To treat neuroblastoma expressing the oncofetal antigen GPC2, Quan and Huo et al. generated "AbTCR-T cells" expressing (1) anti-GPC2 Fab linked to TCRγδ and (2) anti-GPC2 scFv linked to a CD30 costimulatory domain. The GPC2-binding domain was humanized from the murine CT3 antibody, and retained specific GPC2 binding. Compared to CAR-T, AbTCR-T had superior cytotoxicity, tumor T cell infiltration, and in vivo efficacy against tumors with high or, in particular, low antigen expression. AbTCR-T also maintained a less exhausted and more stem-like phenotype, improving serial cytotoxicity, and augmented endogenous TCR and NFAT signaling.
Contributed by Alex Najibi
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 _/_ 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.
Author Info: (1) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (2) Laboratory of Molecular
Author Info: (1) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (2) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (3) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (4) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (5) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (6) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (7) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (8) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (9) Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. (10) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (11) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (12) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (13) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (14) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (15) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (16) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (17) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (18) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (19) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (20) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. Electronic address: homi@mail.nih.gov.
