Completed Clinical Trials of p53 Gene Therapy in Cancer: A ClinicalTrials.gov-Based Analysis

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Alorfi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7240665/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 Background The tumour suppressor gene TP53, frequently mutated in various different types of cancers, plays a vital role in regulating cell cycle arrest, apoptosis, and genomic stability. Gene therapy targeting p53 aims to restore its normal function in tumours with defective p53, offering a novel therapeutic approach. Objective This study aims to systematically characterise the design, therapeutic strategies, and primary outcomes of completed clinical trials investigating p53 gene therapy for cancer, focusing on study design, targeted conditions, intervention strategies, and clinical outcomes. Methods A systematic search of ClinicalTrials.gov database was conducted using the keywords “Cancer” AND “p53 gene therapy,” filtered for completed studies. A total of 23 eligible trials were included. Data on cancer type, intervention, study phase, enrolment, and primary outcomes were extracted and analysed descriptively. Results Of the 23 included trials, 20 (87%) were interventional and 3 were observational. Gene therapy interventions were used in 5 trials, while chemotherapy was included in 13. The most studied conditions were bladder, breast, ovarian, and lung cancers. Adenoviral vectors such as Ad5CMV-p53 were the predominant gene therapy platform. Many trials combined p53 gene therapy with chemotherapy, surgery, or radiation. Total reported enrolment across studies was 2,846 participants. Most trials focused on safety, dose escalation, and biomarker analysis rather than definitive clinical efficacy. Conclusion Completed clinical trials on p53 gene therapy in cancer suggest promising biological rationale but limited clinical translation to date. Most studies remain early-phase, with sparse progression to large-scale efficacy trials. Future efforts should prioritize stratified patient populations, refined gene delivery technologies, and combination approaches to enhance therapeutic impact. p53 gene therapy cancer TP53 clinical trials Ad5CMV-p53 tumour suppressor ClinicalTrials.gov analysis Figures Figure 1 Introduction Cancer is a leading cause of morbidity and mortality worldwide, driven by complex genetic mechanisms that contribute to tumour initiation, progression, and the development of various aggressive human malignancies [ 1 , 2 ]. p53, encoded by the TP53 gene, is a central transcription factor regulating cell cycle arrest, apoptosis, and DNA repair in response to cellular stress [ 3 – 5 ]. Among the most frequently mutated genes in human cancers is the tumour suppressor gene TP53 [ 6 , 7 ]. Mutations in TP53 result in dysfunctional proteins that are unable to perform these tumour-suppressive functions, contributing to the development of a wide range of cancers including breast, lung, bladder, and hematologic malignancies [ 8 , 9 ]. Recent advancements in cancer therapy have increasingly focused on restoring or exploiting the function of p53, a critical tumour suppressor frequently mutated in cancers. Several strategies are being explored to exploit the p53 pathway. These include MDM2 and MDMX inhibitors, which prevent the degradation of WT p53 in cancers where TP53 is not mutated but functionally suppressed [ 10 – 12 ]. Furthermore, efforts to target mutant forms of p53are ongoing, although challenging due to their heterogeneity. Synthetic lethality approaches offer another avenue, selectively targeting vulnerabilities in TP53-mutated cells [ 13 , 14 ]. Moreover, mutant p53-based adoptive cell transfer (ACT), a form of cancer immunotherapy, has shown promise in treating advanced malignancies by directing immune cells to recognize and eliminate tumour cells expressing mutant p53 [ 15 , 16 ]. However, these therapies often face resistance from the tumour microenvironment (TME), particularly in solid tumors [ 17 , 18 ], highlighting the need to address immunosuppressive barriers for successful clinical translation. One promising approach in cancer treatment is gene therapy, specifically targeting the restoration of p53 function. Since many tumours harbor defective or mutated TP53, therapeutic strategies have emerged to reactivate p53 and restore its tumor-suppressive activities. [ 19 , 20 ]. The central role of TP53 in cancer biology makes it an attractive target for pharmacological intervention, with ongoing efforts aimed at restoring wild-type p53 function or selectively targeting mutant p53 to inhibit tumour growth [ 21 – 23 ]. A variety of vectors, particularly adenoviral vectors such as Ad5CMV-p53, have been explored to deliver the functional gene into tumour tissues. Initial clinical trials conducted over the past two decades aimed to determine the safety, tolerability, and preliminary efficacy of this approach, often in combination with conventional treatments such as chemotherapy, radiation, or surgery [ 24 – 26 ]. Despite the growing number of publications on p53-related cancer biology, there has been limited comprehensive synthesis of clinical trial activity surrounding p53 gene therapy. Understanding the scope, methodology, and outcomes of these trials is crucial for informing future research directions and clinical applications. This study aims to systematically examine completed clinical trials listed on ClinicalTrials.gov that involve p53 gene therapy for cancer. By analysing key elements such as intervention types, trial