Clinical Study of MSH2-/- Tumor Cell Vaccines for Advanced pMMR Colorectal Cancer Patients

Official title

A Clinical Trial Evaluating the Safety, Tolerability, and Preliminary Antitumor Activity of MSH2-/- Tumor Cell Vaccines in Patients With Advanced pMMR Colorectal Cancer.

Overview

The goal of this clinical trial is to evaluate the safety and tolerability of an MSH2-/- tumor cell vaccine and to explore its preliminary antitumor activity and immunogenicity in adults with advanced proficient mismatch repair (pMMR) colorectal cancer who have failed, are intolerant of, or decline standard systemic therapies at West China Hospital, Sichuan University. The main objectives are to determine the incidence of dose-limiting toxicities (DLTs) and other treatment-emergent adverse events (TEAEs) related to the vaccine (n/N, %, graded per NCI CTCAE v5.0), to assess preliminary antitumor activity (objective response per RECIST v1.1, progression-free survival, and overall survival), and to characterize the vaccine's immunogenicity profile. This study using a 3+3 dose-escalation design with three dose levels of the MSH2-/- tumor cell vaccine (1×10\^7, 2.5×10\^7, and 5×10\^7 cells per dose), manufactured under GMP conditions and administered by intradermal injection. Each participant will receive four induction vaccinations (three doses every 2 weeks and a fourth dose 1 month after the third), followed by up to eight booster doses every 4 weeks based on tumor response. Participants will undergo protocol-specified safety monitoring with clinical assessments, laboratory tests, and documentation of all AEs/SAEs, and tumor response will be evaluated regularly by imaging per RECIST v1.1. After treatment completion or discontinuation, participants will enter safety and long-term follow-up for disease status and survival.

Interventions

• Biological Low Dose MSH2-/- tumor cell vaccine
  Participants were assigned to receive the MSH2-/- tumor cell vaccine in the number of 1x10e7 tumor cells per dose.
• Biological Medium Dose MSH2-/- tumor cell vaccine
  Patients will receive the MSH2-/- tumor cell vaccine in the number of 2.5x10e7 tumor cells per dose.
• Biological High dose MSH2-/- tumor cell vaccine
  Patients will receive the MSH2-/- tumor cell vaccine in the number of 5x10e7 tumor cells per dose.

Primary outcome measures

• Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v.5.0) [Time frame: From the first dose through 14 days following the third dose.]
• Number of Participants Experienced Treatment-emergent adverse events (TEAEs) according to NCI CTCAE V5.0 [Time frame: 12 months]

Secondary outcome measures (4)

• Number of participants achieving complete response (CR) According to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1 [Time frame: 12 months]
• Number of participants achieving partial response (PR) According to RECIST 1.1 [Time frame: 12 months]
• Progression Free Survival (PFS) According to RECIST 1.1 [Time frame: 6 months]
• Overall Survival(OS) [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Patients aged 18 to 75 years at the time of acquisition informed consent form.
• Patients with histologically or cytologically confirmed pMMR colorectal cancer based on molecular typing, who have experienced failure of, are intolerant to, or refuse standard therapy.

• For patients with RAS/BRAF wild-type disease who are eligible for targeted therapy, enrollment is permitted only after they have previously received standard regimens containing an anti-EGFR monoclonal antibody or an anti-VEGF monoclonal antibody and subsequently experienced disease progression.
• For patients with a BRAF V600E mutation, enrollment is permitted only after failure of prior treatment with a regimen containing a BRAF inhibitor in combination with chemotherapy.
• For patients who do not meet the above molecular criteria, enrollment is permitted only after failure of at least two prior lines of systemic chemotherapy, including platinum-based agents.
• The presence of at least one measurable or evaluable lesion according to RECIST v1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status score: 0-2.
• Predicted survival time ≥3 months.
• The main organs are functioning well and the following requirements are met within 7 days before receiving treatment:

① Hemoglobin (HGB) ≥80 g/L (no blood transfusion within 14 days); Absolute neutrophil count (ANC) >1.5×109/L; White blood cell count ≥3.0×109/L; Platelet count (PLT) ≥80×109/L;

② Total bilirubin ≤1.5× upper limit of normal value (ULN); Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5×ULN; If there was liver metastasis, ALT or AST≤5×ULN;

③ Creatinine (SCr) ≤1.5×ULN or creatinine clearance (CRCI) estimated by Cockcroft-Gault formula ≥60 mL/min;

④ Prothrombin time (PT), international normalized ratio (INR) ≤1.5×ULN (unless anticoagulation with warfarin);

⑤ Cardiac function: left ventricular ejection fraction ≥50%. QTcF interval ≤450 ms.

• Men of childbearing potential and women of childbearing age voluntarily use effective contraceptive methods (e.g., condoms, intrauterine devices, spermicides) from the time of signing the informed form until 6 months after the completion of vaccination, and contraceptive use is not allowed. Female cancer patients who have a negative pregnancy test and agree not to breastfeed during the study and for at least 18 months after receipt of the trial vaccine;
• The washout period of previous anti-tumor therapy should be at least 4 weeks, and the washout period of molecular targeted drugs should be at least 5 half-lives. Palliative radiotherapy needs to have been completed for at least 2 weeks; Chest radiation therapy needed to have been completed for at least 3 months, and major surgery needed to have been completed with at least 4 weeks of recovery.

