Combination Immunotherapy for the Treatment of Chemotherapy-refractory Metastatic MSS CRC

Inclusion Criteria:

* Patients must have a pathologically confirmed diagnosis of non-MSI-H/pMMR CRC.
* Patients must have progressed (clinically or radiographically) on or after standard chemotherapy, including fluoropyrimidines, oxaliplatin, and irinotecan, or are intolerant to standard chemotherapy. Patients may have received, if eligible, anti-VEGF or anti-EGFR antibodies in combination with chemotherapy.
* Patients must have at least 1 measurable target lesion at baseline ≥ 10mm in the longest diameter.
* Patient must be willing and able to provide blood samples (6 heparinized, and two streck tubes, roughly 70 - 80 mL) at the time points indicated in the Study Calendar.
* Patients must have at least 1 lesion suitable for core needle biopsies.
* Patients must be willing and able to have core needle biopsies, if clinically feasible (Goal 3-6 biopsies, final number to be determined by the interventionalist performing the procedure as safe), of tumor prior to initiation of study drug. Should patients undergo pre-treatment or on-treatment biopsy procedure and inadequate number of biopsies are obtained, they may proceed with initiation/continuation of treatment at the discretion of the investigator and treating physician.
* Age ≥ 18 years.
* ECOG Performance Status 0-1 (Karnofsky ≥60%, see https://ecog-acrin.org/resources/ecog-performance-status/). o Patients with performance status \>1 carrying long-term disability (such as cerebral palsy) where the disability is not acute nor progressive, and unlikely to significantly affect their response to therapy may be enrolled at the investigator's discretion
* Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months following completion of therapy. Should a study participant become pregnant or suspect pregnancy while participating in this study, the study participant should inform the treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: o Has not undergone a hysterectomy or bilateral oophorectomy; or o Has not been naturally postmenopausal for at least 12 consecutive months
* Ability to understand and the willingness to sign a written informed consent. • Adequate organ and marrow function

Exclusion Criteria:

* Patients who have had chemotherapy within 14 days from start of therapy.
* Palliative radiotherapy is permitted at anytime, if deemed in the best interest of the patient.
* Patients may not be receiving any other investigational agents.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (exception is a brief (≤10days) course of antibiotics to be completed before initiation of treatment), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients who have undergone major surgery within 4 weeks prior to the first dose of treatment.
* Patients who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
* Patients who discontinued prior immune checkpoint inhibitors due to immune-related adverse events are not eligible for enrollment.
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients on chronic steroids (more than 4 weeks at stable dose) equivalent to ≤ 10mg prednisone will not be excluded.
* Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
* HIV positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen, or with \<200 CD4+ T cells/microliter in the peripheral blood. HIV testing is mandatory for patients with no known history of HIV. For such patients HIV testing will be considered SOC.
* Has known active Hepatitis B (e.g., HBV detected by PCR or active Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). Patients with hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.
* History of allogeneic hematopoietic cell transplantation or solid organ transplantation.
* Receipt of a live vaccine within 28 days of planned start of study medication.
* Receipt of etanercept or other TNF-α inhibitors within 28 days of planned start of the study medication.
* Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor traps).
* Principal investigator believes that for one or multiple reasons the patient will be unable to comply with all study visits, or if they believe the trial is not clinically in the best interest of the patient.
* History of irAE in response to prior immunotherapy that has not improved to a Grade 0 or 1; this does not include chronic conditions such as endocrinopathies which can be treated with hormone replacement therapy.
* History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis attributed to prior use of cancer immunotherapy that required immune-suppressive doses of glucocorticoids to assist with management. A history of radiation pneumonitis in the radiation field is permitted.