SD)/progression of disease (PD) after radiotherapy (those who achieved complete response (CR)/partial response (PR) in radiotherapy were excluded from receiving subsequent CAR T-cell therapy). Seventeen patients with R/R DLBCL (patients 15–31) in the C-R group who achieved CR/PR/SD/PD in anti-CD19 CAR T-cell therapy received radiotherapy 2–3 months after CAR T-cell therapy (C-R group). Among these, six patients (patients 18, 19, 21, 24, 25, and 31) who obtained CR in CAR T-cell therapy and had at least one lesion > 10 cm in size (10.1–14.1 cm) before CAR T-cell therapy received radiotherapy after CAR T-cell therapy. For this large lesion, the patients received radiotherapy after CAR T-cell therapy. The radiation dose was 30–40 Gy in 20 fractions. The remaining 11 patients who achieved PR/SD/PD in anti-CD19 CAR T-cell therapy received radiotherapy 2–3 months after CAR T-cell infusion. Additionally, the radiation dose was 40–45 Gy in 15–20 fractions. 2.6 Expression of CD19 CAR T-Cells and Cytokines During anti-CD19 CAR T-cell therapy and subsequent radiotherapy, the expression of CD19 CAR T-cells was observed using flow cytometry. The levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay on days 0, 7, 14, 21, and 28 in anti-CD19 CAR T-cell therapy. 2.7 Adverse Events During anti-CD19 CAR T-cell therapy, the grade of CRS was evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03 [ 18 ]. Neurotoxicity was evaluated based on ICANS [ 19 ]. Radiotherapy toxicity was graded using CTCAE v5 [ 19 ]. 2.8 Statistical Analysis Data are expressed as mean ± standard deviation, and differences between groups were compared using the log-rank test. Unpaired Student’s t-test was used to compare quantitative values between groups. The Kaplan–Meier method was used to estimate survival time. Additionally, the non-parametric independent samples median test was used to compare the median values between groups. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, N.Y., USA) and GraphPad Prism software (version 8.0). Statistical significance was set at P < 0.05. 3. Results 3.1 Baseline Characteristics of Patients In all 31 patients with R/R DLBCL, no differences were found in age, subtype, stage, IPI scores, poor prognosis and extranodal lesions between the R-C (1–3 months), R-C (> 3 months) and C-R groups, except for sex, prior lines of therapy and maximum tumor diameter (Table 1 ). Table 1 Comparison of baseline characteristics between the three groups R-C (1–3 mons) group (n = 8) R-C (> 3 mons) group (n = 6) C-R group (n = 17) P value Sex Male: Femal 3:5 5:1 15:2 P = 0.0219 Age (years) 46.9 ± 12.8 48.8 ± 12.2 58.2 ± 12.0 P = 0.1366 Subtype Non-GCB: GCB 5:3 4:2 11:6 P = 0.9868 Stage I-II: III-IV 2:6 1:5 4:13 P = 0.5712 IPI (Score) 1–2:3–4 1:7 1:5 3:14 P = 0.9474 Prior lines of therapy 4.5 ± 0.8 4.2 ± 1.1 3.3 ± 0.8 P = 0.0160 Poor prognosis With: Without 6:2 5:1 12:5 P = 0.8270 Max tumor diameter before enrollment (cm) 12.5 ± 3.1 8.5 ± 1.3 9.1 ± 1.3 P = 0.0183 More than 1 Extranodal lesions (n) 4 2 2 P = 0.1123 Disease status Relapsed: Refractory 1:7 1:5 2:15 P > 0.9999 NOTE 1: Poor prognosis including : DH : Double Hit, TH : Triple Hit, DE : Double expression, TE : Triple expression, TP53 : TP53 gene is deleted(FISH P53/CEP17)or TP53 mutated (Immunohistochemical method). 3.2 Anti-CD19 CAR T-Cell Infusion Dose On the infusion day, all patients received a single infusion of 2.07 ± 0.31 × 10 6 cells/kg autologous anti-CD19 CAR T-cell intravenously. 3.3 Clinical Responses Eleven patients were evaluated in the R-C group, except for three patients who died of CRS during anti-CD19 CAR T-cell therapy. Four (4/4, 100%) and five (5/7, 71.43%) patients in the R-C (1–3 months) and R-C (> 3 months) groups, respectively, obtained ORR, while only two (2/7, 28.57%) in the R-C (> 3 months) group achieved SD/PD. The ORR and CR were 81.82% (9/11) and 54.55% (6/11), respectively, in the R-C group (Fig. 1 a). Additionally, the disease in two patients (patients 9 and 11) who achieved PR and one (patient 1) who achieved CR relapsed, leading to their subsequent deaths (Fig. 1 b). None of the patients in the C-R group died of CRS or ICANS during anti-CD19 CAR T-cell therapy. Specifically, the ORR and CR were 64.71% (11/17) and 35.29% (6/17), respectively, in the C-R group 2 months after CAR T-cell therapy (Fig. 1 a). After 2 months of radiotherapy in the C-R group, all patients who achieved CR in CAR T-cell therapy retained CR. Four patients (patients 15, 16, 17, and 29) who achieved PR in CAR T-cell therapy also achieved CR in subsequent radiotherapy. One patient (patient 20) who obtained SD in CAR T-cell therapy achieved CR in subsequent radiotherapy. Additionally, one patient (patient 27) who achieved PR progressed to SD after radiotherapy but survived until the cutoff date (later received CD22 CAR T-cell therapy) (Fig. 1 b). The ORR and CR were 64.71% (11/17) and 64.71% (11/17), respectively, in the C-R group after radiotherapy (Fig. 1 a). However, in the C-R group, two patients (patients 17 and 20) who achieved CR experienced disease relapse and died. 3.4 Survival Results Three patients died of CRS in the R-C (1–3 months) group. No significant difference in PFS ( P = 0.7292 and P = 0.3763, respectively) or OS ( P = 0.3197 and P = 0.3646, respectively) was found between the R-C and C-R groups at 6 and 12 months. Additionally, no significant difference in PFS ( P = 0.7424 and P = 0.6592, respectively) or OS ( P = 0.6071 and P = 0.3473, respectively) was found between the R-C (1–3 months) and R-C (> 3 months) groups at 6 and 12 months (Fig. 2 ). 3.5 Anti-CD19 CAR T-Cell Amplification in Peripheral Blood During anti-CD19 CAR T-cell therapy, the proportion of CAR T-cells in the peripheral blood was detected at days 0, 7, 14, 28, and 60 in all patients (Fig. 3 a). The peaks of CAR T-cells were higher in the R-C group than in the C-R group and higher in the R-C (1–3 months) group than in the R-C (> 3 months) group ( P = 0.0378 and P = 0.0007, respectively) (Fig. 3 b and c). However, no significant difference in the peaks of anti-CD19 CAR T-cells was found between the R-C and C-R groups in patients who obtained ORR in CAR T-cell therapy ( P = 0.2328) (Fig. 3 d). The peak time of anti-CD19 CAR T-cells was earlier in the R-C group than in the C-R group ( P = 0.0189) (Fig. 3 e). No difference in the peak time of anti-CD19 CAR T-cells was found between the R-C (1–3 months) and R-C (> 3 months) groups ( P > 0.9999) (Fig. 3 f). The peak time of anti-CD19 CAR T-cells was earlier in the R-C group than in the C-R group in patients who obtained ORR in CAR T-cell therapy ( P = 0.0300) (Fig. 3 g). However, in the C-R group, only two patients (patients 21 and 25) showed a re-expansion of CD19 CAR T-cells 2–3 weeks during radiotherapy. The peak of CAR T-cells was 2.92% and 3.42% in patients 21 and 25, respectively. Notably, these two patients achieved CR and survived until the cutoff date. 3.6 Cytokine Secretion During anti-CD19 CAR T-cell therapy, the mean peak of IL-6 and TNF-α was higher in R-C group than that in C-R group ( P = 0.0427 and P = 0.0227, respectively) and higher in R-C (1–3 months) group than that in R-C (> 3 months) group ( P = 0.0152 and P = 0.0174, respectively) (Fig. 4 a, b, d, and e). However, no difference in the peak time of IL-6 or TNF-α was found between the R-C and C-R groups ( P = 0.3144 and P = 0.1201, respectively) and between the R-C (1–3 months) and R-C (> 3 months) groups ( P = 0.3939 and P > 0.9999, respectively) (Fig. 4 a, b, d, and e). In patients who obtained ORR in anti-CD19-CAR T-cell therapy, no significant difference in the peak time of IL-6 or TNF-α was found between the R-C and C-R groups ( P = 0.7154 and P = 0.1196, respectively) (Fig. 4 c). No significant difference in the peak time of IL-6 between the R-C and C-R groups in patients who achieved ORR in CAR T-cell therapy ( P = 0.0872) (Fig. 4 c). The peak time of TNF-α was earlier in the R-C group than in the C-R group ( P = 0.0318) (Fig. 4 f). 3.7 AEs in Anti-CD19 CAR T-Cell Therapy During anti-CD19 CAR T-cell therapy, except for three patients in the R-C group (patients 3, 5, and 6) who died of CRS, the remaining patients in the R-C group recovered from their adverse events (AEs) 10–25 days after CAR T-cell infusion. The AE symptoms of anti-CD19-CAR T-cell therapy are shown in Table 2 . Except for dyspnoea, there was no difference in AE symptoms between the R-C (1–3 months), R-C (1–3 months), and C-R groups (Table 2 ). Table 2 Grade 3–4 of AEs in CAR T-cell therapy Adverse events R-C (1–3 mons) group (n = 8) R-C (> 3 mons) group (n = 6) C-R group (n = 17) P value Temperature 5/8 (62.5%) 3/6 (50%) 7/17 (41.2%) P = 0.6071 Chills 5/8 (62.5%) 2/6 (33.3%) 6/17 (35.3%) P = 0.3907 Fatigue 4/8 (50%) 3/6 (50%) 6/17 (35.3%) P = 0.7111 Rash 1/8 (12.5%) 0/6 (0%) 2/17 (11.8%) P = 0.6701 Muscular Weakness 2/8 (25%) 4/6 (66.7%) 4/17 (23.5%) P = 0.1329 Hypotension 2/8 (25%) 1/6 (16.7%) 1/17 (5.9%) P = 0.3940 Hypoxia 2/8 (25%) 1/6 (16.7%) 2/17 (11.8%) P = 0.7026 Tachycardia 4/8 (50%) 2/6 (33.3%) 6/17 (35.3%) P = 0.7458 Dyspnoea 2/8 (25%) 0/6 (0%) 0/17 (0%) P = 0.0463 Cough 2/8 (25%) 1/6 (16.7%) 3/17 (17.6%) P = 0.8945 Pleural effusion 4/8 (50%) 1/6 (16.7%) 3/17 (17.6%) P = 0.1922 Nausea or Vomiting 3/8 (37.5%) 1/6 (16.7%) 4/17 (23.5%) P = 0.6443 Increased serum ALT, AST 2/8 (25%) 1/6 (16.7%) 3/17 (17.6%) P = 0.8945 Increased serum bilirubin levels 1/8 (12.5%) 0/6 (0%) 1/17 (5.9%) P = 0.6351 Acute kidney injury 2/8 (25%) 1/6 (16.7%) 3/17 (17.6%) P = 0.8945 Oliguria 2/8 (25%) 1/6 (16.7%) 4/17 (23.5%) P = 0.9252 Diarrhea 1/8 (12.5%) 0/6 (0%) 1/17 (5.9%) P = 0.6351 Neutropenia 6/8 (75%) 4/6 (66.7%) 8/17 (47.1%) P = 0.3734 Anemia 4/8 (50%) 2/6 (33.3%) 7/17 (41.2%) P = 0.8187 Thrombocytopenia 3/8 (37.5%) 1/6 (16.7%) 5/17 (29.4%) P = 0.6960 Neurotoxicity 3/8 (37.5%) 1/6 (16.7%) 2/17 (11.8%) P = 0.3099 NOTE : 1 The AEs in CAR T-cell therapy were according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.03). 