phases, enrolment sizes, cancer types targeted, and outcome measures, this paper seeks to map the landscape of translational research in this area. Insights from this analysis will highlight gaps in therapeutic development, identify cancer subtypes where p53 therapy has shown promise, and support evidence-based strategies for future clinical translation. Methods A structured search was performed on ClinicalTrials.gov using the terms “Cancer” AND “p53 gene therapy” with filters applied for “Completed Studies” and last accessed the database on 1st July 2025. The search included both interventional and observational trials. From the resulting studies, only those specifically incorporating p53 as a gene therapy agent (e.g., Ad5CMV-p53) were selected. A total of 23 studies met the inclusion criteria. Relevant variables were extracted including NCT number, study title, summary, cancer conditions, interventions, trial phase, enrolment size, and primary outcome measures. Trials without posted results were included; missing data (e.g., enrollment or outcome) were noted but not excluded. Data were curated in Microsoft Excel and analysed descriptively to generate summaries of enrolment, study design, cancer types, and therapeutic strategies. Results This analysis included data from a set of interventional clinical trials focusing on p53 gene therapy (predominantly using Ad5CMV-p53) across various cancer types. A total of 23 completed studies were included in this analysis, of which 20 (87%) were interventional and 3 were observational. Among the trials reporting enrolment data, the cumulative number of participants was 2,846. Although 23 completed trials were included, only 16 had posted enrolment data and 14 reported primary outcomes. The majority of studies focused on solid tumors, particularly bladder, breast, lung, and ovarian cancers. The majority of studies were Phase I trials, indicating that they primarily aimed to assess safety, dosing, and early biological activity rather than efficacy as shown in Table 1 . Figure 1 illustrates the distribution of the top ten cancer types targeted in p53-based gene therapy clinical trials. The most frequently investigated cancers include lung cancer, breast cancer, and central nervous system tumors, each represented in three separate trials. Ovarian cancer and acute myeloid leukaemia also featured prominently. This distribution reflects the therapeutic interest in restoring p53 function in malignancies with high TP53 mutation prevalence. The figure highlights the emphasis on solid tumours and hematologic malignancies where p53-targeted approaches hold translational promise. Table 1 Distribution of included trials by clinical phase. Study Phase Number of Trials Phase I 12 Phase I/II 4 Phase II 2 Phase III 2 Unspecified 3 Total 23 Table 2 categorizes clinical trials based on the number of enrolled participants. The majority of trials were small-scale studies with fewer than 50 participants, highlighting the exploratory phase of p53-based gene therapy research. Table 2 Classification of trials based on participant enrolment size. Enrolment Range Number of Trials 1–50 (Small) 9 51–100 (Medium) 4 101–1000 (Large) 3 All the trials employed a biological intervention using Ad5CMV-p53 (a recombinant adenoviral vector delivering wild-type p53). In some studies, this intervention was combined with chemotherapy or conventional surgery, highlighting a multi-modal therapeutic approach. Despite the diversity of cancer types and intervention combinations, all available records indicated "NO" under the Study Results column, suggesting that published outcome data was not yet posted on ClinicalTrials.gov for these trials. The classification of interventions in p53-based cancer clinical trials reveals that chemotherapy is the most commonly used therapeutic category, followed by diagnostic and gene therapy strategies. Table 3 categorizes interventions by therapeutic type, their intended objective (e.g., curative, diagnostic), and provides an explanation of each category's role in the context of p53-targeted studies. Table 3 Categorization of interventions by therapeutic type, objective, functional role in p53 gene therapy and an illustrative example agent from the included trials. Therapeutic Category Number of Interventions Therapeutic Objective Explanation Example Agent Chemotherapy 13 Curative/Palliative Cytotoxic agents used to kill rapidly dividing tumor cells or sensitize tumors to other treatments. Cisplatin Diagnostic 8 Diagnostic Tools and techniques used to assess tumor biology or treatment response, such as biomarker or gene expression analysis. Immunohistochemistry Other 6 Supportive/Experimental Miscellaneous or unspecified interventions including supportive, experimental, or non-therapeutic components. Filgrastim Gene Therapy 5 Curative Delivery of functional p53 genes to tumor cells to restore tumor‑suppressor activity, often using viral vectors. Ad5CMV‑p53 Surgical 4 Curative/Diagnostic Physical procedures such as tumor resection, biopsy, or laparoscopy aimed at diagnosis or tumor removal. Conventional Surgery Immunotherapy 4 Curative Treatments that enhance the immune system’s ability to attack tumors (e.g., checkpoint inhibitors, vaccines). Nivolumab Hormonal Therapy 4 Curative/Palliative Interventions targeting hormonal pathways, primarily in prostate or breast cancer. Abiraterone Acetate Radiation 2 Curative/Palliative Use of ionizing radiation to kill or shrink cancer cells, often used in combination therapies. External‑Beam Radiation Targeted Therapy 1 Curative