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Remodeling the immune microenvironment: Engineering IL-2 variants to overcome clinical bottlenecks in PD-1 inhibitor
Ting Yang1, Yiming Lu2, Pengfei Yu3
1Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, China; Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, China.
Abstract:
The perioperative regimen of chemotherapy plus PD-1 inhibitors in gastric cancer has significantly improved event-free survival (EFS), yet its translation into overall survival (OS) benefits remains frequently inadequate, constituting a core clinical dilemma. This review systematically elucidates the potential reasons for the significant improvement in event-free survival (EFS) but insufficient improvement in overall survival (OS) from the perspective of the immune microenvironment, particularly emphasizing the incomplete remodeling of the immunosuppressive microenvironment, which specifically includes the failure to induce stem cell-like memory T cells capable of conferring long-term protection. In this field, current research is increasingly focused on interleukin-2 (IL-2) variants, with PD-1/IL-2 bispecific antibodies, in particular, representing a significant research hotspot that holds considerable promise for achieving breakthroughs. Through precise synergy with existing regimens, they achieve profound immune reprogramming across three dimensions: expanding tumor-specific T cell clones, reversing T cell exhaustion and driving memory differentiation, and inverting the balance between effector cells and suppressor cells in the. Overall, the emergence of PD-1/IL-2 bispecific antibodies, represents a promising approach in cancer therapy with the potential to enhance long-term survival outcomes for patients.
Insights
Perioperative chemotherapy with PD-1 inhibitors improves event-free survival in gastric cancer but not overall survival. Novel PD-1/IL-2 bispecific antibodies show promise for enhancing long-term patient outcomes by reprogramming the tumor immune microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Immunology
Background:
- Perioperative chemotherapy combined with PD-1 inhibitors has shown efficacy in gastric cancer, improving event-free survival (EFS).
- However, this combination frequently fails to translate into significant improvements in overall survival (OS), posing a clinical challenge.
- The inadequacy is linked to incomplete remodeling of the immunosuppressive tumor microenvironment and insufficient induction of long-term protective memory T cells.
Purpose of the Study:
- To systematically review the reasons behind the discrepancy between improved EFS and insufficient OS in gastric cancer patients treated with perioperative chemotherapy and PD-1 inhibitors.
- To explore the role of the immune microenvironment in this context.
- To highlight the potential of novel immunotherapeutic strategies, specifically PD-1/IL-2 bispecific antibodies.
Main Methods:
- Systematic review of existing literature.
- Analysis of the tumor immune microenvironment.
- Focus on the mechanisms of action of PD-1/IL-2 bispecific antibodies.
Main Results:
- The immunosuppressive tumor microenvironment is not fully remodeled by current regimens.
- There is a failure to induce stem cell-like memory T cells crucial for long-term immunity.
- PD-1/IL-2 bispecific antibodies are emerging as a promising therapeutic strategy.
Conclusions:
- PD-1/IL-2 bispecific antibodies offer a potential breakthrough by synergizing with existing treatments.
- These antibodies can induce profound immune reprogramming, including expansion of tumor-specific T cells, reversal of T cell exhaustion, and promotion of memory differentiation.
- This approach may invert the balance of effector and suppressor cells, potentially enhancing long-term survival outcomes in gastric cancer.
