COLONYVAQ™, a Quantum-Classical Guided Personalized Neoantigen Vaccine for MSS Stage III Colorectal Cancer

* Eligibility * Inclusion Criteria * \*\*Diagnosis / Histology\*\* * Histologically confirmed adenocarcinoma of the colon or rectum. * Pathology report available for central or sponsor review (if requested), including: * Primary tumor site (colon vs rectum) * Grade of differentiation * Resection margins * \*\*Stage and Surgical Status\*\* * Pathologic stage III disease (any T, N1-2, M0) per AJCC 8th edition. * R0 resection of the primary tumor documented by operative and pathology reports (no macroscopic or microscopic residual tumor at margins). * No evidence of distant metastatic disease (M1) on staging imaging (CT chest/abdomen/pelvis ± MRI/PET per institutional standard) within a protocol-defined window (e.g., ≤8 weeks prior to enrollment). * Enrollment and treatment initiation planned within a protocol-defined timeframe after surgery (e.g., 4-12 weeks post-resection), allowing appropriate recovery. * \*\*Molecular Subtype (MSS/pMMR)\*\* * Tumor confirmed MSS or pMMR by local testing using one or more of the following: * IHC for MLH1, MSH2, MSH6, and PMS2 * PCR-based MSI panel * NGS-based MSI/MMR assessment * No evidence of dMMR/MSI-H status or POLE ultramutated phenotype. * \*\*High-Risk Recurrence Profile\*\* * At least one protocol-defined high-risk feature, including one or more of the following: * Pathologic T4 tumor * Pathologic N2 nodal status (≥4 positive lymph nodes) * Positive postoperative ctDNA (MRD) by a validated tumor-informed assay within a protocol-defined window after surgery/chemotherapy initiation * Other protocol-specified high-risk features (e.g., lymphovascular invasion, perineural invasion, poorly differentiated histology, inadequate lymph node sampling), as defined in the protocol/statistical analysis plan * \*\*Suitability for Standard Adjuvant Chemotherapy\*\* * Candidate for oxaliplatin-based adjuvant chemotherapy with one of the following: * mFOLFOX6 every 14 days for \~6 months, \*\*or\*\* * CAPOX (XELOX) every 21 days for \~3-6 months * Chemotherapy regimen (mFOLFOX6 vs CAPOX) determined before enrollment and recorded as a stratification factor. * No contraindications to oxaliplatin, 5-fluorouracil, leucovorin, or capecitabine (e.g., severe DPD deficiency; prior severe 5-FU/capecitabine toxicity). * \*\*Suitability for Nivolumab\*\* * Eligible in the investigator's judgment to receive anti-PD-1 therapy (nivolumab 3 mg/kg IV every 2 weeks), including: * No history of severe (Grade ≥3) immune-related adverse events from prior immunotherapy * No active autoimmune disease requiring systemic immunosuppression * \*\*Performance Status\*\* * ECOG performance status 0-1 at screening. * \*\*Adequate Organ and Marrow Function\*\* (documented within 14 days prior to enrollment; no transfusions/growth factors solely to meet eligibility) * \*\*Hematologic\*\* * ANC ≥ 1.5 × 10⁹/L * Platelets ≥ 100 × 10⁹/L * Hemoglobin ≥ 9.0 g/dL (transfusions allowed if clinically indicated, but not solely to qualify) * \*\*Hepatic\*\* * Total bilirubin ≤ 1.5 × ULN (≤3 × ULN allowed for known Gilbert's syndrome if direct bilirubin is normal) * AST and ALT ≤ 2.5 × ULN * Alkaline phosphatase ≤ 2.5 × ULN (higher thresholds may be allowed for non-malignant causes per protocol) * \*\*Renal\*\* * Serum creatinine ≤ 1.5 × ULN \*\*or\*\* creatinine clearance ≥ 50 mL/min (Cockcroft-Gault or institutional standard) * \*\*Biospecimen Availability (COLONYVAQ)\*\* * Adequate tumor tissue available from resected primary tumor (and/or metastases if applicable), including one of the following: * Fresh frozen tissue (preferred), \*\*or\*\* * FFPE block(s), \*\*or\*\* * ≥15 unstained slides (or equivalent) suitable for DNA/RNA extraction * Matched normal sample (peripheral blood) available for germline DNA sequencing. * Willingness to provide additional blood samples for ctDNA, immune monitoring, and exploratory assays per schedule. * Pre-existing WES/RNA-seq may be accepted if meeting COLONYVAQ requirements per protocol. * \*\*Neoantigen Suitability\*\* * At least one predicted high-quality tumor neoantigen identified by the COLONYVAQ pipeline meeting prespecified criteria, including: * Strong predicted binding to patient-specific HLA alleles (e.g., Kd in an established binder range) * Evidence of tumor RNA expression of the source gene/allele * Prioritization by multi-algorithm immunogenicity scoring and passage through COLONYVAQ quantum-geometric, thermodynamic, and immunogenicity gates * \*\*OR\*\* * Availability of pre-manufactured GMP-grade neoantigen peptides with demonstrated in vitro immunogenicity and acceptable safety profile. * \*\*Life Expectancy\*\* * Investigator-estimated life expectancy ≥ 3 years in the absence of CRC recurrence. * \*\*Contraception and Pregnancy\*\* * \*\*Women of childbearing potential (WOCBP)\*\* * Negative serum or urine pregnancy test within 7 days prior to randomization * Agreement to use highly effective contraception during treatment and for a