Exclusion criteria

• The patient has a history of other tumors in the past, except for the history of malignant tumors that have been cured and have not recurred within 5 years before screening, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, cervical cancer in situ, and intramucosal cancer of the gastrointestinal tract, which the investigator considers to be eligible for enrollment.
• Have any uncontrolled clinical diseases (e.g., diseases of the respiratory system, circulatory system, digestive system, nervous system, hematologic system, urogenital system, endocrine system) or psychiatric or other major medical condition that the investigator considers to interfere with the provision of informed consent, to interfere with the interpretation of the trial results, to pose a risk to the study participants, or to otherwise interfere with the achievement of the study objectives.
• Have any active autoimmune disease or a history of autoimmune disease. Participants with asthma for which medical intervention with bronchodilators was required could not be included.
• Allergy to the trial drug (including any excipients). Previous history of severe allergy to any drug, food or vaccination, such as anaphylactic shock, allergic laryngeal edema, allergic dyspnea, allergic purpura, thrombocytopenic purpura, local allergic necrosis reaction (Arthus reaction), etc.
• There are contraindications to subcutaneous injection.
• Received prior antitumor therapeutic vaccine or cellular immunotherapy.
• Participated in other drug or device clinical trials 4 weeks before screening.
• Study participants on systemic therapy with corticosteroids (>10 mg/ day of prednisone or equivalent doses of other glucocorticoids) or other immunosuppressive agents within 14 days before the first dose of vaccine. Inhaled or topical steroids and adrenal hormone replacement at a therapeutic dose of prednisone of 10 mg or less per day were allowed in the absence of active autoimmune disease.
• Before the first dose of the study drug. Any toxic effects from previous antineoplastic therapy have not recovered to NCI CTCAE grade 5.0 ≤1 (any degree of alopecia, other than grade 2 previous platinum-based treatment-related neuropathy).
• Has active infection including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.
• Have a history of substance abuse or known medical, psychological, or social conditions such as alcohol or drug abuse.
• Have received any vaccine within 30 days before receiving the study vaccine or plan to receive any vaccine other than the study vaccine during the study.
• The presence of any other factor that was deemed by the investigator to preclude study participant entry into the trial or that study participant had any medical condition that could interfere with the assessment of the safety or efficacy of the study treatment.
• Study participants who were unwilling or unable to comply with study requirements.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• West China Hospital, Sichuan University — Chengdu
• West China Hospital, Sichuan University — Chengdu

Publications

• Pang K, Sun P, Liu X, Yang D, Zhao P, Huang Y, Cao S, Gao Y, Chen G, Yu H, Duan L, Yang Y, Zhang Z. Development of the rationale of a personalized cancer vaccine based on the in situ vaccine effect of radiotherapy: a mechanistic study of the POLARSTAR trial. Cancer Immunol Immunother. 2025 Nov 12;74(12):369. doi: 10.1007/s00262-025-04229-3. PMID 41222702
• De Marco L, Micarelli E, Panula J, Nikkola J, Moilanen L, Annala M, Harkonen J, Hokkanen KE, D'Alise AM, Pylvanainen K, Peltomaki PT, Ahtiainen M, Bohm J, Mecklin JP, Scarselli E, Seppala TT. NOUS-209 Off-the-shelf Immunotherapy Has the Potential to Hit Primary and Metachronous Colorectal and Urothelial Cancers in Lynch Syndrome. Mol Cancer Ther. 2026 Apr 2;25(4):650-661. doi: 10.1158/1535-7163.MC PMID 41232028
• Li J, Wang P. Advances in Cancer Vaccines for Digestive System Cancers: A Systematic Analysis of Clinical Trials. Cancer Manag Res. 2025 Nov 11;17:2691-2703. doi: 10.2147/CMAR.S561298. eCollection 2025. PMID 41245584
• Passardi A, Sullo FG, Bittoni A, Matteucci L, De Rosa F, Bulgarelli J, Tazzari M, Petrini M, Scarpi E, Testoni S, Miserocchi A, Tartagni O, Zani C, Iaia ML, Toma I, Viola MG, Mita MT, Tamburini E, Ridolfi L. CombiCoR-Vax trial: study protocol for a phase II, single-arm, multicenter trial of sequential pembrolizumab plus dendritic cell vaccine followed by trifluridine/tipiracil and bevacizumab in r PMID 41275134
• Karimzadeh F, Heidari R, Lamooki FM, Soureshjani EH, Aziz S, Mirzaei SA. Design of a multi-epitope vaccine against intestinal parasites associated with colorectal cancer using immunoinformatics approaches. Sci Rep. 2025 Dec 8;16(1):1487. doi: 10.1038/s41598-025-31713-8. PMID 41360964
• D'Alise AM, Willis J, Duzagac F, Hall MJ, Cruz-Correa M, Idos GE, Thirumurthi S, Ballester V, Leoni G, Garzia I, Antonucci L, De Marco L, Micarelli E, Deng N, Secli L, Gogov S, Dong W, Jack Lee J, Bowen CM, Vornik LA, Garcia-Gonzalez A, Reyes-Uribe L, Richmond E, Umar A, Brown PH, Sinha KM, Rodriguez LM, Scarselli E, Vilar E. Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carr PMID 41545594
• Huang J, Tian G. Immunotherapy in advanced colorectal cancer: Current landscape, mechanisms, challenges, and future directions. J Oncol Pharm Pract. 2026 Jan 22:10781552251414845. doi: 10.1177/10781552251414845. Online ahead of print. PMID 41571235
• Hamdan F, Gandolfi S, D'Alessio F, Giannoula Y, Kolikova J, Fusciello M, Zaghen E, Napolano A, Russo S, Izci O, Bottega P, Chiaro J, Alanen KM, Antignani G, Feodoroff M, Stigzelius V, Sakalauskaite M, Sandberg J, Nieminen AI, Zambrano N, Eriksson O, Mustjoki S, Seppala TT, Gronholm M, Cerullo V. Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to PMID 41605920

Identifiers

NCT: NCT07510308 · 2025-2583

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