Cytokine and Immunoglobulin Dynamics in Phage Therapy: Insights from Clinical Cases

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Ritter , Justin Clark , Keiko Salazar , View ORCID Profile Saima Aslam , Anthony Maresso doi: https://doi.org/10.1101/2025.11.21.689765 Samantha R. Ritter 1 TAILΦR Labs, Molecular Virology and Microbiology Department, Baylor College of Medicine , Houston, 77030 TX, USA MS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Justin Clark 1 TAILΦR Labs, Molecular Virology and Microbiology Department, Baylor College of Medicine , Houston, 77030 TX, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Keiko Salazar 1 TAILΦR Labs, Molecular Virology and Microbiology Department, Baylor College of Medicine , Houston, 77030 TX, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Saima Aslam 2 Center for Innovative Phage Applications and Therapeutics, Division of Infectious Diseases and Global Public Health, University of California , San Diego, 92021 CA, USA MD, MS Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Saima Aslam For correspondence: saslam{at}health.ucsd.edu maresso{at}bcm.edu Anthony Maresso 1 TAILΦR Labs, Molecular Virology and Microbiology Department, Baylor College of Medicine , Houston, 77030 TX, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: saslam{at}health.ucsd.edu maresso{at}bcm.edu Abstract Full Text Info/History Metrics Preview PDF Abstract Background Bacteriophage therapy is increasingly used for antibiotic-refractory infections, yet its immunologic effects in humans remain poorly defined. We evaluated cytokine and immunoglobulin responses in nine compassionate-use cases of intravenous phage therapy, including solid organ transplant recipients and patients with device-associated or refractory bacterial infections. Methods Serial serum samples were analyzed by multiplex Luminex immunology and isotyping assays, with results correlated to host immune status, infecting organism, and clinical outcome. Results Cytokine patterns were heterogeneous and appeared to reflect the infecting pathogen more than phage exposure. Pseudomonas aeruginosa infections elicited broad pro-inflammatory cytokine increases (notably MCP-3 and TNF-β), while Staphylococcus aureus infection was associated with overall cytokine reduction except for IL-6. Most immunocompetent patients exhibited an early IgM response within 1–2 weeks of phage initiation, whereas immunocompromised hosts demonstrated attenuated antibody levels. Neither cytokine nor humoral responses correlated with clinical outcome. In one case, serum neutralization developed against a specific phage but not against a subsequent, distinct phage cocktail targeting the same organism, suggesting variability in phage immunogenicity. Conclusion Overall, intravenous phage therapy frequently induces IgM responses, which are more pronounced in immunocompetent patients, while cytokine dynamics depend more on pathogen and immune status than on phage administration itself. These findings underscore the need for standardized immune profiling in clinical phage trials to delineate beneficial versus detrimental immune responses and to inform the design of phage formulations with optimized immunogenic profiles. Introduction Phage therapy has been used to treat antibiotic-refractory infections with variable success, and clinical trials are ongoing. 1 , 2 The immune response to phages—particularly serum neutralization seen in both animal models and humans—remains poorly defined. Murine studies with Pseudomonas phages suggest that bacterial clearance may result from combined phage and host immune activity, but most work has been limited to animal models, leaving major gaps in human data. 3 We sought to characterize immune responses before, during, and after phage therapy in recent compassionate-use cases, focusing on cytokine and immunoglobulin patterns associated with clinical outcomes and the potential influence of immunosuppression. Materials and Methods Serum samples were collected from patients undergoing compassionate use phage therapy at the University of California San Diego (UCSD) under local Institutional Review Board (IRB) protocol #200163 after obtaining informed consent. Each patient received phage therapy under individual, expanded access Investigational New Drug (IND) applications with oversight from the US Food and Drug Administration (FDA) and local IRB. Patient serum samples were analyzed using multiplex Luminex immunology and isotyping assays, with results normalized to baseline and log-transformed for visualization as heatmaps. Raw assay data were integrated with de-identified clinical metadata (infection