Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR) T cell therapy faces challenges in solid tumors like neuroblastoma due to poor tumor trafficking and an immunosuppressive tumor microenvironment (TME).
• Previous GPC2 CAR T cell optimization in xenografts led to clinical translation, but efficacy in immunocompetent models remained unstudied.

Purpose of the Study:

• To evaluate murine GPC2 CAR T cells in neuroblastoma syngeneic allografts.
• To investigate the impact of the TME on CAR T cell persistence and function.
• To engineer CAR T cells to overcome immune suppression mediated by myeloid-derived suppressor cells (MDSCs).

Main Methods:

• Generated murine GPC2 CAR T cells using a clinically relevant single-chain variable fragment.
• Tested CAR T cells in neuroblastoma syngeneic allografts and performed immune profiling.
• Engineered GPC2 CAR T cells to express CXCR2 to target MDSC-recruiting chemokines (CXCL1/2).

Main Results:

• CAR T cell treatment reprogrammed the TME, with poor CAR T cell persistence linked to increased MDSC recruitment via CXCL1/2 chemokines.
• Tumor-infiltrating MDSCs directly inhibited CAR T cell activation, proliferation, and cytotoxicity.
• CXCR2-engineered CAR T cells enhanced anti-neuroblastoma efficacy and reduced MDSCs by migrating towards CXCL1/2 gradients.

Conclusions:

• Immunocompetent models are crucial for understanding solid tumor immune escape mechanisms.
• Rational design of 'armored' CAR T cells, like CXCR2-expressing variants, can improve efficacy and lead to durable responses in neuroblastoma.