Abstract Autologous chimeric antigen receptor (CAR) T-cell therapy have demonstrated remarkable success in the treatment of CD19 and BCMA positive malignancies. However, such success has not been replicated in solid tumor malignancies, possibly due to significant challenges in identifying the right tumor antigen, encouraging tumor homing and infiltration, and overcoming an immunosuppressive tumor microenvironment. Limitations of autologous CAR-T therapy including manufacturing costs and accessibility, inconsistencies in the starting material and long vein-to-vein time restrict the availability of such therapies to a wider patient population. Allogeneic Epstein-Barr virus specific T cells (EBVSTs) have been well tolerated in recent trials, leading to its approval for the treatment of post-transplant lymphoproliferative disease (PTLD) by the European Medicines Agency while currently also under priority review by the FDA. Consequently, CAR EBVSTs have been evaluated in clinic and demonstrated similar tolerability with minimal graft versus host disease. However, there are still significant challenges to the persistence of allogeneic CAR EBVSTs, due to the immune rejection by the patient’s immune system. Granzyme B- and Fas/Fas ligand- initiated caspase-mediated cell death are key mechanisms of allo-rejection by T/NK cells. We thus explored a novel strategy of armoring CAR EBVSTs with an engineered serine protease inhibitor, SerpinB9 (CAS), with broadened specificity to inhibit Granzyme B and caspases. We demonstrate that armoring CAR EBVSTs with SerpinB9 (CAS) not only reduced allo-rejection but also conferred resistance to activation induced cell death (AICD) due to chronic antigen exposure. The B7 homolog 3 protein (B7-H3) is over-expressed in various tumors, stromal and immunosuppressive cells, making it an attractive target for solid tumors. Our data show that SerpinB9 (CAS) armored B7-H3 specific CAR EVBSTs is an attractive strategy that can potentially overcome significant challenges in CAR T therapies for solid tumors, supporting its future development for evaluation in clinic. Citation Format: Lindsay Kua, Pei Yun Teo, Joanna Koh, Jin Wei Tan, Richard Ong, Fiona Wong, Marvin Chew, Angeline Goh, Ivan Horak, Tan Kar WaiLionel Low. Targeting B7-H3 Positive Solid Tumor Malignancies with Chimeric Antigen Receptor Epstein-Barr Virus Specific T Cells Armoured with An Engineered SerpinB9 Molecule for Improved Persistence and Performance abstract. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P30.
Kua et al. (Fri,) studied this question.