type, pathogen, treatment timeline, and outcome) and assessed using AI-assisted pattern recognition; trends were subsequently validated in GraphPad Prism (v10.4.1). Serum neutralization assays were performed by incubating patient sera with the phage cocktail and enumerating plaques to determine titers. Cytokine and immunoglobulin responses were grouped by treatment timepoints (baseline, Weeks 1–4, and post-treatment), and statistical comparisons were performed using Mann-Whitney U tests with Holm-Šídák correction for multiple comparisons. Full assay protocols, preprocessing steps, and instrument specifications are provided in the Supplement. Results Seven patients received nine separate courses of compassionate-use phage therapy under FDA/IRB oversight, including three solid organ transplant recipients and three with device infections. 1 , 4 – 7 Three were treated with phage manufactured at TAILOR Labs. Most infections were due to Gram-negative rods (3 Escherichia coli , 4 Pseudomonas aeruginosa , 1 Klebsiella pneumoniae ), with one Staphylococcus aureus case ( Table S1 ). Across the cohort, cytokine responses varied considerably ( Figure 1 – 2 ). Immunocompetent hosts demonstrated consistently higher levels of IL-6, TNF-α, IL-10, and IL-1β compared with immunosuppressed patients, though these differences were not statistically significant. No consistent association was observed between cytokine levels and clinical outcome ( Figure 3 ). Download figure Open in new tab Figure 1. Unified heatmap of patient cytokine levels throughout the course of treatment. This heatmap groups cytokines into four categories; anti-inflammatory, pro-inflammatory, cellular immunity pro-inflammatory, and humoral immunity anti-inflammatory. Additional metadata is displayed to the right of the heatmap with a legend. Download figure Open in new tab Figure 2. Grouped bar graph showing the difference of cytokines levels (pg/mL) transformed to Log 10, at different timepoints of treatment. Cytokine levels were measured from patient serum samples and were grouped into immunocompetent and immunocompromised groups. Cytokine levels were averaged for each group at every timepoint. The x-axis contains the timepoints in treatment in which cytokine levels were measured. Differences between the immunocompetent and immunocompromised groups were not found to be significant for all cytokines. Download figure Open in new tab Figure 3. Plot of IL-6 and TNF-α levels throughout the course of treatment. For each separate case, data was normalized to the baseline value (day 1) by subtracting the baseline value from all other time points. Data was then transformed using Log 10 . Orange indicates success, and blue indicates failure. The x-axis contains the timepoints in treatment in which cytokine levels were measured. Differences between the success and failure groups were not found to be significant for both cytokines. Cytokine responses appeared organism specific. In the S. aureus case, most pro-inflammatory cytokines decreased during phage therapy except IL-6, which rose; in contrast, P. aeruginosa cases demonstrated broad increases in pro-inflammatory cytokines, notably MCP-3 and TNF-β ( Figure 4 ). This may indicate that the infecting organism is a stronger driver of cytokine response than the use of phage therapy. Download figure Open in new tab Figure 4. Cytokine response in patients with left ventricular device infection due to Staphylococcus aureus (n=1, blue) compared to Pseudomonas aeruginosa (n=3, red). The top two patients in the red box had an infected LVAD, and the patient on the bottom had pelvic osteomyelitis. Red indicates an increase in cytokine levels and blue indicates a decrease in cytokine levels. As noted in Figure 5 , seven of nine phage therapy cases developed an IgM response within 1-2 weeks after initiation of intravenous (IV) phage; the majority of these were in immunocompetent individuals. Levels of each immunoglobulin isotype varied per individual. Isotype levels in immunocompetent hosts were higher when compared to those that were immunocompromised ( Figure 6 ). IgM had a higher median at all measured time points for immunocompetent hosts; Day 1–1·7 times higher (IQR 172·4-14·5), Week 1–2·4 times higher (IQR 181·9-30·3), Week 2– 5·0 times higher (IQR 213·8-126·6), Week 4–4·3 times higher (IQR 171·0-104·1), Post-RX–28 times higher (IQR 129·3-62·2). There was a peak in IgM response during the first or second week of treatment with phage therapy. In contrast, in the immunocompromised patients, there was little to no increase in IgM throughout the entire course of treatment. Additionally, all immunoglobulin isotypes in the