2 The AEs in PD-1 salvage therapy were evaluated according to the CTCAE. 3 The causal relationship between study drugs and AEs was determined by the investigator. Additionally, no significant difference in the grades of CRS and ICANS was found between the R-C and C-R groups ( P = 0.1461 and P = 0.1680, respectively) (Fig. 5 a and d). The grades of CRS and ICANS were higher in the R-C (1–3 months) group than in the R-C (> 3 months) group ( P = 0.0073 and P = 0.0310, respectively) (Fig. 5 b and e). However, no significant difference in the grades of CRS and ICANS was found between the R-C and C-R groups in patients who achieved ORR in CAR T-cell therapy ( P = 0.8815 and P > 0.9999, respectively) (Fig. 5 c and f). All patients were diagnosed with grade ≥ 3 CRS, and those with grade 2 ICANS received tocilizumab and methylprednisolone. Specifically, patients 3, 5, and 6 in the R-C group died of CRS despite receiving tocilizumab and dexamethasone therapies. Patients 3 and 6 with gastrointestinal lymphoma died of gastrointestinal perforation and haemorrhage 24 and 15 days after CAR T-cell infusion, respectively. Patient 5 with pulmonary lymphoma died of respiratory failure due to pulmonary oedema 8 days after CAR T-cell infusion. However, only one patient (patient 18) died of bacterial infections 4 months after CAR T-cell infusion and 2 months after radiotherapy. None of the patients were diagnosed with invasive fungal disease. 3.8 AEs in Radiotherapy In our study, all radiotherapy toxicities were grades 1 and 2. Grade 1 radiotherapy toxicities were observed in 5/14 and 6/17 of patients in the R-C and C-R groups, respectively, while grade 2 radiotherapy toxicities were observed in 2/14 and 3/17 of patients in the R-C and C-R groups, respectively. In particular, grade 1 radiotherapy-related toxicities included fatigue, nausea, anorexia, cough, radiation dermatitis, and leukopenia. Grade 2 radiotherapy-related toxicities included dysphagia, limb oedema, keratitis, weight loss, and leukopaenia. However, no grade ≥ 3 radiotherapy toxicities occurred. The radiotherapy toxicities resolved after symptomatic treatment in all patients, and none of them had secondary infections. 4. Discussion Anti-CD19 CAR T-cell therapy for patients with R/R DLBCL has achieved satisfactory efficacy but still faces the challenge of improving efficacy, reducing AEs, and preventing recurrence. However, this therapy still has some limitations. Many strategies have been developed to improve the safety and efficacy of anti-CD19 CAR T-cell therapy in patients with R/R DLBCL. Notably, radiotherapy has become an effective combination therapy with CAR T-cell therapy [ 7 – 9 ]. It can effectively address the disease burden in a bridging setting and improve outcomes when combined with CAR T-cell therapy [ 8 , 20 , 21 ]. Furthermore, radiotherapy can also serve as an effective salvage therapy for patients with R/R DLBCL who are unresponsive to CAR T-cell therapy or experience disease relapse after CAR T-cell therapy [ 10 ]. The mechanisms of radiotherapy combined with T-cell therapy have been explored in some studies. Radiotherapy can increase the expression of tumour-specific antigens, improve therapeutic effects, and reduce the side effects of anti-tumour immunotherapy [ 22 , 23 ]. The migration of T-cells to solid tumour tissues is suppressed by the immunosuppressive signalling pathway, which comprises chemokines secreted by solid tumours [ 24 ]. Furthermore, preclinical studies have shown that radiotherapy can enhance the recruitment of activated T-cells by increasing the secretion of chemokines, such as C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL16 [ 25 ]. Radiotherapy has been shown to improve T-cell trafficking to the tumour site by enhancing immunogenicity [ 23 , 26 , 27 ] and can induce immune stimulatory responses through immunogenic cell death of tumour cells [ 28 ]. These theoretical studies on radiotherapy provide a basis for its combined application with CAR T-cell therapy. However, this mechanism might also increase the side effects of CAR T-cell therapy after radiotherapy. In our study, the ORR of the R-C group was higher than that of the C-R group in all the R/R DLBCL patients with at least one bulky disease. In particular, the three patients in the R-C group who received CAR T-cell therapy immediately after radiotherapy, died of CRS. Although the number of cases was very small, this side effect should cause our attention. Extending the time between radiotherapy and CAR T-cell therapy might be one of the possible methods to prevent this deadly side effect. Our clinical trial compared the efficacy and side effects of radiotherapy before and after CAR T-cell therapy in patients with R/R DLBCL. The ORR and CR were 81.82% and 54.55%, respectively, in the R-C group but were 64.71% and 35.29%, respectively, in the C-R group after CAR T-cell therapy. After radiotherapy in the C-R group, the ORR was 64.71%, while the CR changed to 64.71% because some patients achieved CR after radiotherapy. In our previous study [ 29 ], patients with R/R DLBCL with a high tumour load achieved 62.11% ORR and 38.89% CR in CAR T-cell therapy. Compared to our previous study, radiotherapy after CAR T-cell therapy did not improve the ORR, but the proportion of CR increased significantly. In this study, no difference in PFS or OS was found between the R-C and C-R groups at 6 and 12 months. Although all patients in the R-C (1–3 months) group achieved ORR, three in the R-C (1–3 months) group died of CRS. The final results showed that no difference in PFS and OS was found between the R-C (1–3 months) and R-C (> 3 months) groups at 6 and 12 months. The peaks of anti-CD19 CAR T cells were higher in the R-C group than in the C-R group and higher in the R-C (1–3 months) group than in the R-C (> 3 months) group. Moreover, the peak time of CAR T-cells was earlier in the R-C group than in the C-R group. These results showed that CAR T-cell amplification was more obvious and occurred earlier in the R-C group. Therefore, attention should be paid to side effects in patients who receive radiotherapy before anti-CD19 CAR T-cell therapy. In the C-R group, two patients showed re-expansion of anti-CD19-CAR T-cells during radiotherapy. This result is consistent with that of our previous study on CAR T-cell re-expansion caused by subsequent radiotherapy [ 30 ]. Therefore, this might be one of the reasons why some patients with R/R DLBCL achieved CR in salvage radiotherapy following CAR T-cell therapy. Consistent with CAR T-cell amplification, the grades of CRS and ICANS were higher in the R-C (1–3 months) group than in the R-C (> 3 months) group. The combination of radiotherapy with anti-CD19 CAR T-cell therapy may be more effective than CAR T-cell therapy alone. Radiotherapy results in increased MHC class I molecules, antigen presentation, and enhanced recognition of cytotoxic T lymphocytes. CAR T-cells are programmed against specific antigens. However, whether this specific antigen can be enhanced by radiotherapy is yet to be determined [ 13 , 22 ]. Radiotherapy also leads to the release of pro-inflammatory cytokines through the activation of nuclear factor-κappa B and type 1 interferon [ 31 ]. Several clinical trials have also reported that radiotherapy may increase the sensitivity and side effects of subsequent CAR T-cell therapy in some systems or tissues, such as the gastrointestinal system [ 32 ]. However, our study had some limitations, including small sample size, heterogeneous population and differences in radiotherapy protocols. The baseline characteristics including age, staging of disease, risk stratification, prior chemotherapy, history of targeted drugs and immunomodulatory drugs are all factors that might affect the overall outcome of CAR T-cell therapy [ 33 ]. Based on the results of this study, a prospective study should be conducted. In conclusion, radiotherapy combined with anti-CD19 CAR T-cell therapy has a synergistic effect in patients with R/R DLBCL. Notably, radiotherapy followed by CAR T-cell therapy resulted in a higher ORR, with higher grades of CRS and ICANS, which occurred particularly in the R-C (1–3 months) group. However, CAR T-cell therapy followed by radiotherapy improved CR in patients with R/R DLBCL, but the grades of CRS and ICANS did not increase. Declarations Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics Approval This study was approved by the Medical Ethics Committee of the Department of Hematology at the Tianjin First Center Hospital (Tianjin, China) (approval number: 2018N105KY). All patients provided written informed consent, and the study protocol was performed in accordance with the Declaration of Helsinki. This clinical trial registration number is ChiCTR1800019622, and registered on 21-11-2018 . Funding This study was supported by Tianjin Health Research Projects (TJWJ2023ZD003), and the Chinese Society of Clinical Oncology Beijing Xisike Clinical Oncology Research Foundation (Y-NCJH202201-0027 and Y-2022YMJN/MS-0001). Author Contribution Conceptualisation and design: DQ. Writing draft and manuscript revision: LJY, MJ, LX, and WJ. Data acquisition: MJ and JYY. Data analysis and interpretation: LX and LQ. Writing, reviewing, and/or revising the manuscript: LJY and CR. Study supervision: DQ. Acknowledgements We thank all of our patients for their participation in our clinical trials and Shanghai Genbase Biotechnology Co., Ltd. for providing us with anti-CD19 CAR T-cells. Patient Consent for Publication All patients agreed to the use of their specimens and data for this study. Data Availability Data are available upon reasonable request. References Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med (2019) 380:45–56. doi: 10.1056/NEJMoa1804980 . Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med (2017) 377:2531–44. doi: 10.1056/NEJMoa1707447 . Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med (2020) 382:1331–42. doi: 10.1056/NEJMoa1914347 . 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Blood Adv (2020) 4:2871–83. doi: 10.1182/bloodadvances.2020001837 . Sim AJ, Jain MD, Figura NB, Chavez JC, Shah BD, Khimani F, et al. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys (2019) 105:1012–21. doi: 10.1016/j.ijrobp.2019.05.065 . Lutfi F, Holtzman NG, Kansagra AJ, Mustafa Ali M, Bukhari A, Yan J, et al. The impact of bridging therapy prior to CD19-directed chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma. Br J Haematol (2021) 195:405–12. doi: 10.1111/bjh.17738 . Imber BS, Sadelain M, DeSelm C, Batlevi C, Brentjens RJ, Dahi PB, et al. Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy. Br J Haematol (2020) 190:45–51. doi: 10.1111/bjh.16541 . Nashwa EK, Sherief G, Passant E, Mariam M, Diaaeldeen R, Yasmeen KF, et al. Chimeric antigen receptor T cells immunotherapy: challenges and opportunities in hematological malignancies. Immunotherapy (2020) 12:1341–57. doi: 10.2217/imt-2020-0181 . Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, Phase I-II trial. Lancet Oncol (2019) 20: 31–42. doi: 10.1016/S1470-2045(18)30864-7 . Tseng YD, Chen YH, Catalano PJ, Ng A. Rates and durability of response to salvage radiation therapy among patients with refractory or relapsed aggressive non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys (2015) 91:223–31. doi: 10.1016/j.ijrobp.2014.09.041 . Lai JZ, Zhu YY, Ruan M, Chen L, Zhang QY. Local irradiation sensitized tumors to adoptive T cell therapy via enhancing the cross-priming, homing, and cytotoxicity of antigen-specific CD8 T cells. Front Immunol (2019) 10:2857. doi: 10.3389/fimmu.2019.02857 . DeSelm C, Palomba ML, Yahalom J, Hamieh M, Eyquem J, Rajasekhar VK, et al. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther (2018) 26:2542–52. doi: 10.1016/j.ymthe.2018.09.008 . International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med (1993) 329:987–94. doi: 10.1056/NEJM199309303291402 . Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol (2014) 32:3059–68. doi: 10.1200/JCO.2013.54.8800 . Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant (2019) 25:625–38. doi: 10.1016/j.bbmt.2018.12.758 . Common Terminology Criteria for Adverse Events (CTCAE). v5.0 (2017). https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf . Plastaras JP, Chong EA, Schuster SJ. Don’t get stuck on the shoulder: radiation oncologists should get into the CAR with T-cell therapies. Int J Radiat Oncol Biol Phys (2019) 105:1022–4. doi: 10.1016/j.ijrobp.2019.09.005 . Wright CM, LaRiviere MJ, Baron JA, Uche C, Xiao Y, Arscott WT, et al. Bridging radiation therapy before commercial chimeric antigen receptor T-cell therapy for relapsed or refractory aggressive B-cell lymphoma. Int J Radiat Oncol Biol Phys (2020) 108:178–88. doi: 10.1016/j.ijrobp.2020.05.014 . Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov (2016) 6:80–95. doi: 10.1158/2159-8290.CD-15-0224 . Teitz-Tennenbaum S, Li Q, Davis MA, Wilder-Romans K, Hoff J, Li M, et al. Radiotherapy combined with intratumoral dendritic cell vaccination enhances the therapeutic efficacy of adoptive T-cell transfer. J Immunother (2009) 32:602–12. doi: 10.1097/CJI.0b013e3181a95165 . Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med (2006) 203:1259–71. doi: 10.1084/jem.20052494 . Siva S, MacManus M, Kron T, Best N, Smith J, Lobachevsky P, et al. A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer. PLOS ONE (2014) 9:e109560. doi: 10.1371/journal.pone.0109560 . Spary LK, Al-Taei S, Salimu J, Cook AD, Ager A, Watson HA, et al. Enhancement of T cell responses as a result of synergy between lower doses of radiation and T cell stimulation. J Immunol (2014) 192:3101–10. doi: 10.4049/jimmunol.1302736 . Dovedi SJ, Cheadle EJ, Popple AL, Poon E, Morrow M, Stewart R, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res (2017) 23:5514–26. doi: 10.1158/1078-0432.CCR-16-1673 . Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front Oncol (2012) 2:191. doi: 10.3389/fonc.2012.00191 . Mu J, Deng H, Lyu C, Yuan J, Li Q, Wang J, et al. Efficacy of programmed cell death 1 inhibitor maintenance therapy after combined treatment with programmed cell death 1 inhibitors and anti-CD19-chimeric antigen receptor T cells in patients with relapsed/refractory diffuse large B-cell lymphoma and high tumor burden. Hematol Oncol (2023) 41:275–84. doi: 10.1002/hon.2981 . Jiang YL, Li Q, Yuan T, Jiang YY, Deng Q. Case report of anti-CD123 chimeric antigen receptor T-cell therapy followed by radiotherapy for a recurrence of blastic plasmacytoid dendritic cell neoplasm after allogeneic hematopoietic stem cell transplantation. Onco Targets Ther (2020) 13:3425–30. doi: 10.2147/OTT.S250016 . Spiotto M, Fu YX, Weichselbaum RR. The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications. Sci Immunol (2016) 1. doi: 10.1126/sciimmunol.aag1266 . Finnberg NK, Gokare P, Navaraj A, Lang Kuhs KA, Cerniglia G, Yagita H, et al. Agonists of the TRAIL death receptor DR5 sensitize intestinal stem cells to chemotherapy-induced cell death and trigger gastrointestinal toxicity. Cancer Res (2016) 76:700–12. doi: 10.1158/0008-5472.CAN-15-2759 . Li X, Chen W. Mechanisms of failure of chimeric antigen receptor T-cell therapy. Curr Opin Hematol. (2019) 26:427–33. doi: 10.1097/MOH.0000000000000548 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8589923","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":597752433,"identity":"87e8dc78-0171-4c81-99a9-be0a181a0a70","order_by":0,"name":"Jingyi Li","email":"","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jingyi","middleName":"","lastName":"Li","suffix":""},{"id":597752434,"identity":"ec1c5a90-0c98-4530-981f-8347ed401155","order_by":1,"name":"Juan Mu","email":"","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Mu","suffix":""},{"id":597752435,"identity":"6d9798f1-31b2-4bd5-a996-723a4ac9d33b","order_by":2,"name":"Xin Li","email":"","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Li","suffix":""},{"id":597752436,"identity":"5edbfb75-d71a-49c6-af80-ee5fb5c732c6","order_by":3,"name":"Qing Li","email":"","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Li","suffix":""},{"id":597752437,"identity":"dca40243-4ceb-475b-93a9-6c5baaab7037","order_by":4,"name":"Rui Cui","email":"","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Cui","suffix":""},{"id":597752438,"identity":"90e1cd03-07cb-402d-9293-d8b1ebbadb98","order_by":5,"name":"YIli Jiang","email":"","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"YIli","middleName":"","lastName":"Jiang","suffix":""},{"id":597752439,"identity":"a9c8bf77-5bbc-4e44-a000-e30a7a21be0e","order_by":6,"name":"JIa Wang","email":"","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"JIa","middleName":"","lastName":"Wang","suffix":""},{"id":597752440,"identity":"3299ec7c-b976-4f94-8e32-267756eada2c","order_by":7,"name":"Qing Deng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYBACCQYGNjBiYG9sfPCBNC08h5sNZ5CmRSK9TZqDGC2S7YefPeYps8mTj3zYIM3AYCen20BAizRPmrkxz7m0YsPbiQ3GBQzJxmYHCGiRY8hhk+ZtO5y4cXZiQ/IMhgOJ2whq4X8D0vI/cePMgw2HeYjRIi0BtuVA4nwJxsZmorRIznhmJjnnXHLiBp7EZsYZBkT4ReJ88jOJN2V2ifPbjz//8aHCTo6gFhBg4gESBmCVBkQoBwHGH0BCvoFI1aNgFIyCUTDyAACUREJUsNz4IwAAAABJRU5ErkJggg==","orcid":"","institution":"Tianjin First Center Hospital","correspondingAuthor":true,"prefix":"","firstName":"Qing","middleName":"","lastName":"Deng","suffix":""}],"badges":[],"createdAt":"2026-01-13 09:24:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8589923/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8589923/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103728671,"identity":"954635c1-76f0-49d4-a1aa-9ea2632083ae","added_by":"auto","created_at":"2026-03-02 08:43:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74363,"visible":true,"origin":"","legend":"\u003cp\u003eClinical responses of this study.