Challenges to addressing the unmet medical needs for immunotherapy targeting cold colorectal cancer

Table 1 Key categories for non-clinical strategies to overcome obstacles in cancer immunotherapy

Strategy	Therapeutic approach	Ref.
Increase in antigen-specific T-cells and T-cell priming	Adoptive cell therapy (CAR-T and -NK)	[30-44,49]
	Adjuvant immunotherapy
	Epigenetic modification inhibitors
	Cancer vaccine
	Oncolytic viruses
	Combined with conventional therapies
Promoting T-cell trafficking and infiltration	TGF-β suppression	[50-58,60,61]
	Oncogenic pathway inhibitors
	Angiogenesis inhibitors
	CXCR4 inhibitors
	Immunocytokines

CAR: Chimeric antigen receptor; NK: Natural killer; TGF: Transforming growth factor; CXCR: C-X-C motif chemokine receptor.

Table 2 A list of completed clinical trials to improve response to immunotherapies targeting colorectal cancer

Regimen	NCT number	Outcome	Completion
T-cell bispecific antibody and CEA combined with atezolizumab	NCT02650713	20% PR and 50% SD	January 2020
Copanlisib plus nivolumab	NCT03711058	No results available	January 2022
Fruquintinib plus geptanolimab	NCT03977090	26.7% ORR, 80% DCR, and 7.33 mo median PFS	December 2021
Regorafenib plus toripalimab	NCT03946917	15.2% ORR and the 36.4% DCR	November 2021
Durvalumab plus tremelimumab	NCT02870920	2% DCR, 1.8 mo PFS, and 6.6 mo OS	December 2021
Anti-TGF-β antibody plus spartalizumab	NCT02947165	Clinical proof of concept with 2 PR cases	June 2021
Pembrolizumab plus celebrex	NCT03638297	83.3% ORR, 12.5% SD, and 4.2% PD	August 2021
Durvalumab and tremelimumab plus FOLFOX	NCT03202758	31.2% PR and CR, 25% SD, and 6 mo PFS	August 2020

CR: Colorectal; CEA: Carcinoembryonic antigen; PR: Partial response; SD: Stable disease; ORR: Objective response rate; DCR: Disease control rate; PFS: Progression-free survival; OS: Overall survival; PD: Progression disease; FOLFOX: Folinic acid, fluorouracil, and oxaliplatin; TGF: Transforming growth factor.

Table 3 Ongoing clinical trials to improve response to immunotherapies targeting colorectal cancer

Strategy	NCT number	Intervention
Targeting tyrosine kinase	NCT04764006	Surufatinib (VEGFR1, VEGFR2, VEGFR3, FGFR1, and CSF-1R inhibitor)
	NCT04819516	High-intensity focused ultrasound therapy; toripalimab (anti-PD-1 antibody)
	NCT04963283	Cabozantinib (anti-VEGFR2) plus nivolumab (anti-PD-1 antibody)
Targeting TGF-β	NCT03724851	TEW-7197 (TGF-β receptor ALK4/ALK5 inhibitor)
Targeting Wnt signaling	NCT02521844	ETC-159 (Porcupine inhibitor) plus Pembrolizumab (anti-PD-1 antibody)
Combination with chemotherapy	NCT04301557	Pembrolizumab plus binimetinib (MEK 1/2 inhibitor) plus FOLFOX plus irinotecan
	NCT04895137	FOLFOX6 plus bevacizumab (anti-VEGF A) plus anti-PD-1 antibody
	NCT03374254	Anti-PD-1 antibody plus oxaliplatin plus capecitabine plus radiotherapy then mesorectal excision
Cancer vaccine	NCT04046445	ATP128 (chimeric recombinant protein vaccine) plus BI754091 (IgG4Pro antibody inhibitor) plus VSV-GP128 (recombinant vesicular stomatitis virus)
	NCT04117087	KRAS peptide vaccine plus nivolumab (anti-PD-1 antibody) plus ipilimumab (anti-CTLA4 inhibitor)
	NCT04912765	Neoantigen dendritic cell vaccine plus nivolumab

VEGFR: Vascular endothelial growth factor receptor; FGFR1: Fibroblast growth factor receptor 1; CSF-1R: Colony stimulating factor 1 receptor; PD-1: Programmed cell death 1; TGF-β: Transforming growth factor beta; MEK 1/2: Mitogen-activated protein kinase 1/2; FOLFOX: Folinic acid, fluorouracil, and oxaliplatin; VEGF A: Vascular endothelial growth factor A; CTLA4: Cytotoxic T lymphocyte antigen-4.