Combined Immunotherapy and Radiosurgery for Metastatic Colorectal Cancer

Inclusion Criteria: Disease factors * Histologically- or cytologically-confirmed diagnosis of colorectal cancer (CRC). * Metastatic or recurrent CRC, deemed surgically or medically unresectable. * Subjects have received two or more standard available therapies known to prolong survival and for which they would be considered eligible, whether in adjuvant or metastatic setting. Such therapies should include regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine, if appropriate (e.g., FOLFOX and FOLFIRI, or their variants). Subjects that are unable to receive oxaliplatin and/or irinotecan due to allergy or hypersensitivity, or due to concerns regarding the side effects of oxaliplatin and/or irinotecan, will be allowed to receive less than two lines of standard therapies prior to enrollment to this study. * Patients must have at least two liver metastases, separated by ≥2 cm, and measured in at least one dimension (longest diameter) as ≥2 cm by CT/MRI. One of the metastases must be amenable to biopsy and SBRT. General considerations * Age ≥18 years. * ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A). * Life expectancy of ≥ 3 months * Patients must have normal organ and marrow function as defined below: * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * hemoglobin ≥ 9.0 g/dL * total bilirubin ≤ 1.5 x ULN except subjects with Gilbert Syndrome who must have a total bilirubin level \< 3.0 mg/dL). * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal * creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 mL/min (using the Cockcroft Gault formula) * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment. * Signed Written Informed Consent * Subjects must have signed and dated an IRB approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. * Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing. Exclusion Criteria: Disease factors / Tumor characteristics * Has an MSI-H phenotype or a known MMR deficiency. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. Previous treatments and trials * Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 3 weeks of the first dose of treatment. * Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. * Has had prior chemotherapy, targeted small molecule therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.° Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. * If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Comorbidities, medications and immune modulation agents * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. * Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with type I diabetes mellitus, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects that require intermittent use of bronchodilators or local steroids, e.g., inhaled or topical steroids, at a dose of less than the equivalent of 10mg prednisone daily, would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. * Has evidence of interstitial lung disease or active, non-infectious pneumonitis. * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. * 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. * Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Has received a live vaccine within 30 days prior to the first dose of trial treatment. * Known medical condition that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results. * History of allergy or hypersensitivity to any study drug components, to compounds of similar chemical or biologic composition * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Previous stem cell transplant. * Significant bleeding event within the last 12 months that places the patient at risk for intrahepatic IT injection procedure based on Investigator assessment. * Anticoagulant or anti-platelet medication that cannot be interrupted prior to CMP-001 intratumoral injection, including: * Aspirin that cannot be discontinued for 7 days prior to CMP-001 intratumoral injection. * Coumadin that cannot be discontinued for 7 days prior to CMP-001 intratumoral injection. * Low molecular weight heparin (LMWH) that cannot be discontinued \>24 hours prior to CMP-001 intratumoral injection. * Unfractionated heparin (UFH) that cannot be discontinued \>4 hours prior to CMP-001 intratumoral injection. * Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban, apixiban, and endoxaban) that cannot be discontinued for 4 days prior to CMP-001 intratumoral injection. * NOTE: LMWH or UFH may be used to transition patients on and off of the above anti-coagulants (if deemed appropriate by the treating physician) prior to CMP-001 intratumoral injection as long as the last dose of LMWH is administered \>24 hours prior to treatments and last dose of UFH is administered \>4 hours prior to treatments.