\u003cstrong\u003e (a) \u003c/strong\u003eIn the R-C group,\u003cstrong\u003e \u003c/strong\u003ethe ORR and CR were 81.82% and 54.55%, respectively. Four and five patients in the R-C (1–3 months) and R-C (\u0026gt;3 months) groups, respectively, obtained ORR.\u003cstrong\u003e \u003c/strong\u003eIn the C-R group,\u003cstrong\u003e \u003c/strong\u003ethe ORR was 64.71%, and CR was 35.29% after CAR T-cell therapy. Two months after radiotherapy in the C-R group, the ORR and CR were 64.71% and 64.71%, respectively.\u003cstrong\u003e (b)\u003c/strong\u003e In the R-C group, two patients who obtained PR and one who achieved CR progressed to SD and died. In the C-R group, four patients who obtained PR and one who achieved SD in CAR T-cell therapy reached CR after radiotherapy. One patient who achieved PR in CAR T-cell therapy progressed to SD after radiotherapy. ORR, objective response rate; CR, complete response; C-R, radiotherapy after CAR T-cell therapy;R-C, radiotherapy before CAR T-cell therapy; SD, stable disease; PR, partial response; CAR, chimeric antigen receptor\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8589923/v1/a16a558d26c993357d8a3ce4.png"},{"id":103728675,"identity":"3d7e2597-6c76-4fe7-85bc-4b8be6c76631","added_by":"auto","created_at":"2026-03-02 08:43:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":229414,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival results.\u003cstrong\u003e (a)\u003c/strong\u003eThere was no difference of PFS between the three groups at 3 months, 6 months, and 12 months. \u003cstrong\u003e(b)\u003c/strong\u003eThe OS of R-C (1-3 mons) group was lower than that of the R-C (more than 3 mons) group and C-R group. There was no difference of the OS between the three groups at 6 months, and 12 months. PFS, progression-free survival; OS, overall survival; C-R, radiotherapy after CAR T-cell therapy; R-C, radiotherapy before CAR T-cell therapy; CAR, chimeric antigen receptor\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8589923/v1/a4e492a19cfe1fbf29bf9a25.png"},{"id":103728674,"identity":"22009cd8-e345-45ff-9ccb-d4a6e3240138","added_by":"auto","created_at":"2026-03-02 08:43:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":78659,"visible":true,"origin":"","legend":"\u003cp\u003eAnti-CD19 CAR T-cell amplification.\u003cstrong\u003e (a) \u003c/strong\u003eThe proportion of CAR T-cells in the peripheral blood was detected at days 0, 7, 14, 28, and 60 after CAR T-cell infusion.\u003cstrong\u003e (b, c) \u003c/strong\u003eThe peaks of CAR T-cells were higher in the R-C group than in the C-R group and higher in the R-C (1–3 months) group than in the R-C (\u0026gt;3 months) group.\u003cstrong\u003e (d) \u003c/strong\u003eNo difference in the peaks of CAR T-cells was found between the R-C and C-R groups who obtained ORR in CAR T-cell therapy.\u003cstrong\u003e (e) \u003c/strong\u003eThe peak time of CAR T-cells was earlier in the R-C group than in the C-R group.\u003cstrong\u003e (f) \u003c/strong\u003eNo difference in the peak time of CAR T-cells was found between the R-C (1–3 months) and R-C (\u0026gt;3 months) groups.\u003cstrong\u003e (g)\u003c/strong\u003e The peak time of CAR T-cells was earlier in the R-C group than in the C-R group in patients who obtained ORR in CAR T-cell therapy. ORR, objective response rate; C-R, radiotherapy after CAR T-cell therapy; R-C, radiotherapy before CAR T-cell therapy; CAR, chimeric antigen receptor\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8589923/v1/8138b21624fc25f6b246a5ba.png"},{"id":103728673,"identity":"063188a2-6d1c-4b65-81ec-5ee046b8e1cc","added_by":"auto","created_at":"2026-03-02 08:43:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":29304,"visible":true,"origin":"","legend":"\u003cp\u003eCytokine secretion.\u003cstrong\u003e (a, b, d, e) \u003c/strong\u003eThe mean peak of IL-6 and TNF-α was higher in the R-C group than in the C-R group and higher in the R-C (1–3 months) group than in the R-C (\u0026gt;3 months) group. No difference in the peak time of IL-6 or TNF-α was found between the R-C and C-R groups and between the R-C (1–3 months) and R-C (\u0026gt;3 months) groups. (\u003cstrong\u003ec)\u003c/strong\u003e No difference in the peak time of IL-6 or TNF-α was found between the R-C and C-R groups in patients who obtained ORR.\u003cstrong\u003e (f)\u003c/strong\u003e The peak time of TNF-α was earlier in the R-C group than in the C-R group. ORR, objective response rate; C-R, radiotherapy after CAR T-cell therapy; R-C, radiotherapy before CAR T-cell therapy; CAR, chimeric antigen receptor; IL-6, interleukin-6; TNF-α, tumour necrosis factor-α\u003c/p\u003e","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8589923/v1/43c60b5b72aad205cc81af2d.png"},{"id":103728672,"identity":"c2e299d7-3786-4e5f-9b0e-f589daff069c","added_by":"auto","created_at":"2026-03-02 08:43:39","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":36755,"visible":true,"origin":"","legend":"\u003cp\u003eAEs in anti-CD19 CAR T-cell therapy.\u003cstrong\u003e (a, d)\u003c/strong\u003e No difference in the grades of CRS and ICANS was found between the R-C and C-R groups.\u003cstrong\u003e (b, e) \u003c/strong\u003eThe grades of CRS and ICANS were higher in the R-C (1–3 months) group than in the R-C (\u0026gt;3 months) group.\u003cstrong\u003e (c, f) \u003c/strong\u003eNo difference in the grades of CRS and ICANS was found between the R-C and C-R groups in patients who obtained ORR. ORR, objective response rate; C-R, radiotherapy after CAR T-cell therapy; R-C, radiotherapy before CAR T-cell therapy; CAR, chimeric antigen receptor.\u003c/p\u003e","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8589923/v1/c9be6fdb22f4258a7f757d02.png"},{"id":108299679,"identity":"4dea670c-882b-4157-8319-c61863171ddc","added_by":"auto","created_at":"2026-05-02 01:10:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":964053,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8589923/v1/1802e950-5f16-48df-b828-8fadcf22e177.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"To compare the efficacy and safety of radiotherapy before and after CD19 CAR T-cell therapy in patients with R/R DLBCL","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an effective and promising salvage therapy for patients with relapsed/refractory (R/R) B-cell lymphoma [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, some patients are unresponsive to CD19 CAR T-cell therapy and are at risk of disease relapse [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Patients with R/R diffuse large B-cell lymphoma (DLBCL) who have adverse factors to CD19 CAR T-cell therapy, including bulky disease, international prognostic index (IPI) score of \u0026ge;\u0026thinsp;3, and elevated lactate dehydrogenase, have been reported to benefit from combination or bridging therapy with CD19 CAR T-cell infusion [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These therapies include steroids, chemotherapy, targeted treatment, radiotherapy, systemic therapy, and combined modality treatment. Radiotherapy bridging treatment has been reported to improve the survival rate of CD19 CAR T-cell therapy, provided the intensive management of prolonged cytopenia after CAR T-cell therapy is strengthened [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, another study reported that progression-free survival (PFS) and overall survival (OS) were similar between the bridging therapy group, no-bridging therapy group, and bridging therapy subgroups [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Additionally, low-dose radiotherapy could be an effective salvage treatment for patients with R/R DLBCL who are unresponsive to CAR-T therapy or experience disease relapse after CAR T-cell treatment [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere was literature outlining the problem of employing different strategies to overcome different obstacles [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Especially, R/R DLBCL patients with CD19-negative tumor cells, diminished CD19 expression, low CD19 expression are all in a higher risk of failure or relapses in CD19 CAR T-cell therapy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Radiotherapy is an effective treatment strategy for patients with R/R DLBCL [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and has been shown to provide tumour-associated antigens for antigen-specific T-cells, enhance cytotoxicity and proliferation of native T-cells and adoptively transferred T-cells [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Another finding suggests that the mechanism of radiotherapy combined with CAR T-cell therapy involves overcoming antigen escape [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, CAR T-cell therapy in combination with radiotherapy may be more effective than CAR T-cell treatment alone. In this study, we investigated the efficacy and side effects of radiotherapy before and after CAR T-cell therapy in patients with R/R DLBCL.