Combined PD-1 and CCR5 Inhibition for the Treatment of Refractory Microsatellite Stable mCRC

Inclusion Criteria: 1. Histologically confirmed metastatic colorectal cancer. Microsatellite stability (MSS) is confirmed by PCR or immunohistochemistry. 2. Patient failed standard therapy or is intolerable towards standard therapy which must include a fluoropyrimidine, oxaliplatin, irinotecan, an antiangiogenic monoclonal antibody (e.g. bevacizumab, aflibercept, ramucirumab), an EGFR inhibitor in case of RAS/BRAF wildtype tumors and optional regorafenib or TAS 102 3. Measurable disease as per RECIST 1.1 4. Metastatic lesion accessible for repetitive biopsies and patient willing to provide tissue from newly obtained biopsies. Patients without accessible lesions might be enrolled after discussion with the principle investigator. 5. ECOG performance status 0 or 1 6. Adequate hematological, hepatic and renal function parameters: * Leucocytes\> 3.000/μl * Hemoglobin \>9 g/dl * Thrombocytes \> 100.000/μl * Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or GFR ≥60 mL/min for subject with creatinine levels \> 1.5 x institutional ULN * Serum total bilirubin ≤ 1.5 x upper limit of normal or direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN * AST and ALT ≤ 2.5 x upper limit of normal (or ≤ 5 x if liver metastases are present) * Albumin ≥ 2.5 mg/dL 7. Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile. 8. Female and male patients' ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and 4 months after the end of the study (appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and doublebarrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception. Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start. 9. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures. Exclusion Criteria: 1. Inability to understand the aims of the study and/or protocol procedures 2. Hypersensitivity towards pembrolizumab, maraviroc, or any ingredients of the formulations administered 3. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies 4. Any other concurrent antineoplastic treatment including irradiation (local radiation of single non-target lesions for palliation only allowed) 5. Active autoimmune disease requiring immunosuppressive therapy 6. Any condition requiring continuous systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks prior to first dose of study treatment. Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. 7. Secondary malignant disease during the last 5 years (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). 8. Clinical relevant comorbidity also including significant psychiatric disease 9. Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV 10. Cardiocirculatory insufficiency with hypotension (systolic blood pressure \<100 mmHg) 11. Cirrhosis of the liver (Child \> Grade A), pronounced alcohol abuse with anticipated detoxification, severe pulmonary infection with considerable reduction of pulmonary function 12. Prior allogeneic bone marrow transplantation 13. Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 therapeutic antibody 14. Administration of a live, attenuated vaccine within four weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 15. Chronic intake of drugs that lead to known interference with Maraviroc metabolism through strong Cytochrome P450 3A4 (CYP3A4) interaction: e.g. Rifampicin, Rifabutin, Clarithromycin, Telithromycin, Ketoconazole, Itraconazole, Fluconazole, Hypericum perforatum (St. John's Worth /Johanniskraut) or any strong CYP3A4 inducing or inhibiting drug (See Section 5.5.2) 16. Positive test for human immunodeficiency virus (HIV) or HIV infection 17. Active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test) or hepatitis C. Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. 18. Active or latent tuberculosis 19. Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy and have no evidence of disease progression on imaging studies (MRI/CT scan). 20. On-treatment participation in another clinical study in the period 30 days prior to start of study treatment and during the study 21. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4) 22. Pregnancy or lactation 23. Known history of, or any evidence of active, non-infectious pneumonitis or interstitial lung disease. 24. Active infection requiring systemic therapy.