This phase II trial studies the effect of fecal microbiota transplant and re-introduction of anti-PD-1 therapy (pembrolizumab or nivolumab) in treating anti-PD-1 non-responders with colorectal cancer that has spread to other places in the body (metastatic). Fecal microbiota transplants contain the normal bacteria and viruses found in fecal (stool) material. Immunotherapy with monoclonal antibodies, such as pembrolizumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab or nivolumab with fecal microbiota transplants may help to control the disease.

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of pembrolizumab or nivolumab in conjunction with fecal microbiota transplant (FMT) from PD-1 responding mismatch-repair deficiency (dMMR) colorectal cancer (CRC) patients for treatment of PD-1 non-responding dMMR CRC patient.

Eligibility Criteria:

Participant Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

1. At least 18 years of age on the day of signing informed consent

2. Histologically/cytologically confirmed diagnosis of solid tumor

3. Tumor that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-H) as determined by one of three methods:

   1. Immunohistochemistry determined dMMR by complete loss of MLH1, PMS2, MSH2 or MSH6
   2. PCR determined microsatellite instability at >30% of tested microsatellites
   3. Next-generation determined MSI-H based upon instability at multiple microsatellites as determined by the specific next generation sequencing panel

4. Have metastatic disease that is measurable based on iRECIST v1.1.

5. Demonstrated prior progression on anti-PD1/L1 based therapy by radiographic progression. The potential for psuedoprogression should be excluded by concurrent carcinoembryonic antigen (CEA) or other tumor marker or ctDNA elevation, or clinical symptom progression, or short interval repeat imaging confirming progression.

   1. Must have received at least 2 doses of a PD1/PD-L1 inhibitor
   2. Progressive disease either during therapy or within 2 months of last dose of therapy.

6. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

7. Patients must be willing to undergone mandatory tumor biopsies at pre-treatment, at time of colonoscopy if possible and on-treatment (unless deemed unsafe by interventional radiology or by approval by study PI).

8. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

9. Estimated life-expectancy of > 4 months.

10. Adequate hematological function, defined by white blood cell (WBC) count ≥ 3,000/microL, platelet count ≥75,000/microL, and Hgb ≥ 8 g/dL.

11. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN)[except if Gilberts syndrome and then total bilirubin ≤ 3x is allowed], an AST, level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN. If liver metastases are present, then AST and ALT levels must be ≤ 4 × ULN

12. Adequate renal function defined by an estimated creatinine clearance >30 mL/min according to the Cockcroft-Gault formula or by a creatinine clearance measurement from a 24-hour urine collection.

13. Highly effective contraception for both male and female subjects if the risk of conception exists. Highly effective contraception must be used 30 days prior to first study-drug administration, for the duration of trial treatment, and for at least for 6 months (women and men after taking your last dose of any of the trial drugs (see Appendix 3 for further details). Should a female patient (or male patient's sexual partner) become pregnant or should either the female patient (or male patient's partner) suspect she is pregnant while the patient's study-participation is ongoing, the treating physician should be informed immediately.

Participant Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

1. Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks of study treatment (excluding continuation of ongoing nivolumab or pembrolizumab therapy).

2. If participant received major surgery within last 4 weeks, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

3. Has an ileostomy or colostomy bag.

4. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities (excluding skin toxicity), not require corticosteroids, and not have had radiation pneumonitis.

5. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

6. Has a diagnosis of immunodeficiency (excluding IgA deficiency).

7. Has an active autoimmune condition and is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

   1. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10mg of prednisone or equivalent per day.
   2. Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.

8. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or nivolumab and/or any of its excipients.

9. Serious adverse immune related adverse events (grade 3 or 4) with previous immune checkpoint therapy, that were symptomatic and required prolong immunosuppression (>6weeks).

10. Has an active infection requiring systemic therapy.

11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the study subject's best interest to participate, in the opinion of the treating investigator.

12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

13. Pregnant or nursing women

14. For women of childbearing age, a positive urine pregnancy test within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.