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1Study Participants\u003c/h2\u003e \u003cp\u003eIn this study, 31 patients with R/R DLBCL received anti-CD19-CAR T-cell therapy between January 2019 and June 2021. All 31 patients had at least one bulky disease (maximum diameter of \u0026ge;\u0026thinsp;7.5 cm), and none of them underwent hematopoietic stem cell transplantation before this study. Because all the 31 patients with R/R DLBCL had at least one bulky disease, they had received anti-CD19 CAR T-cell therapy combined with radiotherapy. In our study, the cutoff date was 30 June 2023. The follow-up period was from the day of CAR T-cell infusion to the cutoff date or the day of death.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Response Criteria and Study Endpoint\u003c/h2\u003e \u003cp\u003eThe IPI was based on the disease state when patients underwent leukapheresis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, the efficacy of anti-CD19 CAR T-cell therapy was evaluated according to the Lugano Revised Criteria [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] 2 months after the infusion date. In our study, response was evaluated using positron emission tomography-computed tomography or computed tomography.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Anti-CD19 CAR T-Cell Therapy\u003c/h2\u003e \u003cp\u003eAll 31 patients with R/R DLBCL received anti-CD19 CAR T-cell therapy (trial registration number: \u003cem\u003eChiCTR1800019622\u003c/em\u003e), which was approved by the Medical Ethics Committee of the Department of Hematology at the Tianjin First Central Hospital, Tianjin, China (approval number: 2018N105KY). The study protocol was performed in accordance with the guidelines of the Declaration of Helsinki. All patients signed a written informed consent form prior to this therapy. In our study, fludarabine (30 mg/m\u003csup\u003e2\u003c/sup\u003e/day) and cyclophosphamide (400 mg/m\u003csup\u003e2\u003c/sup\u003e/day) for 3 days were selected for lymphodepleting chemotherapy. The infusion dose of CAR T-cells was 2 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e cells/kg on day 0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Grouping Method\u003c/h2\u003e \u003cp\u003eAll 31 patients with R/R DLBCL were categorised into the following groups according to the sequence in which they received radiotherapy and anti-CD19 CAR T-cell therapy: radiotherapy before CAR T-cell therapy (R-C group) and after CAR T-cell therapy (C-R group). The R-C group was further classified into two subgroups according to the interval between radiotherapy and CAR T-cell therapy as follows: radiotherapy for 1\u0026ndash;3 (1-3-month group) and \u0026gt;\u0026thinsp;3 (\u0026gt;\u0026thinsp;3-month group) months before CAR T-cell therapy. All patients received radiotherapy before the leukapheresis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Radiotherapy\u003c/h2\u003e \u003cp\u003eFourteen patients with R/R DLBCL (patients 1\u0026ndash;14) received radiotherapy 1\u0026ndash;7 months before enrolment into our clinical trial (R-C group). The largest lymphoma lesions in the 14 patients with R/R DLBCL were selected for radiotherapy. All 14 patients in R-C group received a radiation dose of 40\u0026ndash;45 Gy in 15\u0026ndash;20 fractions before leukapheresis. When evaluated before CAR T-cell infusion, all patients in the R-C group achieved stable disease (SD)/progression of disease (PD) after radiotherapy (those who achieved complete response (CR)/partial response (PR) in radiotherapy were excluded from receiving subsequent CAR T-cell therapy).\u003c/p\u003e \u003cp\u003eSeventeen patients with R/R DLBCL (patients 15\u0026ndash;31) in the C-R group who achieved CR/PR/SD/PD in anti-CD19 CAR T-cell therapy received radiotherapy 2\u0026ndash;3 months after CAR T-cell therapy (C-R group). Among these, six patients (patients 18, 19, 21, 24, 25, and 31) who obtained CR in CAR T-cell therapy and had at least one lesion\u0026thinsp;\u0026gt;\u0026thinsp;10 cm in size (10.1\u0026ndash;14.1 cm) before CAR T-cell therapy received radiotherapy after CAR T-cell therapy. For this large lesion, the patients received radiotherapy after CAR T-cell therapy. The radiation dose was 30\u0026ndash;40 Gy in 20 fractions. The remaining 11 patients who achieved PR/SD/PD in anti-CD19 CAR T-cell therapy received radiotherapy 2\u0026ndash;3 months after CAR T-cell infusion. Additionally, the radiation dose was 40\u0026ndash;45 Gy in 15\u0026ndash;20 fractions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Expression of CD19 CAR T-Cells and Cytokines\u003c/h2\u003e \u003cp\u003eDuring anti-CD19 CAR T-cell therapy and subsequent radiotherapy, the expression of CD19 CAR T-cells was observed using flow cytometry. The levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay on days 0, 7, 14, 21, and 28 in anti-CD19 CAR T-cell therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Adverse Events\u003c/h2\u003e \u003cp\u003eDuring anti-CD19 CAR T-cell therapy, the grade of CRS was evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Neurotoxicity was evaluated based on ICANS [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Radiotherapy toxicity was graded using CTCAE v5 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8 Statistical Analysis\u003c/h2\u003e \u003cp\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and differences between groups were compared using the log-rank test. Unpaired Student\u0026rsquo;s t-test was used to compare quantitative values between groups. The Kaplan\u0026ndash;Meier method was used to estimate survival time. Additionally, the non-parametric independent samples median test was used to compare the median values between groups. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, N.Y., USA) and GraphPad Prism software (version 8.0). Statistical significance was set at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Baseline Characteristics of Patients\u003c/h2\u003e \u003cp\u003eIn all 31 patients with R/R DLBCL, no differences were found in age, subtype, stage, IPI scores, poor prognosis and extranodal lesions between the R-C (1\u0026ndash;3 months), R-C (\u0026gt;\u0026thinsp;3 months) and C-R groups, except for sex, prior lines of therapy and maximum tumor diameter (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of baseline characteristics between the three groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR-C (1\u0026ndash;3 mons) group (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eR-C (\u0026gt;\u0026thinsp;3 mons) group (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC-R group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003e\u003cem\u003eMale: Femal\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5:1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15:2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0219\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e46.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e48.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e58.2\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1366\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSubtype\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eNon-GCB: GCB\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5:3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4:2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11:6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9868\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eI-II: III-IV\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2:6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4:13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.5712\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIPI (Score)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e1\u0026ndash;2:3\u0026ndash;4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3:14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9474\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior lines of therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.0160\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePoor prognosis\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eWith: Without\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6:2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12:5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8270\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMax tumor diameter before enrollment (cm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e8.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.0183\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMore than 1 Extranodal lesions (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1123\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease status\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eRelapsed: Refractory\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2:15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.9999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eNOTE 1: Poor prognosis including\u003c/b\u003e: \u003cb\u003eDH\u003c/b\u003e: Double Hit, \u003cb\u003eTH\u003c/b\u003e: Triple Hit, \u003cb\u003eDE\u003c/b\u003e: Double expression, \u003cb\u003eTE\u003c/b\u003e: Triple expression, \u003cb\u003eTP53\u003c/b\u003e: TP53 gene is deleted(FISH P53/CEP17)or TP53 mutated (Immunohistochemical method).