Therapies acting on specific molecular targets involved in tumor growth and survival. Everolimus The analysis of primary objectives from 23 completed p53-related cancer trials registered on ClinicalTrials.gov reveals that the majority of studies were designed to evaluate safety, tolerability, and dose-limiting toxicity (DLT), particularly in early-phase settings as shown in Table 4 . Maximum tolerated dose (MTD) determination was a key outcome across several trials, reflecting the exploratory nature of novel gene or combination therapies. A smaller subset of studies aimed to measure tumor response rates—such as partial or complete responses—based on clinical or radiological criteria. Other objectives included the assessment of biomarker expression (e.g., p53 activity or apoptosis markers), feasibility of treatment protocols, patient-reported quality of life, and immune-related endpoints. Additionally, one translational study focused on establishing tumor cell lines and xenografts for future drug development. Table 4 Primary outcome objectives in p53-based cancer trials. Primary Objective Category Description Number of Trials Safety / Dose-limiting Toxicity (DLT) Determine adverse effects, tolerability, and MTD of investigational therapies. 7 Tumour Response Assessment Measure tumor shrinkage or remission (e.g., CR, PR, SD). 2 Biomarker Expression Evaluate biological activity through protein or gene expression markers. 1 Immunogenicity Assess immune response triggered by therapies or vaccines. 0 Survival Outcomes Track progression-free or overall survival post-treatment. 1 Feasibility / Protocol Completion Measure the practicality of treatment completion and adherence. 1 Translational / Cell Models Establish cell lines or xenografts for future research. 1 Quality of Life Evaluate patient-reported outcomes using validated QoL instruments. 1 Discussion TP53, the most frequently mutated gene across a wide range of human cancers, plays a pivotal role in tumorigenesis. Its alterations often occur as early events in cancer development, contributing to the loss of normal p53 tumour suppressor function [ 7 , 27 , 28 ]. This gene plays a pivotal role in maintaining genomic integrity by regulating cell cycle arrest, apoptosis, DNA repair, and senescence [ 29 – 31 ]. By restoring p53’s tumour-suppressor function, treatment strategies can induce apoptosis, halt cell-cycle progression, and enhance DNA repair in malignant cells, offering a powerful mechanism to counteract tumour growth [ 4 , 32 ] This analysis of completed clinical trials on p53 gene therapy in cancer highlights both the breadth and limitations of current clinical research efforts. Most studies were early-phase (Phase 1 or Phase 1/2), underscoring the experimental nature of p53 gene therapy and its position in the translational pipeline. The limited progression to Phase 3 trials suggests ongoing challenges in demonstrating consistent therapeutic efficacy across cancer types. The use of Ad5CMV-p53, a recombinant adenovirus vector, dominated intervention strategies, reflecting its historical use in early gene therapy development due to efficient gene delivery into tumour cells [ 33 , 34 ]. Studies combining p53 gene therapy with chemotherapy or radiation aimed to potentiate cytotoxic effects, leveraging p53’s pro-apoptotic and cell-cycle regulatory functions. For example, combined regimens involving cisplatin and Ad5CMV-p53 targeted platinum-resistant tumours such as ovarian and bladder cancers [ 35 – 37 ]. These approaches align with findings from preclinical models that suggest synergistic effects between wild-type p53 and DNA-damaging agents. Interestingly, the trials targeted a wide array of malignancies, indicating broad scientific interest in this therapeutic modality. However, no clear consensus has emerged on which cancer subtypes derive the greatest benefit, and the inclusion of rare tumors (e.g., prolymphocytic leukaemia) suggests a need for better prioritization based on molecular profiles. When comparing to the literature, few studies reported significant clinical responses, and most outcomes were limited to safety profiles and biomarker changes. This mirrors broader gene therapy challenges, including immune responses to viral vectors, short-lived transgene expression, and heterogeneous tumour environments.. Nonetheless, the presence of two Phase 3 trials offers a degree of optimism and may pave the way for future validation if positive results are confirmed. Advances in gene-editing technologies like CRISPR/Cas9 may also rejuvenate interest in targeting TP53 by offering more precise, durable genetic correction strategies. Conclusion This analysis highlights the experimental nature and evolving landscape of p53 gene therapy in cancer. While the majority of studies were early-phase trials focusing on feasibility and safety, progress toward late-phase trials is limited. Future research should emphasize patient stratification, combination strategies, and next-generation vector technologies to enhance therapeutic outcomes. Limitations This analysis was limited to completed studies registered on ClinicalTrials.gov and may not capture unregistered or unpublished trials. Many studies lacked detailed result postings, restricting quantitative efficacy comparisons. Additionally, heterogeneity in cancer types and interventions prevented pooled analysis. Declarations Competing Interests The author reports no conflicts of interest related to this work. Informed consent This study was based solely on publicly available data from ClinicalTrials.gov and did