Inclusion Criteria for Cohort A and B:
- Age ≥70 years.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 -2
- Have histologically proven localized or locally advanced mismatch repair deficient (dMMR) or microsatellite unstable (MSI-H) colorectal cancer.
- Must not have received any prior systemic treatment or radiation.
- Must be agreeable to endoscopic, and CT surveillance for a total of 24 months.
- Patient's acceptance to have a tumor biopsy.
- Patients must have adequate organ and marrow function defined by study-specified laboratory tests and procedures.
- LVEF assessment with documented LVEF ≥ 45% by either TTE or MUGA (TTE preferred) within 6 months from first study drug administration.
- For both Women and Men, must use acceptable form of birth control while on study.
- Ability to understand and willingness to sign a written informed consent document.
Inclusion Criteria for Cohort C and D:
- Age ≥18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 -3.
- Have histologically proven localized or locally advanced mismatch repair deficient (dMMR) or microsatellite unstable (MSI-H) colorectal cancer.
- Patient deemed a poor surgical candidate after evaluation by a surgeon or unwilling to undergo surgery.
- Must not have received any prior systemic treatment or radiation.
- Must be agreeable to endoscopic, and CT surveillance for a total of 24 months.
- Patient's acceptance to have a tumor biopsy.
- Patients must have adequate organ and marrow function defined by study-specified laboratory tests and procedures.
- For both Women and Men, must use acceptable form of birth control while on study.
- Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria for Cohorts A and B:
- Have received an investigational agent or used an investigational device within 28 days of the first dose of study drug.
- Have expected to require any other form of systemic or localized antineoplastic therapy while on study.
- Have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.).
- History of prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, or anti-Lag-3 antibodies for any reason in the 5 years proceeding their colorectal cancer diagnosis.
- Currently using any chronic systemic steroids.
- Patient has received a live vaccine within 30 days of the first dose of study drug.
- History of severe hypersensitivity reaction to any monoclonal antibody.
- Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements.
- Active autoimmune disease.
- Any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft.
- Patient has a pulse oximetry of <92% on room air.
- Patient is on supplemental home oxygen.
- Has clinically significant heart disease.
- Cohort B Only: Troponin T (TnT) or troponin I (TnI) > 2x institutional ULN at baseline.
- Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures.
- Unwilling or unable to follow the study schedule for any reason
Exclusion for Cohort C and D:
- Have received an investigational agent or used an investigational device within 28 days of the first dose of study drug.
- Have expected to require any other form of systemic or localized antineoplastic therapy while on study.
- Currently using any chronic systemic steroids.
- Patient has received a live vaccine within 30 days of the first dose of study drug.
- History of severe hypersensitivity reaction to any monoclonal antibody.
- Any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft.
- Patient is pregnant or breastfeeding.
- Cohort D Only: Troponin T (TnT) or troponin I (TnI) > 2x institutional ULN at baseline.
- Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures.
- Participation deemed not in the best interest of the patient.
- Unwilling or unable to follow the study schedule for any reason.