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.
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.
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.
Sequential
Low Dose MSH2-/- tumor cell vaccine
Biological/VaccineParticipants were assigned to receive the MSH2-/- tumor cell vaccine in the number of 1x10e7 tumor cells per dose.
Medium Dose MSH2-/- tumor cell vaccine
Biological/VaccinePatients will receive the MSH2-/- tumor cell vaccine in the number of 2.5x10e7 tumor cells per dose.
High dose MSH2-/- tumor cell vaccine
Biological/VaccinePatients will receive the MSH2-/- tumor cell vaccine in the number of 5x10e7 tumor cells per dose.
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)
DLTs are defined as treatment-related adverse events (graded according to NCI-CTCAE v5.0) occurring during the DLT observation period that meet specific protocol-defined criteria for hematologic and non-hematologic toxicity.
Number of Participants Experienced Treatment-emergent adverse events (TEAEs) according to NCI CTCAE V5.0
Treatment-emergent adverse events (TEAEs) related to the study drug (including definitely related, probably related, and possibly related), graded according to NCI CTCAE V5.0
Number of participants achieving complete response (CR) According to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1
CR was defined as participants in the analysis population who had a confirmed disappearance of all lesions according to Response Evaluation Criteria in Solid RECIST 1.1
Number of participants achieving partial response (PR) According to RECIST 1.1
PR was defined as participants in the analysis population who had a confirmed at least a 30% decrease according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1
Progression Free Survival (PFS) According to RECIST 1.1
PFS is defined as the duration until disease progression or death in participants from the first dose of immunization.
Overall Survival(OS)
OS is defined as the duration until death in participants from the first dose of immunization.
Assessment of Tumor Immune Microenvironment Changes
Evaluation of the changes in the tumor immune microenvironment before and after vaccination, including the infiltration and activation status of immune cells within the tumor tissue and peripheral blood.
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