not involve human participants or identifiable personal data. Clinical trial number Not applicable. Ethical declaration Not applicable. Funding declaration The author declares that no funds, grants, or other support were received during the preparation of this manuscript Author Contribution Am sole author and wrote the whole manuscript. Availability of Data Statement All data analysed during this study are available in the attached supplementary file. The dataset was obtained from publicly accessible records on ClinicalTrials.gov. References Fischer, E.G. Nuclear Morphology and the Biology of Cancer Cells. Acta Cytol 2020 , 64 , 511–519, doi:10.1159/000508780. Hill, B.T.; Shah, H.; Winter, A. Etiology of Cancer. Clinical Ophthalmic Oncology: Basic Principles, Fourth Edition 2025 , 17–22, doi:10.1007/978-3-031-75907-9_3. Huang, Y.; Jiao, Z.; Fu, Y.; Hou, Y.; Sun, J.; Hu, F.; Yu, S.; Gong, K.; Liu, Y.; Zhao, G. An Overview of the Functions of P53 and Drugs Acting Either on Wild- or Mutant-Type P53. Eur J Med Chem 2024 , 265 , doi:10.1016/J.EJMECH.2024.116121,. Wang, H.; Guo, M.; Wei, H.; Chen, Y. 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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-7240665","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":504328185,"identity":"c6ce0998-939c-4dd4-a519-42a2a9de2cbe","order_by":0,"name":"Nasser M. Alorfi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYLCCCgMbCIOHaC1nDNJI1sJwmAQt5mKHj304UHA+se9GAuODt20M9vwNBLRYzk5LnnHA4HbizBsJzIZz2xgSZxwgoMXgdo4x8weglg03EtikedsYEhiI0cJwwOAcSAv7b6AWe3kitRwA28IM1MK4gbCWtGSglmTjmWceNkvOOSeRuJGwluTDDAf+2Mn2HU8++OFNmY29HCEtCHCAsQFIShCtHqSFFMWjYBSMglEwogAAQ91FOI9ZmzYAAAAASUVORK5CYII=","orcid":"","institution":"Umm Al-Qura University","correspondingAuthor":true,"prefix":"","firstName":"Nasser","middleName":"M.","lastName":"Alorfi","suffix":""}],"badges":[],"createdAt":"2025-07-29 08:08:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7240665/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7240665/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89978505,"identity":"95580cb9-b78c-442b-9628-4b7319631c2f","added_by":"auto","created_at":"2025-08-27 06:15:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77106,"visible":true,"origin":"","legend":"\u003cp\u003eTop 10 cancer types targeted in p53-based gene therapy clinical trials.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7240665/v1/964355de36f1e203b78b81fe.jpg"},{"id":93568247,"identity":"98e1986c-86b9-4e89-b5e3-e33a14645dc8","added_by":"auto","created_at":"2025-10-15 08:48:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":776889,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7240665/v1/155c73a3-6511-43c0-8752-7bde5bd90cde.pdf"},{"id":89978502,"identity":"2688173d-e418-4a12-8220-1f676ab6e509","added_by":"auto","created_at":"2025-08-27 06:15:27","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":31893,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfilealldataset.docx","url":"https://assets-eu.researchsquare.com/files/rs-7240665/v1/9460ee462dc1606413ed5549.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Completed Clinical Trials of p53 Gene Therapy in Cancer: A ClinicalTrials.gov-Based Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCancer is a leading cause of morbidity and mortality worldwide, driven by complex genetic mechanisms that contribute to tumour initiation, progression, and the development of various aggressive human malignancies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. p53, encoded by the TP53 gene, is a central transcription factor regulating cell cycle arrest, apoptosis, and DNA repair in response to cellular stress [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Among the most frequently mutated genes in human cancers is the tumour suppressor gene TP53 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Mutations in TP53 result in dysfunctional proteins that are unable to perform these tumour-suppressive functions, contributing to the development of a wide range of cancers including breast, lung, bladder, and hematologic malignancies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recent advancements in cancer therapy have increasingly focused on restoring or exploiting the function of p53, a critical tumour suppressor frequently mutated in cancers.\u003c/p\u003e\u003cp\u003eSeveral strategies are being explored to exploit the p53 pathway. These include MDM2 and MDMX inhibitors, which prevent the degradation of WT p53 in cancers where TP53 is not mutated but functionally suppressed [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e–\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, efforts to target mutant forms of p53are ongoing, although challenging due to their heterogeneity. Synthetic lethality approaches offer another avenue, selectively targeting vulnerabilities in TP53-mutated cells [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Moreover, mutant p53-based adoptive cell transfer (ACT), a form of cancer immunotherapy, has shown promise in treating advanced malignancies by directing immune cells to recognize and eliminate tumour cells expressing mutant p53 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, these therapies often face resistance from the tumour microenvironment (TME), particularly in solid tumors [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], highlighting the need to address immunosuppressive barriers for successful clinical translation.