Cancer immunotherapy with immunostimulatory antibodies targeting the CTLA-4 or PD-1/PD-L1 pathways has demonstrated its efficacy in variable proportions of cancer. For metastatic colorectal cancer (mCRC) it appeared that only the small subgroup of patients with MSI-H tumors (microsatellite instability-high phenotype) had a clinically meaningful response to the anti-PD-1- L1 antibodies. In the majority group of non-MSI-H CRC (90-95% of patients), current research expect that additional means would be able to render the tumor "immunogenic" (like MSI-H CRC) and increase the intratumoral immune infiltrate which is the prerequisite to observe a benefit from PD1-PD-L1 inhibitors. Combinations of immune checkpoint inhibitors and procedures that increase intratumoral immune responses, such as targeted therapy, are actively explored.

Inclusion Criteria:

• Age 18 and over, Performance status: ECOG 0-1
• Histologically proven metastatic colorectal adenocarcinoma, refractory to standard chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan) and anti-EGFR treatment (only for RAS WT tumor)
• Measurable disease (RECIST 1.1)
• Metastasis accessible for sequential biopsies
• Patient consent for metastasis biopsies in the study protocol
• BRAF V600E wild-type and MSS tumors
• Adequate normal organ and marrow function (see adequate section of the full protocol for definition)
• Life expectancy of at least 4 months

Exclusion Criteria:

• Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy that are not indicated in the study protocol
• Systemic autoimmune disease,
• Chronic treatment with corticoids or other immunosuppressive treatment
• Clinically significant cardiac, lung or general disease despite optimal treatment
• Non-progressive disease following irinotecan-based treatment.
• For RAS WT, non-progressive disease following anti-EGFR treatment.