Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density

TL;DR

Engineered T cells using antibody-T cell receptors targeting GPC2 show better results than CAR T cells in treating neuroblastoma, even when the tumor has low antigen levels.

Contribution

Engineering T cells with antibody-T cell receptors (AbTCRs) targeting GPC2 improves efficacy in neuroblastoma therapy compared to CAR T cells.

Findings

hCT3 AbTCR T cells induce regression in neuroblastoma with low GPC2 antigen density.

Enhanced efficacy is linked to stronger TCR signaling and increased CD8+ T cell infiltration.

AbTCR T cells show superior antitumor efficacy compared to CAR T cells in neuroblastoma.

Abstract

Chimeric antigen receptor (CAR) T cells have shown promise in hematological cancers but face challenges in solid tumors, partly due to heterogeneous antigen density. Glypican-2 (GPC2) is an oncofetal antigen highly expressed in neuroblastoma and under evaluation in phase 1 clinical trials. Here, we engineer T cells with antibody-T cell receptors (AbTCRs) targeting GPC2. We generate autologous AbTCR T cells using CT3 or humanized CT3 (hCT3) antigen-binding fragments (Fab) linked to γ/δ T cell receptors (TCRs), along with a CD30 co-stimulatory domain. Both CT3 and hCT3 AbTCR T cells show superior antitumor efficacy compared to CT3 CAR T cells, with hCT3 AbTCR T cells inducing significant regression in neuroblastoma with low GPC2 antigen density. Enhanced efficacy is associated with stronger TCR signaling, expansion of stem cell-like memory T cells, and improved CD8+ T cell infiltration. These results highlight the potential of hCT3 AbTCR T cells for neuroblastoma and indicate broad application of AbTCR T cells in solid tumors.

•T cells are engineered with AbTCRs by fusing antibody Fab fragments to γ/δ TCRs•hCT3 AbTCR T cells targeting GPC2 regress neuroblastoma with low antigen density•AbTCR efficacy is linked to improved CD8+ T cell infiltration and TCR signaling•hCT3 AbTCR T cells show promising potential for neuroblastoma therapy

T cells are engineered with AbTCRs by fusing antibody Fab fragments to γ/δ TCRs

hCT3 AbTCR T cells targeting GPC2 regress neuroblastoma with low antigen density

AbTCR efficacy is linked to improved CD8+ T cell infiltration and TCR signaling

hCT3 AbTCR T cells show promising potential for neuroblastoma therapy

Quan et al. demonstrate that T cells engineered with antibody-T cell receptors (AbTCRs) targeting GPC2 outperform CAR T cells in neuroblastoma, showing improved efficacy due to stronger TCR signaling, greater memory T cell expansion, and increased CD8+ T cell infiltration, offering promising potential for neuroblastoma therapy.

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