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.