\u003c/p\u003e\u003cp\u003eOne promising approach in cancer treatment is gene therapy, specifically targeting the restoration of p53 function. Since many tumours harbor defective or mutated TP53, therapeutic strategies have emerged to reactivate p53 and restore its tumor-suppressive activities. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The central role of TP53 in cancer biology makes it an attractive target for pharmacological intervention, with ongoing efforts aimed at restoring wild-type p53 function or selectively targeting mutant p53 to inhibit tumour growth [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e–\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A variety of vectors, particularly adenoviral vectors such as Ad5CMV-p53, have been explored to deliver the functional gene into tumour tissues. Initial clinical trials conducted over the past two decades aimed to determine the safety, tolerability, and preliminary efficacy of this approach, often in combination with conventional treatments such as chemotherapy, radiation, or surgery [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e–\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite the growing number of publications on p53-related cancer biology, there has been limited comprehensive synthesis of clinical trial activity surrounding p53 gene therapy. Understanding the scope, methodology, and outcomes of these trials is crucial for informing future research directions and clinical applications. This study aims to systematically examine completed clinical trials listed on ClinicalTrials.gov that involve p53 gene therapy for cancer. By analysing key elements such as intervention types, trial phases, enrolment sizes, cancer types targeted, and outcome measures, this paper seeks to map the landscape of translational research in this area. Insights from this analysis will highlight gaps in therapeutic development, identify cancer subtypes where p53 therapy has shown promise, and support evidence-based strategies for future clinical translation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA structured search was performed on ClinicalTrials.gov using the terms “Cancer” AND “p53 gene therapy” with filters applied for “Completed Studies” and last accessed the database on 1st July 2025.\u003c/p\u003e\u003cp\u003eThe search included both interventional and observational trials. From the resulting studies, only those specifically incorporating p53 as a gene therapy agent (e.g., Ad5CMV-p53) were selected. A total of 23 studies met the inclusion criteria. Relevant variables were extracted including NCT number, study title, summary, cancer conditions, interventions, trial phase, enrolment size, and primary outcome measures. Trials without posted results were included; missing data (e.g., enrollment or outcome) were noted but not excluded. Data were curated in Microsoft Excel and analysed descriptively to generate summaries of enrolment, study design, cancer types, and therapeutic strategies.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis analysis included data from a set of interventional clinical trials focusing on p53 gene therapy (predominantly using Ad5CMV-p53) across various cancer types. A total of 23 completed studies were included in this analysis, of which 20 (87%) were interventional and 3 were observational. Among the trials reporting enrolment data, the cumulative number of participants was 2,846. Although 23 completed trials were included, only 16 had posted enrolment data and 14 reported primary outcomes. The majority of studies focused on solid tumors, particularly bladder, breast, lung, and ovarian cancers.\u003c/p\u003e\u003cp\u003eThe majority of studies were Phase I trials, indicating that they primarily aimed to assess safety, dosing, and early biological activity rather than efficacy as shown in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the distribution of the top ten cancer types targeted in p53-based gene therapy clinical trials. The most frequently investigated cancers include lung cancer, breast cancer, and central nervous system tumors, each represented in three separate trials. Ovarian cancer and acute myeloid leukaemia also featured prominently. This distribution reflects the therapeutic interest in restoring p53 function in malignancies with high TP53 mutation prevalence. The figure highlights the emphasis on solid tumours and hematologic malignancies where p53-targeted approaches hold translational promise.\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\u003eDistribution of included trials by clinical phase.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy Phase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of Trials\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhase I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhase I/II\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhase II\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhase III\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnspecified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e23\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e categorizes clinical trials based on the number of enrolled participants. The majority of trials were small-scale studies with fewer than 50 participants, highlighting the exploratory phase of p53-based gene therapy research.\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\u003eClassification of trials based on participant enrolment size.