Ongoing clinical trials based on combination immunotherapy for CRC treatment.
| Therapy | Targets | Type of cancer, sample size | Efficiency of therapy | Macrophages as indicators of response to therapy | ID clinical trials | Adverse events (rates) |
|---|---|---|---|---|---|---|
| Regorafenib plus nivolumab [117, 124] | Kinase, PD-1 | MSS/pMMR CRC, n = 22 | ORR in 36% of cases (in clinical trial) | CD206+CD11b+ M2-like macrophages within the tumor were significantly higher in responders before treatment | Phase Ib (NCT03406871) | Liver transaminase increased, creatinine increased, and platelet count decreased (the most common, 70% in the clinical trial) |
| Pimitespib plus nivolumab [117, 125] | Hsp90, PD-1 | MSS CRC, n = 23 | ORR in 16% of cases (in clinical trial) | CD206+CD11b+ M2-like macrophages within the tumor were significantly higher in non-responders before treatment | Phase Ib (UMIN000032801) | Rash, proteinuria, palmar-plantar erythrodysesthesia (the most common, grade 3 or worse, 7% in clinical trial) |
| Pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab (group with first-line therapy) [118, 123] | PD-1 | hypermutated CRC, n = 16 | Persistent response in 56% of cases | CD68+CD74+ cells were observed in CRC tumors with a durable response. 80% of CD68+CD74+ cells expressed markers HLA-ABC, HLA-DR, CD40, CD16, and CD163 | Phase 3 (NCT02563002) + patients with first-line therapy | Diarrhea, fatigue, nausea, abdominal pain, anemia, hypertension (97% patients in clinical trial) |
| Oncolytic virotherapy plus LP002 [99] | Tumor cells, PD-1 | MSS CRC with liver metastasis, n = 4 | One out of four patients demonstrated a durable response | Responder had elevated levels of both M1-like and M2-like macrophages | Phase I (NCT04755543) | Fever, nausea, fatigue, constipation, dry mouth (100% patients) |
| Pembrolizumab with or without XL888 [119] | PD-1, Hsp90 | Advanced CRC with liver metastasis, n = 18 | No ORR with combination therapy. 25% of patients had stable disease | Decreased CD68+ and CD68+IL6+ in liver metastasis with combination therapy | Phase Ib/II (NCT03095781) | Diarrhea, fatigue, abdominal pain, constipation, nausea, vomiting, eye disorders, anorexia, hypomagnesemia, cough, increased liver enzymes (grade 3–4, 12.5% patients in combination therapy) |
| Pembrolizumab plus maraviroc [121] | CCR5, PD-1 | pMMR CRC, n = 20 | One patient achieved a partial response, 94.7% patients had disease progression (ORR in 5.3% of cases) | Anti-tumor macrophage activation | Phase I (NCT03274804) | Hyperglycemia (1 case, grade 4) |
| Sintilimab plus chidamide with or without bevacizumab [122] | PD-1, HDAC, VEGF | Unresectable chemotherapy-refractory locally advanced or MSS/pMMR CRC, n = 48 | 18-week PFS of triple combination therapy vs. double combination (64.0% vs. 21.7%) ORR of triple combination therapy vs. double combination (44.0% vs. 13.0%) | Increased the number of monocytic lineage cells in triple therapy responders | Phase 2 (NCT04724239) | Proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia, diarrhea (96% patients in triple combination therapy, 100% patients in double combination therapy) |
CCR5: C-C motif chemokine receptor 5; CRC: colorectal cancer; HDAC: histone deacetylase; MSS: microsatellite stable; ORR: objective response rate; PD-1: programmed cell death-1; PFS: progression-free survival; pMMR: mismatch repair proficient; VEGF: vascular endothelial growth factor.
TS: Writing—original draft, Visualization. KS: Writing—original draft. ES: Writing—original draft, Visualization. PI: Writing—original draft. AD: Writing—review & editing. IL: Conceptualization, Project administration, Writing—review & editing. JK: Conceptualization, Project administration, Writing—review & editing. All authors read and approved the submitted version.
The author declares that there are no conflicts of interest.
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The study was supported by the Russian Science Foundation, grant [RSF 25-25-00904]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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