Tumors harboring non-synonymous deoxyribonucleic acid (DNA) mutations can present peptides containing these mutations as non-self antigens in the context of human leukocyte antigens (HLAs) on the tumor cell surface. A fraction of mutated peptides result in neoantigens capable of generating T-cell responses that exclusively target tumor cells. Sensitive detection of these mutations allows for the identification of neoantigens unique to each patient's tumor to be included in a patient-specific cancer vaccine that targets these neoantigens. This vaccine regimen uses two vaccine vectors as a heterologous prime/boost approach (GRT-C901 first followed by GRT-R902) to stimulate an immune response. This study will explore the anti-tumor activity of this patient-specific immunotherapy in combination with checkpoint inhibitors in addition to fluoropyrimidine/bevacizumab.
Inclusion Criteria:
* Patients with histologically confirmed metastatic colorectal cancer (CRC) who are planned for, or have received \<30 days of first-line treatment in the metastatic setting with FOLFOX/bev, CAPEOX/bev, FOLFOXIRI/bev, or CAPOXIRI/bev per SOC
* Measurable and unresectable metastatic disease according to RECIST v1.1
* Availability of formalin-fixed paraffin-embedded (FFPE) tumor specimens.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Patient has adequate organ function per defined criteria
* If women of childbearing potential (WCBP), must be willing to undergo pregnancy testing and agrees to the use at least 1 highly effective contraceptive method during the study treatment period and for 150 days after last investigational study treatment.
Exclusion Criteria:
* Patients with deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) phenotype
* Patient has a known tumor mutation burden \<1 non-synonymous mutations/megabase
* Known DNA Polymerase Epsilon mutations
* Patients with known BRAFV600E mutations
* Bleeding disorder or history of significant bruising or bleeding following IM injections or blood draws
* Immunosuppression anticipated at time of study treatment
* History of allogeneic tissue/solid organ transplant
* Active or history of autoimmune disease or immune deficiency
* Patient with symptomatic or actively progressing central nervous system (CNS) metastases, carcinomatous meningitis, or has been treated with whole brain radiation
* History of other cancer within 2 years with the exception of neoplasm that has undergone potentially curative therapy
* Any severe concurrent non-cancer disease that, in the judgment of the Investigator, would make the patient inappropriate for the current study
* Active tuberculosis or recent (\<2 weeks) clinically significant infection, evidence of active hepatitis B or hepatitis C, or known history of positive test for HIV
* History of pneumonitis requiring systemic steroids for treatment (with the exception of prior resolved in-field radiation pneumonitis)
* Myocardial infarction within previous 3 months, unstable angina, serious uncontrolled cardiac arrhythmia, history of myocarditis, or congestive heart failure (Class III or IV).
* Pregnant, planning to become pregnant, or nursing.