Immunotherapy for Third Line Metastatic Colorectal Cancer

Inclusion Criteria:

1. Adult males and female subjects aged 18-80 years at screening visit
2. Pathologically confirmed diagnosis of colorectal adenocarcinoma
3. Presenting with metastatic disease:
4. Previous treatment failure of two previous lines of active systemic chemotherapy:

   * Previous chemotherapy must have included an oxaliplatin-containing (e.g. FOLFOX) and an irinotecan-containing (e.g. FOLFIRI) regimen
   * With or without bevacizumab
   * Administered in adjuvant setting or for treatment of metastatic disease
   * If KRAS wild type, must have at least one prior anti-EGFR therapy
   * Treatment failure can be due to disease progression or toxicity
   * Disease progression on second line therapy must be documented radiologically and must have occurred during or within 30 days following the last administration of treatment for metastatic disease
5. ECOG performance score: 0-1
6. Adequate hematological function:

   * Absolute granulocyte count ≥ 1,200/mm3
   * Platelet count ≥ 100,000/mm3
   * PT/INR ≤ 1.5 or correctable to \<1.5 at time of interventional procedures
   * Hemoglobin ≥ 9 g/dL (may be corrected by transfusion)
7. Adequate Organ Function:

   * Creatinine ≤ 1.5 mg/dL
   * Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
   * Alkaline phosphatase ≤ 2.5 times ULN \*
   * Aspartate aminotransferase (AST) or (SGOT) ≤ 2.5 times ULN \*
   * Alanine aminotransferase (ALT) or (SGPT) ≤ 2.5 times ULN \* \*or ≤5x ULN if liver involvement
8. EKG without clinically relevant abnormalities
9. Female subjects: Not pregnant or lactating
10. Patients with child bearing potential must agree to use adequate contraception
11. Study specific informed consent in the native language of the subject.

Exclusion Criteria:

1. high frequency microsatellite instability (MSI-H)
2. Bowel obstruction or high risk for obstruction if tumors become inflamed
3. Moderate or severe ascites requiring medical intervention
4. Clinical evidence or radiological evidence of brain metastasis or leptomeningeal involvement
5. Peritoneal carcinomatosis
6. Symptomatic asthma or COPD
7. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment; or, oxygen saturation \<92% on room air
8. Bevacizumab (Avastin®) treatment within 6 weeks of baseline scheduled biopsy procedure
9. Any of the following mood disorders: active major depressive episode, history of suicidal attempt or ideation
10. Prior allogeneic bone marrow/stem cell or solid organ transplant
11. Chronic use (\> 2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to \> 5 mg/day of prednisone) within 30 days of the first day of study drug treatment

    * Topical corticosteroids are permitted
12. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis).

    * Well controlled Type I diabetes allowed
13. Prior experimental therapy
14. History of blood transfusion reactions
15. Progressive viral or bacterial infection

    * All infections must be resolved and the subject must remain afebrile for seven days without antibiotics prior to being placed on study
16. Cardiac disease of symptomatic nature
17. History of HIV positivity or AIDS
18. Concurrent medication known to interfere with platelet function or coagulation (e.g., aspirin, ibuprofen, clopidogrel, or warfarin) unless such medications can be discontinued for an appropriate time period based on the drug half-life and known activity (e.g., aspirin for 7 days) prior to biopsy procedures
19. History of severe hypersensitivity to monoclonal antibody drugs
20. Psychiatric or addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation.
21. Subjects that lack ability to provide consent for themselves.