immunocompromised hosts decreased over the course of treatment. Download figure Open in new tab Figure 5. Unified heatmap of serum immunoglobulin levels throughout the course of treatment of all nine cases. This heatmap defines different isotypes and tracks their levels throughout treatment. Additionally, metadata is displayed to the right of the heatmap with a legend. Case I is included separately from the unified heatmap because individual immunoglobulin levels were very high and inclusion with the other cases skewed the heatmap visualization of change for all other cases. Download figure Open in new tab Figure 6. Patient immunoglobulin levels comparing immunocompetent (a) and immunocompromised hosts (b). The IgM response is indicated by a black outlined box. ( a ) Serum samples from immunocompetent cases A, B, F, H, and I were analyzed using an isotyping assay. ( b ) Serum samples from immunocompromised cases D, E, and G were analyzed using an isotyping assay. Finally, immune responses differed by phage composition. In one patient who received two separate LVAD-targeted P. aeruginosa phage regimens, serum neutralization developed against one phage during the first course, necessitating a switch in therapy, whereas the second regimen elicited minimal to no neutralization ( Figure 7 ). These findings suggest variability in phage immunogenicity across preparations or types of phages. Download figure Open in new tab Figure 7. Isotype levels from an LVAD recipient with recurrent Pseudomonas aeruginosa bacteremia treated with two separate course of different phages about three months apart. Case A indicates the first round of treatment with this patient. Case B indicates the second round of treatment with this patient, which occurred 3 months after the end of phage therapy in Case A. The first round of treatment developed serum neutralization, and the second treatment developed little to no serum neutralization. Discussion Phage therapy shows promise for the treatment of multidrug-resistant infections, but its interactions with the human immune system remain are not clear. To address this knowledge gap, we analyzed immune responses before, during, and after IV phage therapy in nine compassionate-use cases. Our findings highlight three themes: (1) IV phage therapy commonly elicits an IgM response, particularly in immunocompetent hosts; (2) cytokine responses are variable, influenced more by infection type and host immune status rather than by phage administration itself; and (3) the immune response differs depending on the phages used, suggesting variability in phage immunogenicity. The transplant recipients that received phage therapy in this series were immunocompromised due to a combination of agents that inhibit both B and T cell function, including agents such as tacrolimus, prednisone and mycophenolate mofetil. Comparisons of the cytokines IL-6, TNF-α, IL-10, and IL-1β between immunocompetent and immunocompromised individuals revealed that immunocompetent individuals had higher levels of these cytokines at all timepoints, including prior to and following phage therapy. However, despite apparent differences between cytokine levels, the clinical outcome (success or failure) of phage therapy was independent of the individual’s immune status. We report that from the five successful cases, two were from immunocompromised hosts, and three were from immunocompetent hosts. Currently, it is thought that synergy with the host immune system may be important for successful phage therapy. 3 , 8 , 9 Supporting evidence is provided from a study on a 7-year-old child with an extensive chronic P. aeruginosa osteoarticular infection who received phage therapy. 10 The phage stimulated the child’s innate and adaptive immune response and contributed to treatment success. However, these claims imply that an immunocompromised individual’s immune system would be unable to cooperate effectively with phage therapy and, therefore, result in unsuccessful treatment. 