protocol-defined period after last dose (e.g., 5 months after last nivolumab and 6 months after last chemotherapy, or per label/institutional guidance) * \*\*Men with partners of childbearing potential\*\* * Agreement to use effective contraception and avoid sperm donation during treatment and for the protocol-defined period after last dose * \*\*Informed Consent and Compliance\*\* * Able to understand and voluntarily sign written informed consent. * Willing and able to comply with all study procedures (visits, imaging, blood draws, follow-up). * Exclusion Criteria * \*\*Residual or Metastatic Disease at Baseline\*\* * R2 resection or indeterminate margins not clearly R0. * Radiologic or histologic evidence of distant metastases (M1) at baseline staging (e.g., liver, lung, peritoneum). * Gross residual disease at the primary site. * \*\*Mismatch Repair-Deficient / MSI-High / POLE-Ultramutated Disease\*\* * Known dMMR/MSI-H CRC or POLE ultramutated tumors for which checkpoint inhibition is standard/preferred. * \*\*Prior Anticancer Therapy (Beyond Allowed Neoadjuvant)\*\* * Prior systemic therapy for metastatic CRC. * Neoadjuvant chemotherapy/chemoradiotherapy that: * Was not completed within protocol-defined windows, \*\*or\*\* * Led to unresolved Grade ≥2 non-hematologic toxicity (excluding alopecia or clinically insignificant neuropathy, per protocol) * Prior tumor vaccine targeting TAAs or neoantigens (peptide, DC, viral, RNA, or DNA). * Prior immune checkpoint inhibitor therapy (anti-PD-1, anti-PD-L1, anti-CTLA-4). * \*\*Active or Uncontrolled Infections\*\* * Systemic infection requiring IV or oral antimicrobials that would interfere with study treatment per investigator judgment. * Uncontrolled HIV (e.g., CD4 below protocol threshold or unsuppressed viral load). * Active hepatitis B with HBV DNA above predefined limit, or active hepatitis C with detectable HCV RNA not adequately treated. * Other clinically significant infections posing excessive risk with immunotherapy, vaccine, or chemotherapy. * \*\*Autoimmune Disease / Immunosuppression\*\* * Severe/uncontrolled autoimmune disease requiring systemic immunosuppression (e.g., high-dose corticosteroids, biologics), including (examples): * Systemic lupus erythematosus * Inflammatory bowel disease with recent flares * Rheumatoid arthritis requiring biologics * Multiple sclerosis * Myasthenia gravis * Exceptions may include (per protocol): * Stable autoimmune thyroiditis on replacement therapy * Vitiligo * Well-controlled type 1 diabetes * Chronic systemic corticosteroids \>10 mg prednisone equivalent daily (or other immunosuppressants) within a protocol-defined window prior to first dose (unless physiologic/adrenal replacement). * \*\*Transplant History\*\* * Prior allogeneic hematopoietic stem cell transplantation. * Prior solid organ transplantation (e.g., kidney, liver, heart). * \*\*Hypersensitivity / Drug Intolerance\*\* * Severe hypersensitivity (e.g., anaphylaxis) to any of the following: * COLONYVAQ-CRC components (peptides/excipients) * Poly I:C or similar TLR agonists * Nivolumab or other anti-PD-1/PD-L1 agents * Oxaliplatin, 5-FU, leucovorin, or capecitabine (including severe DPD deficiency) * \*\*Concurrent Malignancy\*\* * Active second primary malignancy requiring systemic therapy or expected to require systemic therapy during the trial. * Exceptions: * Adequately treated basal cell or squamous cell skin carcinoma * Cervical carcinoma in situ * Other malignancies in complete remission not expected to relapse or require systemic therapy within 5 years, per investigator judgment * \*\*Significant Comorbidities\*\* * Clinically significant/unstable cardiovascular disease, including: * MI within 6 months * Unstable angina * Uncontrolled arrhythmias * CHF NYHA class III-IV * Uncontrolled hypertension despite medical therapy * Stroke or TIA within 6 months (if risk is increased per investigator judgment). * Severe COPD or interstitial lung disease with significant impairment, or prior pneumonitis requiring systemic steroids. * Any other serious uncontrolled condition (e.g., poorly controlled diabetes, severe cirrhosis, advanced renal failure) that may compromise safety or adherence. * \*\*Pregnancy / Lactation\*\* * Pregnant at screening (positive pregnancy test). * Breastfeeding (must discontinue lactation before first dose). * \*\*Concurrent Investigational Agents / Confounding Therapies\*\* * Participation in another interventional trial with systemic investigational agents (unless sponsor/IRB-approved and not confounding). * Live attenuated vaccine within a protocol-defined period (e.g., 30 days) prior to first dose of nivolumab or COLONYVAQ-CRC, or during study treatment. * \*\*Other Conditions Affecting Compliance or Assessment\*\* * Psychiatric illness, cognitive impairment, substance abuse, or social situation limiting adherence to study requirements. * Any condition that, in the investigator's opinion, makes the participant unsuitable or interferes with interpretation of safety, immunologic, or clinical outcomes.