Botensilimab, Balstilimab, and SBRT in Colorectal Cancer

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed adenocarcinoma of colorectal origin.
* MSS or pMMR status confirmed by IHC or PCR.
* Must have at least 1 measurable (≥ 1 cm) previously unirradiated hepatic lesion amenable to ablative RT and meeting dose constraints. A maximum of 5 hepatic lesions are allowed provided all are amenable to ablative RT and meet dose constraints. Must have at least 1 other unirradiated measurable (≥ 1cm) extrahepatic lesion, outside of RT field. Patients should ideally have a second unirradiated lesion, outside of RT field, that would be amenable for paired biopsies.
* Must have received or confirmed intolerance to 5-FU, Oxaliplatin, and Irinotecan (in any combination).
* Age ≥18 years
* ECOG performance status ≤ 1
* Life expectancy of greater than 3 months.
* Participants must meet the following organ and marrow function as defined below:

  * Absolute Neutrophil Count (ANC) ≥ 1500 /mcL
  * White Blood Cells (WBC) ≥ 2000 /mcL
  * Platelets (PLT) ≥ 100,000 /mcL
  * Hemoglobin (HGB) ≥ 8 g/dL without transfusion within 2 weeks of measurement
  * AST and ALT ≤ 2.5 x ULN
  * Total Bilirubin ≤ 1.5 x ULN OR \< 3 mg/dL for participants with Gilbert Syndrome
  * Creatinine Clearance ≥ 40 mL/min if calculated using Cockcroft-Gault formula
* The effects of radiation on the developing human fetus are known to be teratogenic and the safety of Botensilimab and Balstilimab in pregnant women and their fetuses has not been established.

  --Woman of childbearing potential (WOCBP) and men with WOCBP partners must agree to use highly effective contraceptive measures starting at screening through 5 months (180 days) after the last dose of balstilimab and/or botensilimab.
* WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG).
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Participants who have had chemotherapy, targeted small molecule therapy or study therapy within 14 days prior to starting protocol treatment, or those who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier.

  * EXCEPTION: Participants with ≤ Grade 2 neuropathy are permitted.
  * If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting protocol treatment.
* Known or suspected, active, autoimmune disease
* Condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to study drug administration.

  --EXCEPTIONS: Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \>10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
* Positive TB (Bacillus Tuberculosis) at screening. NOTE: skin test is not allowed. Interferon-Gamma Release Assay (IGRA)-based tests such as QuantiFERON TB Gold and T-Spot TB tests are acceptable.
* Partial or complete bowel obstruction within the last 3 months, signs/ symptoms of bowel obstruction, or known radiologic evidence of impeding obstruction.
* Refractory ascites defined as requiring 2 or more therapeutic paracenteses within the last 4 weeks, or ≥ times within the last 90 days, or ≥ time within the last 2 weeks prior to study entry, or requiring diuretics within 2 weeks of study entry.
* Known history of active or chronic HBV or HCV infection
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). These participants are at increased risk of lethal infections when treated with marrow-suppressive therapy.

  \-- EXCEPTIONS: Patients with CD4 \>200 cells/mm3 and/or undetectable viral load are eligible.
* 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.
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Participant is pregnant, breastfeeding, expecting to conceive, or father children within the projected duration of the trial, starting with the consent visit through 120 days for woman and 120 days for men, after the last dose of study treatment.

There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with radiation, breastfeeding should be discontinued if the mother is treated with radiation.

* Known history of, or any evidence of active, non-infectious pneumonitis.
* Active infection requiring systemic therapy.
* Has received a live vaccine within 30 days of planned start of study therapy. Intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

  --EXCEPTION: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to any study agents.
* History of severe hypersensitivity reaction to any monoclonal antibody.
* Uncontrolled brain metastases. Participants treated with radiation \> 4 weeks prior to registration, with follow up imaging showing control are eligible.
* Participants who present with significant active diarrhea.