11 We introduce contrary evidence; immunocompromised individuals can succeed with phage therapy, and higher levels of various immune system components do not correlate with the outcome of phage therapy. In 7/9 cases, patients developed an IgM-mediated response within 1-2 weeks of IV phage initiation, consistent with early adaptive immune response. This response was more robust in immunocompetent patients and attenuated in immunocompromised hosts, many of whom were transplant recipients on regimens suppressing both B- and T-cell function. Despite these differences, IgM responses were not associated with treatment success or failure, indicating that antibody development is not associated with clinical outcome. Cytokine responses were heterogeneous across patients, with no consistent pattern linked to outcome. IL-6, TNF-α, IL-10, and IL-1β levels were higher in immunocompetent compared with immunocompromised hosts, both before and during treatment, but outcome was independent of immune status—two immunocompromised and three immunocompetent patients experienced successful treatment. This observation challenges the view that synergy with host immunity is essential for therapeutic success and adds to prior case reports suggesting that immunocompromised patients may benefit from phage therapy. When cytokines were analyzed by pathogen, clearer trends emerged. Patients with P. aeruginosa infection exhibited marked increases in pro-inflammatory cytokines, including MCP-3 and TNF-β, consistent with prior literature. 12 , 13 In contrast, the single S. aureus case showed an overall decrease in many pro-inflammatory cytokines, including IL-8, aligning with reports that immune dysregulation in S. aureus infections is associated with poor outcomes. 14 , 15 These findings suggest that bacterial species, rather than phage exposure itself, may be a stronger determinant of cytokine dynamics during therapy. We also observed that phage composition influenced the immune response. One patient received two distinct phage cocktails for the same LVAD infection, separated by three months. The first regimen induced a strong IgM response and serum neutralization of one phage by day 11, while the second regimen produced minimal IgM response and minimal to no serum neutralization, despite being directed against the same pathogen. Animal studies support this variability, showing that phage immunogenicity differs by morphotype and even by individual proteins on the phage capsid. 16 , 17 This case underscores that phage-specific factors likely shape immunogenicity in humans, with potential implications for phage selection and engineering when developing phage therapy regimens. Taken together, these findings indicate that cytokine responses during phage therapy are more reflective of host immune status and pathogen type than of phage administration, while humoral responses—primarily IgM—occur commonly but do not determine outcome. Notably, serum neutralization of phages, did not correlate with clinical failure, consistent with reports that phage activity may persist despite antibody formation, possibly through compartmentalization or local delivery or perhaps a shorter duration of phage therapy may have been sufficient. This exploratory study has limitations, including small sample size, heterogeneity of infections and pathogens, and variable treatment regimens. However, strengths include serial sampling from all patients, consistent IV phage administration in all patients, and paired baseline and longitudinal immune data. To our knowledge, this is the first systematic effort to examine cytokine and immunoglobulin responses in human IV phage therapy. In summary, we report that (1) most patients mount an IgM response to IV phage therapy within one to two weeks, (2) cytokine responses during phage therapy vary by host immune status and infecting organism and do not impact clinical outcome, and (3) phage-specific factors influence immunogenicity. These results suggest that detailed immune profiling in future clinical trials may help identify patterns of beneficial or detrimental responses. Screening phages for immunogenicity, both in terms of synergy with host immunity and risk of neutralization, may be valuable in optimizing therapeutic design. Further work is needed in larger, more homogeneous populations to define how the human immune response influences phage therapy efficacy and to establish best practices for clinical implementation. Author Contributions Conceptualization, S.R.R, S.A., A.M.; methodology, S.R.R., J.C., K.S., S.A., A.M.; formal analysis, S.R.R., J.C., K.S., S.A.; investigation, S.R.R., J.C., K.S., S.A.; data curation, S.R.R., J.C.; writing—original, draft preparation, S.R.R, S.A.; writing—review and editing, S.R.R., J.C., K.S., S.A., A.M.; project administration, S.A., A.M.; and funding acquisition S.A., A.M. Data Sharing De-identified participant data will be made available upon request to the corresponding authors (S.A., or A.M.). Declaration of Interests S.A. discloses research grant funding from Armata Pharmaceuticals, Adaptive Phage Therapeutics, and Locus BioSciences. Consultant for Phico, BioMx, and Tennor. AM is on the Board of Director for Phiogen Pharmaceuticals. No other declarations from the other authors Funding UCSD Chancellor’s seed award (SA), Baylor College