The purpose of this study is to evaluate the safety and clinical activity of combining cemiplimab, cemiplimab/fianlimab, or cemiplimab/REGN7075 with capecitabine/oxaliplatin (CAPOX) for the neoadjuvant treatment of patients with microsatellite stable (MSS) locally advanced rectal cancer (T2 node-positive, T3 node-negative, T3 node-positive).

Inclusion Criteria:

• Age ≥18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1.

• Rectal cancer (with tumor tissue present at or below the peritoneal reflection) as determined by MRI pelvis or endoscopic ultrasound.

• Have histologically proven mismatch repair proficient (pMMR) or microsatellite stable (MSS) rectal adenocarcinoma.

• Must not have received any prior systemic treatment or radiation.

• Candidate for sphincter-sparing surgical resection after neoadjuvant therapy according to the primary surgeon.

• Patients have the following clinical staging:

  • cT2 node-positive:
  • T: Tumor is invading the muscularis propria but has not grown through it to the serosa
  • N: At least 1 perirectal lymph node ≥5 mm and no more than 4 perirectal lymph nodes >10 mm in short axis
  • M: No evidence of metastasis
  • cT3 node-negative
  • T: Tumor has grown through the muscularis propria into the serosa but has not invaded nearby organs
  • N: No perirectal lymph nodes ≥ 5 mm in size that suggest tumor involvement
  • M: No evidence of metastasis
  • cT3 node-positive
  • T: Tumor has grown through the muscularis propria into the serosa but has not invaded nearby organs
  • N: At least 1 perirectal lymph node ≥ 5 mm and no more than 4 perirectal lymph nodes > 10 mm in size in short axis
  • M: No evidence of metastasis

• Absence of distant metastases on CT or MRI imaging

• Patients must have adequate organ and marrow function defined by study-specified laboratory tests and procedures.

• LVEF assessment with documented LVEF ≥ 50% 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.

Exclusion Criteria:

• 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.
• Currently using any chronic systemic steroids.
• History of severe hypersensitivity reaction to any monoclonal antibody.
• History of encephalitis, meningitis, dementia, Parkinson's or uncontrolled seizures within 1 year prior to the first dose of study drug.
• Uncontrolled infection of HIV, HBV, HCV, or Tuberculosis.
• 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.
• 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.
• Patient is pregnant or breastfeeding.
• Unwilling or unable to follow the study schedule for any reason.
• Patient received a live vaccine within 30 days of planned start of study medication.
• Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication.
• Patients with T4 disease or N2 disease (as defined by >/= 4 lymph nodes, each greater or equal to 10 mm in short axis).
• Evidence that the tumor is adjacent to (defined as within 3 mm of) the mesorectal fascia on pre-operative MRI or endorectal ultrasound or pelvic CT scan.
• Patients with symptomatic untreated bowel obstruction due to rectal cancer.