Compared to TCRs, CARs have poorer recruitment of proximal signaling molecules and antigen (Ag) sensitivity. To improve CAR T cell responses in low-Ag settings, Rotiroti et al. demonstrated that membrane-bound SLP-76 (MT-SLP-76), but not cytosolic SLP-76, improved CAR T cell cytokine responses to diverse Ag levels. In vivo, MT-SLP-76 improved CAR T cell expansion and efficacy in Ag-low models (CD22, CD19, BCMA) and maintained persistence in Ag-high models. MT-SLP-76 was mediated through ITK and PLCγ1, and enriched cytokine pathway expression. MT-SLP-76 also increased the potential for on-target, off-tumor toxicity, which could narrow the therapeutic window.
Contributed by Alex Najibi
ABSTRACT: Chimeric antigen receptor (CAR) T cells can mediate durable complete responses in individuals with certain hematologic malignancies, but antigen downregulation is a common mechanism of resistance. Although the native T cell receptor can respond to very low levels of antigen, engineered CARs cannot, likely due to inefficient recruitment of downstream proximal signaling molecules. We developed a platform that endows CAR T cells with the ability to kill antigen-low cancer cells consisting of a membrane-tethered version of the cytosolic signaling adaptor molecule SLP-76 (MT-SLP-76). MT-SLP-76 can be expressed alongside any CAR to lower its activation threshold, overcoming antigen-low escape in multiple xenograft models. Mechanistically, MT-SLP-76 amplifies CAR signaling through recruitment of ITK and PLC_1. MT-SLP-76 was designed based on biologic principles to render CAR T cell therapies less susceptible to antigen downregulation and is poised for clinical development to overcome this common mechanism of resistance.
Author Info: (1) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Genetics, Stanford University, Stanford, CA, USA. Department of Medicine, Sta
Author Info: (1) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Genetics, Stanford University, Stanford, CA, USA. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (3) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (5) Proteas Health, Torrance, CA, USA. (6) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA. (8) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Department of Radiation Oncology and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (12) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (14) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (15) Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (17) Department of Pathology, Stanford University, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (18) Department of Pediatrics, City of Hope National Medical Center, Duarte, CA, USA. Department of Immuno-oncology, City of Hope National Medical Center, Duarte, CA, USA. (19) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. robbie_majzner@dfci.harvard.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. robbie_majzner@dfci.harvard.edu. Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. robbie_majzner@dfci.harvard.edu. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. robbie_majzner@dfci.harvard.edu.
