The primary objective of the Phase 2 portion of the study is to characterize the clinical activity of maintenance therapy with GRT-C901/GRT-R902 (patient-specific vaccines) in combination with checkpoint inhibitors in addition to fluoropyrimidine/bevacizumab versus a fluoropyrimidine/bevacizumab alone as assessed by molecular response which is based on changes in circulating tumor (ct)DNA. The primary objective of the Phase 3 portion is to demonstrate clinical efficacy of the regimen as assessed by progression-free survival.

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.