ABSTRACT
The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.
Subject(s)
Immunotherapy, Adoptive , Receptors, Chimeric Antigen , Receptors, Immunologic , Receptors, Tumor Necrosis Factor, Member 14 , Tumor Microenvironment , Animals , Humans , Immunotherapy, Adoptive/methods , Receptors, Tumor Necrosis Factor, Member 14/metabolism , Receptors, Tumor Necrosis Factor, Member 14/immunology , Receptors, Tumor Necrosis Factor, Member 14/genetics , Mice , Tumor Microenvironment/immunology , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/metabolism , Receptors, Chimeric Antigen/genetics , Receptors, Immunologic/metabolism , Receptors, Immunologic/genetics , T-Lymphocytes, Regulatory/immunology , Signal Transduction , Cell Line, Tumor , Neoplasms/immunology , Neoplasms/therapy , Mice, KnockoutABSTRACT
We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8+ cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T.
