This is a Phase II, single arm study looking at the rate of major clinical response and non-operative management in Stage II and III colon cancer after 18 weeks (up to 6 cycles) of neoadjuvant dostarlimab.

The purpose of this research study is to look at the effects of the immunotherapy drug dostarlimab on dMMR colon cancer tumors and to see if these patients can avoid surgical resection, with the option to go to surgery only if the tumor does not respond.

Inclusion Criteria:

• Capable of understanding and complying with the protocol requirements and have signed the informed consent document. Patients with mild cognitive impairment may be considered for enrollment in the study if their legally authorized representative provides written informed consent for the patient.
• 18 years or older in age
• Biopsy proven dMMR (by IHC), Stage II or III colon cancer per CT imaging correlation with AJCC 8th edition, 2017, amendable to en block surgical resection as determined by colorectal surgeon.
• Biopsy specimen for diagnosis of dMMR Colon cancer should have enough tissue for minimum 4 and max 6 adjacent unstained FFPE slides (4µm each) as determined by Protocol Pathologist Dr. Anthony Snow for CD3+ and CD8+ analysis. If there is not enough tissue present in original sample, a repeat colonoscopy and biopsy may be performed; otherwise patient is not eligible.
• Potentially surgically resectable Stage II or III patients who are willing to forgo surgical resection if study endpoints are met. Patient with easily manageable bowel changes amenable to laxatives or stool softeners as outpatient per assessment by colorectal surgery are allowed. (See exclusion criteria #2)
• ECOG performance status less than or equal to 1
• Absence of metastatic disease on CT CAP with Contrast within 28 days from treatment start
• Absolute neutrophil count greater than or equal to 1,500/µL
• Platelets greater than or equal to 100,000/µL
• Hemoglobin greater than or equal to 9 g/dL
• Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) or calculated creatinine clearance 60mL/min using the Cockcroft-Gault equation
• Total bilirubin less than or equal to 1.5 x ULN (less than or equal to 2.0 in patients with known Gilberts syndrome) OR direct bilirubin less than or equal to 1 x ULN
• Aspartate aminotransferase and alanine aminotransferase less than or equal to 3.0 x ULN
• International normalized ratio (INR) or prothrombin time (PT) less than or equal to 1.5× ULN unless patient is receiving anticoagulant therapy if PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) less than or equal to 1.5× ULN unless patient is receiving anticoagulant therapy if PT or PTT is within therapeutic range of intended use of anticoagulants
• Participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to taking study treatment and agree to use an adequate method of contraception from screening through 180 days after the last dose of study treatment. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner starting with first dose of study treatment through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

Exclusion Criteria:

• Synchronous primary tumor (i.e. more than 1)
• Obstruction or perforation requiring diverting ostomy or immediate resection, or bright red blood per rectum requiring urgent blood transfusion, from their primary tumor.
• Clinical T4b tumors
• Known hypersensitivity to dostarlimab components or excipients.
• Major surgery less than or equal to 3 weeks prior to initiating protocol therapy
• Received investigational therapy less than or equal to 3 months, or within a time interval less than at least 5 half- lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
• Heavy bleeding from the colon cancer tumors requiring PRBC transfusions that would require palliative surgical resection
• Concurrent, clinically significant, active malignancies within two years of study enrollment.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, glucocorticoids, or immunosuppressive drugs). Other than Replacement hormone therapy with thyroxine for hypothyroidism , insulin for T1 diabetes mellitus , or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.)
• Diagnosis of immunodeficiency or has received any systemic glucocorticoid therapy or any other form of immunosuppressive therapy within 7 days prior to initiating protocol therapy.
• History of greater than or equal to Grade 3 immune-related AE with prior immunotherapy, except for non-clinically significant lab abnormalities.
• Patients with known HIV (Human Immunodeficiency Virus) infection on effective retroviral therapy regardless of CD4 count who have had an opportunistic infection within the past 12 months.
• Organ transplant recipients on immunosuppressive medications
• Patients with chronic HBV infection with active disease who meet the criteria for anti HBV therapy but not on suppressive antiviral therapy prior to initiation of treatment of this protocol are excluded. Also, patients with history of HCV infection that have not completed curative antiviral treatment and the HCV viral load is not below the limit of quantification areexcluded.(e.g. a patient who is HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution is eligible.)
• Prior history of interstitial lung disease.
• Received a live vaccine within 30 days of initiating protocol therapy.
• Not enough tissue for confirming dMMR status and CD3+ /CD8+ testing
• 19. Patients with severe cognitive impairment.