The purpose of this study is to evaluate the safety and clinical activity of nivolumab and relatlimab in patients with metastatic or locally advanced microsatellite stable (MSS) colorectal cancer.

Inclusion Criteria:

• Age ≥18 years.
• ECOG performance status 0 or 1
• Have metastatic or locally advanced microsatellite stable (MSS) colorectal adenocarcinoma.
• Cohort A: Primary lesion has a composite PD-L1/Mucin (CPM) score ≥ 15%.
• Cohort B: Primary lesion has a composite PD-L1/Mucin (CPM) score < 15%.
• Cohort C: Prior surgical resection of primary tumor. Prospective biomarker evaluation not required.
• Must have received at least one chemotherapy regimen.
• Patients with the presence of at least one measurable lesion using RECIST 1.1.
• Patients must have available archival tissue from the surgical resection of their primary tumor.
• Patient's acceptance of tumor biopsies.
• Life expectancy of greater than 3 months.
• Patients must have adequate organ and marrow function defined by study - specified laboratory tests.
• Documented LVEF ≥ 50% - 6 month prior to drug administration.
• Must use acceptable form of birth control while on study.
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Known history or evidence of brain metastases. Patients with previously treated brain metastases may participate if they are stable for 4 weeks prior to beginning treatment, have no new or enlarging brain metastases, and are not using steroids for at least 1 week prior to initiation of study treatment.
• Require any antineoplastic therapy.
• History of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or anti-Lag-3 antibodies.
• Had chemotherapy, radiation, or steroids within 14 days prior to study treatment.
• Had any cytotoxic drug within 4 weeks prior to initiation of study treatment.
• Hypersensitivity reaction to any monoclonal antibody.
• Has uncontrolled intercurrent acute or chronic medical illness.
• Has an active known or suspected autoimmune disease.
• Has a diagnosis of immunodeficiency.
• Prior tissue or organ allograft or allogeneic bone marrow transplantation.
• Requires daily supplemental oxygen
• History of interstitial lung disease.
• Requires daily supplemental oxygen.
• Significant heart disease
• History of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.
• Infection with HIV or hepatitis B or C at screening.
• Has an active infection.
• Unable to have blood drawn.
• Patient with uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Woman who are pregnant or breastfeeding.