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnrolment Range\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of Trials\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u0026ndash;50 (Small)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e51\u0026ndash;100 (Medium)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e101\u0026ndash;1000 (Large)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAll the trials employed a biological intervention using Ad5CMV-p53 (a recombinant adenoviral vector delivering wild-type p53). In some studies, this intervention was combined with chemotherapy or conventional surgery, highlighting a multi-modal therapeutic approach. Despite the diversity of cancer types and intervention combinations, all available records indicated \"NO\" under the Study Results column, suggesting that published outcome data was not yet posted on ClinicalTrials.gov for these trials.\u003c/p\u003e\u003cp\u003eThe classification of interventions in p53-based cancer clinical trials reveals that chemotherapy is the most commonly used therapeutic category, followed by diagnostic and gene therapy strategies. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e categorizes interventions by therapeutic type, their intended objective (e.g., curative, diagnostic), and provides an explanation of each category's role in the context of p53-targeted studies.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCategorization of interventions by therapeutic type, objective, functional role in p53 gene therapy and an illustrative example agent from the included trials.\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=\".\" 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\u003eTherapeutic Category\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of Interventions\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTherapeutic Objective\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExplanation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eExample Agent\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCurative/Palliative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCytotoxic agents used to kill rapidly dividing tumor cells or sensitize tumors to other treatments.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCisplatin\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnostic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDiagnostic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTools and techniques used to assess tumor biology or treatment response, such as biomarker or gene expression analysis.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImmunohistochemistry\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSupportive/Experimental\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMiscellaneous or unspecified interventions including supportive, experimental, or non-therapeutic components.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFilgrastim\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGene Therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCurative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDelivery of functional p53 genes to tumor cells to restore tumor‑suppressor activity, often using viral vectors.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAd5CMV‑p53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCurative/Diagnostic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePhysical procedures such as tumor resection, biopsy, or laparoscopy aimed at diagnosis or tumor removal.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eConventional Surgery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmunotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCurative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTreatments that enhance the immune system\u0026rsquo;s ability to attack tumors (e.g., checkpoint inhibitors, vaccines).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNivolumab\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHormonal Therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCurative/Palliative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInterventions targeting hormonal pathways, primarily in prostate or breast cancer.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAbiraterone Acetate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRadiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCurative/Palliative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUse of ionizing radiation to kill or shrink cancer cells, often used in combination therapies.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eExternal‑Beam Radiation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTargeted Therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCurative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTherapies acting on specific molecular targets involved in tumor growth and survival.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEverolimus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe analysis of primary objectives from 23 completed p53-related cancer trials registered on ClinicalTrials.gov reveals that the majority of studies were designed to evaluate safety, tolerability, and dose-limiting toxicity (DLT), particularly in early-phase settings as shown in Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Maximum tolerated dose (MTD) determination was a key outcome across several trials, reflecting the exploratory nature of novel gene or combination therapies. A smaller subset of studies aimed to measure tumor response rates\u0026mdash;such as partial or complete responses\u0026mdash;based on clinical or radiological criteria. Other objectives included the assessment of biomarker expression (e.g., p53 activity or apoptosis markers), feasibility of treatment protocols, patient-reported quality of life, and immune-related endpoints. Additionally, one translational study focused on establishing tumor cell lines and xenografts for future drug development.