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Anti-CD19 CAR T-Cell Infusion Dose\u003c/h2\u003e \u003cp\u003eOn the infusion day, all patients received a single infusion of 2.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e cells/kg autologous anti-CD19 CAR T-cell intravenously.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Clinical Responses\u003c/h2\u003e \u003cp\u003eEleven patients were evaluated in the R-C group, except for three patients who died of CRS during anti-CD19 CAR T-cell therapy. Four (4/4, 100%) and five (5/7, 71.43%) patients in the R-C (1\u0026ndash;3 months) and R-C (\u0026gt;\u0026thinsp;3 months) groups, respectively, obtained ORR, while only two (2/7, 28.57%) in the R-C (\u0026gt;\u0026thinsp;3 months) group achieved SD/PD. The ORR and CR were 81.82% (9/11) and 54.55% (6/11), respectively, in the R-C group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Additionally, the disease in two patients (patients 9 and 11) who achieved PR and one (patient 1) who achieved CR relapsed, leading to their subsequent deaths (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNone of the patients in the C-R group died of CRS or ICANS during anti-CD19 CAR T-cell therapy. Specifically, the ORR and CR were 64.71% (11/17) and 35.29% (6/17), respectively, in the C-R group 2 months after CAR T-cell therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). After 2 months of radiotherapy in the C-R group, all patients who achieved CR in CAR T-cell therapy retained CR. Four patients (patients 15, 16, 17, and 29) who achieved PR in CAR T-cell therapy also achieved CR in subsequent radiotherapy. One patient (patient 20) who obtained SD in CAR T-cell therapy achieved CR in subsequent radiotherapy. Additionally, one patient (patient 27) who achieved PR progressed to SD after radiotherapy but survived until the cutoff date (later received CD22 CAR T-cell therapy) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The ORR and CR were 64.71% (11/17) and 64.71% (11/17), respectively, in the C-R group after radiotherapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). However, in the C-R group, two patients (patients 17 and 20) who achieved CR experienced disease relapse and died.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Survival Results\u003c/h2\u003e \u003cp\u003eThree patients died of CRS in the R-C (1\u0026ndash;3 months) group. No significant difference in PFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7292 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3763, respectively) or OS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3197 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3646, respectively) was found between the R-C and C-R groups at 6 and 12 months. Additionally, no significant difference in PFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7424 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6592, respectively) or OS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6071 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3473, respectively) was found between the R-C (1\u0026ndash;3 months) and R-C (\u0026gt;\u0026thinsp;3 months) groups at 6 and 12 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Anti-CD19 CAR T-Cell Amplification in Peripheral Blood\u003c/h2\u003e \u003cp\u003eDuring anti-CD19 CAR T-cell therapy, the proportion of CAR T-cells in the peripheral blood was detected at days 0, 7, 14, 28, and 60 in all patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). The peaks of CAR T-cells were higher in the R-C group than in the C-R group and higher in the R-C (1\u0026ndash;3 months) group than in the R-C (\u0026gt;\u0026thinsp;3 months) group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0378 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0007, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb and c). However, no significant difference in the peaks of anti-CD19 CAR T-cells was found between the R-C and C-R groups in patients who obtained ORR in CAR T-cell therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2328) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). The peak time of anti-CD19 CAR T-cells was earlier in the R-C group than in the C-R group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0189) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee). No difference in the peak time of anti-CD19 CAR T-cells was found between the R-C (1\u0026ndash;3 months) and R-C (\u0026gt;\u0026thinsp;3 months) groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.9999) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef). The peak time of anti-CD19 CAR T-cells was earlier in the R-C group than in the C-R group in patients who obtained ORR in CAR T-cell therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0300) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eg).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHowever, in the C-R group, only two patients (patients 21 and 25) showed a re-expansion of CD19 CAR T-cells 2\u0026ndash;3 weeks during radiotherapy. The peak of CAR T-cells was 2.92% and 3.42% in patients 21 and 25, respectively. Notably, these two patients achieved CR and survived until the cutoff date.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Cytokine Secretion\u003c/h2\u003e \u003cp\u003eDuring anti-CD19 CAR T-cell therapy, the mean peak of IL-6 and TNF-α was higher in R-C group than that in C-R group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0427 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0227, respectively) and higher in R-C (1\u0026ndash;3 months) group than that in R-C (\u0026gt;\u0026thinsp;3 months) group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0152 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0174, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, b, d, and e). However, no difference in the peak time of IL-6 or TNF-α was found between the R-C and C-R groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3144 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1201, respectively) and between the R-C (1\u0026ndash;3 months) and R-C (\u0026gt;\u0026thinsp;3 months) groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3939 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.9999, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, b, d, and e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn patients who obtained ORR in anti-CD19-CAR T-cell therapy, no significant difference in the peak time of IL-6 or TNF-α was found between the R-C and C-R groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7154 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1196, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec). No significant difference in the peak time of IL-6 between the R-C and C-R groups in patients who achieved ORR in CAR T-cell therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0872) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec). The peak time of TNF-α was earlier in the R-C group than in the C-R group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0318) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ef).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.7 AEs in Anti-CD19 CAR T-Cell Therapy\u003c/h2\u003e \u003cp\u003eDuring anti-CD19 CAR T-cell therapy, except for three patients in the R-C group (patients 3, 5, and 6) who died of CRS, the remaining patients in the R-C group recovered from their adverse events (AEs) 10\u0026ndash;25 days after CAR T-cell infusion. The AE symptoms of anti-CD19-CAR T-cell therapy are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Except for dyspnoea, there was no difference in AE symptoms between the R-C (1\u0026ndash;3 months), R-C (1\u0026ndash;3 months), and C-R groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGrade 3\u0026ndash;4 of AEs in CAR T-cell therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR-C (1\u0026ndash;3 mons) group (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eR-C (\u0026gt;\u0026thinsp;3 mons) group (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC-R group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTemperature\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5/8 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/6 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7/17 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChills\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5/8 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/6 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6/17 (35.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3907\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFatigue\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4/8 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/6 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6/17 (35.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRash\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/8 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/6 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/17 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6701\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMuscular Weakness\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/6 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/17 (23.