* 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.