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePrimary outcome objectives in p53-based cancer trials.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary Objective Category\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDescription\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNumber of Trials\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSafety / Dose-limiting Toxicity (DLT)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDetermine adverse effects, tolerability, and MTD of investigational therapies.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumour Response Assessment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeasure tumor shrinkage or remission (e.g., CR, PR, SD).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBiomarker Expression\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEvaluate biological activity through protein or gene expression markers.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmunogenicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAssess immune response triggered by therapies or vaccines.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurvival Outcomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTrack progression-free or overall survival post-treatment.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFeasibility / Protocol Completion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeasure the practicality of treatment completion and adherence.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTranslational / Cell Models\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEstablish cell lines or xenografts for future research.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQuality of Life\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEvaluate patient-reported outcomes using validated QoL instruments.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTP53, the most frequently mutated gene across a wide range of human cancers, plays a pivotal role in tumorigenesis. Its alterations often occur as early events in cancer development, contributing to the loss of normal p53 tumour suppressor function [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. This gene plays a pivotal role in maintaining genomic integrity by regulating cell cycle arrest, apoptosis, DNA repair, and senescence [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. By restoring p53\u0026rsquo;s tumour-suppressor function, treatment strategies can induce apoptosis, halt cell-cycle progression, and enhance DNA repair in malignant cells, offering a powerful mechanism to counteract tumour growth [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThis analysis of completed clinical trials on p53 gene therapy in cancer highlights both the breadth and limitations of current clinical research efforts. Most studies were early-phase (Phase 1 or Phase 1/2), underscoring the experimental nature of p53 gene therapy and its position in the translational pipeline. The limited progression to Phase 3 trials suggests ongoing challenges in demonstrating consistent therapeutic efficacy across cancer types.\u003c/p\u003e\u003cp\u003eThe use of Ad5CMV-p53, a recombinant adenovirus vector, dominated intervention strategies, reflecting its historical use in early gene therapy development due to efficient gene delivery into tumour cells [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Studies combining p53 gene therapy with chemotherapy or radiation aimed to potentiate cytotoxic effects, leveraging p53\u0026rsquo;s pro-apoptotic and cell-cycle regulatory functions. For example, combined regimens involving cisplatin and Ad5CMV-p53 targeted platinum-resistant tumours such as ovarian and bladder cancers [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. These approaches align with findings from preclinical models that suggest synergistic effects between wild-type p53 and DNA-damaging agents. Interestingly, the trials targeted a wide array of malignancies, indicating broad scientific interest in this therapeutic modality. However, no clear consensus has emerged on which cancer subtypes derive the greatest benefit, and the inclusion of rare tumors (e.g., prolymphocytic leukaemia) suggests a need for better prioritization based on molecular profiles. When comparing to the literature, few studies reported significant clinical responses, and most outcomes were limited to safety profiles and biomarker changes. This mirrors broader gene therapy challenges, including immune responses to viral vectors, short-lived transgene expression, and heterogeneous tumour environments..\u003c/p\u003e\u003cp\u003eNonetheless, the presence of two Phase 3 trials offers a degree of optimism and may pave the way for future validation if positive results are confirmed. Advances in gene-editing technologies like CRISPR/Cas9 may also rejuvenate interest in targeting TP53 by offering more precise, durable genetic correction strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis analysis highlights the experimental nature and evolving landscape of p53 gene therapy in cancer. While the majority of studies were early-phase trials focusing on feasibility and safety, progress toward late-phase trials is limited. Future research should emphasize patient stratification, combination strategies, and next-generation vector technologies to enhance therapeutic outcomes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis analysis was limited to completed studies registered on ClinicalTrials.gov and may not capture unregistered or unpublished trials. Many studies lacked detailed result postings, restricting quantitative efficacy comparisons. Additionally, heterogeneity in cancer types and interventions prevented pooled analysis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eThe author reports no conflicts of interest related to this work.