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1329\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypotension\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/17 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3940\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypoxia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/17 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTachycardia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4/8 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/6 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6/17 (35.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7458\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDyspnoea\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/6 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/17 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.0463\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCough\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3/17 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8945\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePleural effusion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4/8 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3/17 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1922\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNausea or Vomiting\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/8 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/17 (23.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6443\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIncreased serum ALT, AST\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3/17 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8945\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIncreased serum bilirubin levels\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/8 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/6 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/17 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6351\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAcute kidney injury\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3/17 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8945\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOliguria\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/8 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/17 (23.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9252\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiarrhea\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/8 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/6 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/17 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6351\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeutropenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/8 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/6 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8/17 (47.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3734\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4/8 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/6 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7/17 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8187\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThrombocytopenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/8 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/17 (29.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6960\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeurotoxicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/8 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/17 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3099\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eNOTE\u003c/b\u003e:\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003e1\u003c/b\u003e The AEs in CAR T-cell therapy were according to the National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events (version 4.03).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003e2\u003c/b\u003e The AEs in PD-1 salvage therapy were evaluated according to the CTCAE.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003e3\u003c/b\u003e The causal relationship between study drugs and AEs was determined by the investigator.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdditionally, no significant difference in the grades of CRS and ICANS was found between the R-C and C-R groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1461 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1680, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea and d). The grades of CRS and ICANS were higher in the R-C (1\u0026ndash;3 months) group than in the R-C (\u0026gt;\u0026thinsp;3 months) group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0073 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0310, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb and e). However, no significant difference in the grades of CRS and ICANS was found between the R-C and C-R groups in patients who achieved ORR in CAR T-cell therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8815 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.9999, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec and f). All patients were diagnosed with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 CRS, and those with grade 2 ICANS received tocilizumab and methylprednisolone. Specifically, patients 3, 5, and 6 in the R-C group died of CRS despite receiving tocilizumab and dexamethasone therapies. Patients 3 and 6 with gastrointestinal lymphoma died of gastrointestinal perforation and haemorrhage 24 and 15 days after CAR T-cell infusion, respectively. Patient 5 with pulmonary lymphoma died of respiratory failure due to pulmonary oedema 8 days after CAR T-cell infusion. However, only one patient (patient 18) died of bacterial infections 4 months after CAR T-cell infusion and 2 months after radiotherapy. None of the patients were diagnosed with invasive fungal disease.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.8 AEs in Radiotherapy\u003c/h2\u003e \u003cp\u003eIn our study, all radiotherapy toxicities were grades 1 and 2. Grade 1 radiotherapy toxicities were observed in 5/14 and 6/17 of patients in the R-C and C-R groups, respectively, while grade 2 radiotherapy toxicities were observed in 2/14 and 3/17 of patients in the R-C and C-R groups, respectively. In particular, grade 1 radiotherapy-related toxicities included fatigue, nausea, anorexia, cough, radiation dermatitis, and leukopenia. Grade 2 radiotherapy-related toxicities included dysphagia, limb oedema, keratitis, weight loss, and leukopaenia. However, no grade\u0026thinsp;\u0026ge;\u0026thinsp;3 radiotherapy toxicities occurred. The radiotherapy toxicities resolved after symptomatic treatment in all patients, and none of them had secondary infections.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eAnti-CD19 CAR T-cell therapy for patients with R/R DLBCL has achieved satisfactory efficacy but still faces the challenge of improving efficacy, reducing AEs, and preventing recurrence. However, this therapy still has some limitations. Many strategies have been developed to improve the safety and efficacy of anti-CD19 CAR T-cell therapy in patients with R/R DLBCL. Notably, radiotherapy has become an effective combination therapy with CAR T-cell therapy [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. It can effectively address the disease burden in a bridging setting and improve outcomes when combined with CAR T-cell therapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Furthermore, radiotherapy can also serve as an effective salvage therapy for patients with R/R DLBCL who are unresponsive to CAR T-cell therapy or experience disease relapse after CAR T-cell therapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanisms of radiotherapy combined with T-cell therapy have been explored in some studies. Radiotherapy can increase the expression of tumour-specific antigens, improve therapeutic effects, and reduce the side effects of anti-tumour immunotherapy [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The migration of T-cells to solid tumour tissues is suppressed by the immunosuppressive signalling pathway, which comprises chemokines secreted by solid tumours [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Furthermore, preclinical studies have shown that radiotherapy can enhance the recruitment of activated T-cells by increasing the secretion of chemokines, such as C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL16 [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Radiotherapy has been shown to improve T-cell trafficking to the tumour site by enhancing immunogenicity [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and can induce immune stimulatory responses through immunogenic cell death of tumour cells [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These theoretical studies on radiotherapy provide a basis for its combined application with CAR T-cell therapy. However, this mechanism might also increase the side effects of CAR T-cell therapy after radiotherapy. In our study, the ORR of the R-C group was higher than that of the C-R group in all the R/R DLBCL patients with at least one bulky disease. In particular, the three patients in the R-C group who received CAR T-cell therapy immediately after radiotherapy, died of CRS. Although the number of cases was very small, this side effect should cause our attention. Extending the time between radiotherapy and CAR T-cell therapy might be one of the possible methods to prevent this deadly side effect.