Editor’s Note: Despite the success of immune checkpoint inhibitors (ICIs) in GI tumors, immune resistance and the immunosuppressive tumor microenvironment (TME) remain major barriers. At a recent symposium, Prof. Kohei Shitara (National Cancer Center Hospital East, Japan) outlined emerging strategies to overcome immune evasion.
01. TIGIT and CTLA-4
TIGIT is expressed on Tregs, CD8+ T cells, and NK cells, yet early studies (e.g., tiragolumab) failed to show survival benefit, likely due to Fc-mediated depletion of effector T cells.
Fc-Silent Strategy:
Fc-silent antibodies such as domvanalimab focus on signal blockade. Positive EDGE-Gastric data led to the Phase 3 STAR-221 trial. PD-1/TIGIT bispecifics may further enhance efficacy.
CTLA-4 Evolution:
The Fc-silent PD-1/CTLA-4 bispecific cadonilimab improved survival versus chemotherapy, particularly in CPS <5 patients. In MSS CRC with liver metastases, Fc-active CTLA-4 plus PD-1 remains effective in select settings.
02. TME Remodeling
High infiltration of PD-1+ Tregs and M2 macrophages correlates with resistance.
Anti-angiogenic Combinations:
While lenvatinib + pembrolizumab failed in CRC, zanzalintinib + atezolizumab outperformed regorafenib in MSS CRC, likely due to broader VEGF, MET, and TAM inhibition.
Bispecifics and Cytokines:
PD-1/VEGF bispecifics and PD-1–IL-2 or IL-15 constructs aim for localized immune activation with reduced systemic toxicity.
03. Targeting Suppressive Cells
LIF Inhibitors:
A randomized Phase 2 study showed that adding a LIF inhibitor to chemotherapy and nivolumab met its PFS endpoint. ORR reached 16% in ICI-pretreated gastric cancer.
CCR8 Depletion:
CCR8 is a specific marker of tumor-infiltrating Tregs. Anti-CCR8 antibodies achieved ~30% ORR in ICI-resistant gastric cancer, including liver metastases.
04. Immune Expansion
mRNA Vaccines:
Personalized neoantigen vaccines induce antigen-specific CD8+ T-cell responses in ~50% of patients, enhancing benefit from subsequent PD-1 therapy.
Microbiome:
Specific gut microbes improve PD-1 efficacy by promoting dendritic cell maturation and polyclonal T-cell responses.
05. T-Cell Engagers
CLDN18.2:
CLDN18.2-targeted T-cell engagers show ~30% ORR in ICI-resistant gastric cancer, including liver metastases, though CRS requires careful management.
DLL3:
In extrapulmonary neuroendocrine carcinoma, DLL3-targeted BiTEs showed strong efficacy in high-expression tumors. CRS occurred in ~60% of patients, mostly Grade 1–2 and manageable.
Conclusion and Outlook
GI immunotherapy is moving beyond single checkpoint blockade toward multi-dimensional immune modulation, integrating tumor-specific and immune biomarkers to better match patients with optimal immunotherapeutic strategies
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