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eInformed consent\u003c/h2\u003e\u003cp\u003eThis study was based solely on publicly available data from ClinicalTrials.gov and did not involve human participants or identifiable personal data.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eClinical trial number\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthical declaration\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003edeclaration\u003c/p\u003e\u003cp\u003eThe author declares that no funds, grants, or other support were received during the preparation of this manuscript\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAm sole author and wrote the whole manuscript.\u003c/p\u003e\u003ch2\u003eAvailability of Data Statement\u003c/h2\u003e\u003cp\u003eAll data analysed during this study are available in the attached supplementary file. The dataset was obtained from publicly accessible records on ClinicalTrials.gov.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFischer, E.G. Nuclear Morphology and the Biology of Cancer Cells. \u003cem\u003eActa Cytol\u003c/em\u003e \u003cstrong\u003e2020\u003c/strong\u003e, \u003cem\u003e64\u003c/em\u003e, 511\u0026ndash;519, doi:10.1159/000508780.\u003c/li\u003e\n\u003cli\u003eHill, B.T.; Shah, H.; Winter, A. Etiology of Cancer. \u003cem\u003eClinical Ophthalmic Oncology: Basic Principles, Fourth Edition\u003c/em\u003e \u003cstrong\u003e2025\u003c/strong\u003e, 17\u0026ndash;22, doi:10.1007/978-3-031-75907-9_3.\u003c/li\u003e\n\u003cli\u003eHuang, Y.; Jiao, Z.; Fu, Y.; Hou, Y.; Sun, J.; Hu, F.; Yu, S.; Gong, K.; Liu, Y.; Zhao, G. 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Increased Sensitivity of a Metastatic Model of Prostate Cancer to a Novel Tetravalent Platinum Analog. \u003cem\u003eProstate\u003c/em\u003e \u003cstrong\u003e2005\u003c/strong\u003e, \u003cem\u003e62\u003c/em\u003e, 91\u0026ndash;100, doi:10.1002/pros.20114.\u003c/li\u003e\n\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":"p53, gene therapy, cancer, TP53, clinical trials, Ad5CMV-p53, tumour suppressor, ClinicalTrials.gov analysis","lastPublishedDoi":"10.21203/rs.3.rs-7240665/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7240665/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe tumour suppressor gene TP53, frequently mutated in various different types of cancers, plays a vital role in regulating cell cycle arrest, apoptosis, and genomic stability. Gene therapy targeting p53 aims to restore its normal function in tumours with defective p53, offering a novel therapeutic approach.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThis study aims to systematically characterise the design, therapeutic strategies, and primary outcomes of completed clinical trials investigating p53 gene therapy for cancer, focusing on study design, targeted conditions, intervention strategies, and clinical outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA systematic search of ClinicalTrials.gov database was conducted using the keywords \u0026ldquo;Cancer\u0026rdquo; AND \u0026ldquo;p53 gene therapy,\u0026rdquo; filtered for completed studies. A total of 23 eligible trials were included. Data on cancer type, intervention, study phase, enrolment, and primary outcomes were extracted and analysed descriptively.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf the 23 included trials, 20 (87%) were interventional and 3 were observational. Gene therapy interventions were used in 5 trials, while chemotherapy was included in 13. The most studied conditions were bladder, breast, ovarian, and lung cancers. Adenoviral vectors such as Ad5CMV-p53 were the predominant gene therapy platform. Many trials combined p53 gene therapy with chemotherapy, surgery, or radiation. Total reported enrolment across studies was 2,846 participants. Most trials focused on safety, dose escalation, and biomarker analysis rather than definitive clinical efficacy.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eCompleted clinical trials on p53 gene therapy in cancer suggest promising biological rationale but limited clinical translation to date. Most studies remain early-phase, with sparse progression to large-scale efficacy trials. Future efforts should prioritize stratified patient populations, refined gene delivery technologies, and combination approaches to enhance therapeutic impact.\u003c/p\u003e","manuscriptTitle":"Completed Clinical Trials of p53 Gene Therapy in Cancer: A ClinicalTrials.gov-Based Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 06:15:21","doi":"10.21203/rs.3.rs-7240665/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":"ae7dab3c-b986-43b1-8676-b53d84ef42d8","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-15T08:39:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-27 06:15:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7240665","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7240665","identity":"rs-7240665","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}