\u003c/p\u003e \u003cp\u003eOur clinical trial compared the efficacy and side effects of radiotherapy before and after CAR T-cell therapy in patients with R/R DLBCL. The ORR and CR were 81.82% and 54.55%, respectively, in the R-C group but were 64.71% and 35.29%, respectively, in the C-R group after CAR T-cell therapy. After radiotherapy in the C-R group, the ORR was 64.71%, while the CR changed to 64.71% because some patients achieved CR after radiotherapy. In our previous study [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], patients with R/R DLBCL with a high tumour load achieved 62.11% ORR and 38.89% CR in CAR T-cell therapy. Compared to our previous study, radiotherapy after CAR T-cell therapy did not improve the ORR, but the proportion of CR increased significantly.\u003c/p\u003e \u003cp\u003eIn this study, no difference in PFS or OS was found between the R-C and C-R groups at 6 and 12 months. Although all patients in the R-C (1\u0026ndash;3 months) group achieved ORR, three in the R-C (1\u0026ndash;3 months) group died of CRS. The final results showed that no difference in PFS and OS was found between the R-C (1\u0026ndash;3 months) and R-C (\u0026gt;\u0026thinsp;3 months) groups at 6 and 12 months.\u003c/p\u003e \u003cp\u003eThe peaks of anti-CD19 CAR T cells were higher in the R-C group than in the C-R group and higher in the R-C (1\u0026ndash;3 months) group than in the R-C (\u0026gt;\u0026thinsp;3 months) group. Moreover, the peak time of CAR T-cells was earlier in the R-C group than in the C-R group. These results showed that CAR T-cell amplification was more obvious and occurred earlier in the R-C group. Therefore, attention should be paid to side effects in patients who receive radiotherapy before anti-CD19 CAR T-cell therapy. In the C-R group, two patients showed re-expansion of anti-CD19-CAR T-cells during radiotherapy. This result is consistent with that of our previous study on CAR T-cell re-expansion caused by subsequent radiotherapy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Therefore, this might be one of the reasons why some patients with R/R DLBCL achieved CR in salvage radiotherapy following CAR T-cell therapy.\u003c/p\u003e \u003cp\u003eConsistent with CAR T-cell amplification, the grades of CRS and ICANS were higher in the R-C (1\u0026ndash;3 months) group than in the R-C (\u0026gt;\u0026thinsp;3 months) group. The combination of radiotherapy with anti-CD19 CAR T-cell therapy may be more effective than CAR T-cell therapy alone. Radiotherapy results in increased MHC class I molecules, antigen presentation, and enhanced recognition of cytotoxic T lymphocytes. CAR T-cells are programmed against specific antigens. However, whether this specific antigen can be enhanced by radiotherapy is yet to be determined [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Radiotherapy also leads to the release of pro-inflammatory cytokines through the activation of nuclear factor-κappa B and type 1 interferon [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Several clinical trials have also reported that radiotherapy may increase the sensitivity and side effects of subsequent CAR T-cell therapy in some systems or tissues, such as the gastrointestinal system [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, our study had some limitations, including small sample size, heterogeneous population and differences in radiotherapy protocols. The baseline characteristics including age, staging of disease, risk stratification, prior chemotherapy, history of targeted drugs and immunomodulatory drugs are all factors that might affect the overall outcome of CAR T-cell therapy [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Based on the results of this study, a prospective study should be conducted.\u003c/p\u003e \u003cp\u003eIn conclusion, radiotherapy combined with anti-CD19 CAR T-cell therapy has a synergistic effect in patients with R/R DLBCL. Notably, radiotherapy followed by CAR T-cell therapy resulted in a higher ORR, with higher grades of CRS and ICANS, which occurred particularly in the R-C (1\u0026ndash;3 months) group. However, CAR T-cell therapy followed by radiotherapy improved CR in patients with R/R DLBCL, but the grades of CRS and ICANS did not increase.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of Interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003ch2\u003eEthics Approval\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Medical Ethics Committee of the Department of Hematology at the Tianjin First Center Hospital (Tianjin, China) (approval number: 2018N105KY). All patients provided written informed consent, and the study protocol was performed in accordance with the Declaration of Helsinki. This clinical trial registration number is ChiCTR1800019622, and registered on 21-11-2018 .\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was supported by Tianjin Health Research Projects (TJWJ2023ZD003), and the Chinese Society of Clinical Oncology Beijing Xisike Clinical Oncology Research Foundation (Y-NCJH202201-0027 and Y-2022YMJN/MS-0001).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eConceptualisation and design: DQ. Writing draft and manuscript revision: LJY, MJ, LX, and WJ. Data acquisition: MJ and JYY. Data analysis and interpretation: LX and LQ. Writing, reviewing, and/or revising the manuscript: LJY and CR. Study supervision: DQ.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe thank all of our patients for their participation in our clinical trials and Shanghai Genbase Biotechnology Co., Ltd. for providing us with anti-CD19 CAR T-cells.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Consent for Publication\u003c/strong\u003e All patients agreed to the use of their specimens and data for this study.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eData are available upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. 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(2019) 26:427\u0026ndash;33. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MOH.0000000000000548\u003c/span\u003e\u003cspan address=\"10.1097/MOH.0000000000000548\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chimeric antigen receptor (CAR), Relapsed/refractory, Diffuse large B-cell lymphoma, Radiotherapy, Efficacy, Side effects","lastPublishedDoi":"10.21203/rs.3.rs-8589923/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8589923/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRadiotherapy is an effective salvage treatment after CAR T-cell therapy. However, the differences between the efficacy and side effects of radiotherapy before and after CAR T-cell therapy are still unknown. 14 and 17 patients received radiotherapy 1\u0026ndash;7 months before CAR T-cell therapy (R-C group) and 2\u0026ndash;3 months after CAR T-cell therapy (C-R group), respectively. The R-C group was categorised into the following subgroups according to the duration of radiotherapy: 1-3-month group and \u0026gt;\u0026thinsp;3 (\u0026gt;\u0026thinsp;3-month group. We compared the differences in efficacy and side effects between groups. The ORR and CR were 81.82% and 54.55%, respectively, in the R-C group and 64.71% and 35.29%, respectively, in the C-R group. However, the ORR and CR increased to 64.71% and 64.71%, respectively, in the C-R group after salvage radiotherapy. The peaks of CAR T-cells were higher in the R-C group than in the C-R group and higher in the R-C (1\u0026ndash;3 months) group than in the R-C (\u0026gt;\u0026thinsp;3 months) group. No difference was observed in the grades of CRS and ICANS between the R-C and C-R groups. CAR T-cell therapy followed by radiotherapy improved the CR without significant increase the severe adverse events.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrial registration number\u003c/b\u003e: \u003cem\u003eChiCTR1800019622\u003c/em\u003e, registered date: 21-11-2018 \u003cem\u003e.\u003c/em\u003e\u003c/p\u003e","manuscriptTitle":"To compare the efficacy and safety of radiotherapy before and after CD19 CAR T-cell therapy in patients with R/R DLBCL","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-02 08:43:32","doi":"10.21203/rs.3.rs-8589923/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"512a3cd0-9646-4501-be57-1be3b3326b19","owner":[],"postedDate":"March 2nd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-02T00:55:56+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-02T01:09:41+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-02 08:43:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8589923","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8589923","identity":"rs-8589923","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}