of Medicine seed funds to TAILOR Labs (AM). SUPPLEMENT View this table: View inline View popup Table S1. Clinical details regarding seven patients treated with nine courses of compassionate use phage therapy. LVAD is left ventricular assist device, IV is intravenous, ESBL is extended spectrum beta lactamase, UTI is urinary tract infection. All Day1 serum samples were obtained at baseline prior to phage initiation. Acknowledgements We would like to thank the Texas Medical Center Digestive Diseases Center and Sridevi Devaraj and Xinpu Chen for their help with the Luminex assays. Footnotes ↵ * Joint senior authors References 1. ↵ Aslam S , Lampley E , Wooten D , et al. Lessons Learned From the First 10 Consecutive Cases of Intravenous Bacteriophage Therapy to Treat Multidrug-Resistant Bacterial Infections at a Single Center in the United States . Open Forum Infect Dis 2020 ; 7 ( 9 ): ofaa389 . OpenUrl CrossRef PubMed 2. ↵ Green SI , Clark JR , Santos HH , et al. A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes . Clin Infect Dis 2023 ; 77 ( 8 ): 1079 – 91 . OpenUrl PubMed 3. ↵ Roach DR , Leung CY , Henry M , et al. Synergy between the Host Immune System and Bacteriophage Is Essential for Successful Phage Therapy against an Acute Respiratory Pathogen . Cell Host Microbe 2017 ; 22 ( 1 ): 38 - 47 .e4. OpenUrl CrossRef PubMed 4. ↵ Aslam S , Pretorius V , Lehman SM , Morales S , Schooley RT . Novel bacteriophage therapy for treatment of left ventricular assist device infection . J Heart Lung Transplant 2019 ; 38 ( 4 ): 475 – 6 . OpenUrl CrossRef PubMed 5. Le T , Nang SC , Zhao J , et al. Therapeutic Potential of Intravenous Phage as Standalone Therapy for Recurrent Drug-Resistant Urinary Tract Infections . Antimicrob Agents Chemother 2023 ; 67 ( 4 ): e0003723 . OpenUrl PubMed 6. Aslam S , Roach D , Nikolich MP , et al. Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases . Antimicrob Agents Chemother 2024 ; 68 ( 4 ): e0172823 . OpenUrl CrossRef PubMed 7. ↵ Onallah H , Hazan R , Nir-Paz R , et al. Refractory Pseudomonas aeruginosa infections treated with phage PASA16: A compassionate use case series . Med 2023 ;S2666-6340(23)00225-8. 8. ↵ Krut O , Bekeredjian-Ding I. Contribution of the Immune Response to Phage Therapy . J Immunol 2018 ; 200 ( 9 ): 3037 – 44 . OpenUrl Abstract / FREE Full Text 9. ↵ Leung CYJ , Weitz JS . Modeling the synergistic elimination of bacteria by phage and the innate immune system . J Theor Biol 2017 ; 429 : 241 – 52 . OpenUrl CrossRef PubMed 10. ↵ Khatami A , Lin RCY , Petrovic-Fabijan A , et al. Bacterial lysis, autophagy and innate immune responses during adjunctive phage therapy in a child . EMBO Mol Med 2021 ; 13 ( 9 ): e13936 . OpenUrl CrossRef PubMed 11. ↵ Borysowski J , Górski A. Is phage therapy acceptable in the immunocompromised host? Int J Infect Dis 2008 ; 12 ( 5 ): 466 – 71 . OpenUrl CrossRef PubMed 12. ↵ Han Y , Ge C , Ye J , Li R , Zhang Y. Demethyleneberberine alleviates Pseudomonas aeruginosa-induced acute pneumonia by inhibiting the AIM2 inflammasome and oxidative stress . Pulm Pharmacol Ther 2023 ; 83 : 102259 . OpenUrl PubMed 13. ↵ Britton N , Villabona-Rueda A , Whiteside SA , et al. Pseudomonas-dominant microbiome elicits sustained IL-1β upregulation in alveolar macrophages from lung transplant recipients . J Heart Lung Transplant 2023 ; 42 ( 9 ): 1166 – 74 . OpenUrl PubMed 14. ↵ Salas DE , Minejima E , Wu J , et al. Staphylococcus aureus Bacteremia in Patients not Meeting Sepsis Criteria: Clinical Features, Host Immune Response and Outcomes . J Clin Med Ther 2017 ; 2 ( 4 ): 27 . OpenUrl PubMed 15. ↵ Minejima E , Bensman J , She RC , et al. A Dysregulated Balance of Proinflammatory and Anti-Inflammatory Host Cytokine Response Early During Therapy Predicts Persistence and Mortality in Staphylococcus aureus Bacteremia . Crit Care Med 2016 ; 44 ( 4 ): 671 – 9 . OpenUrl CrossRef PubMed 16. ↵ Dąbrowska K , Miernikiewicz P , Piotrowicz A , et al. Immunogenicity studies of proteins forming the T4 phage head surface . J Virol 2014 ; 88 ( 21 ): 12551 – 7 . OpenUrl Abstract / FREE Full Text 17. ↵ Chechushkov A , Kozlova Y , Baykov I , et al. Influence of Caudovirales Phages on Humoral Immunity in Mice . Viruses 2021 ; 13 ( 7 ): 1241 . OpenUrl PubMed View the discussion thread. Back to top Previous Next Posted November 24, 2025. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Cytokine and Immunoglobulin Dynamics in Phage Therapy: Insights from Clinical Cases Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Cytokine and Immunoglobulin Dynamics in Phage Therapy: Insights from Clinical Cases Samantha R. 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