Following promising preclinical results using CAR T cells that target c-met (expressed on ~46% of breast cancers), Tchou et al. performed a cautious phase 0 clinical trial in six patients with metastatic breast cancer. c-met-CAR T cells were generated by electroporation with mRNA (ensuring transient expression of the CAR construct) and injected intratumorally. The therapy was well tolerated in all patients and caused tumor necrosis, hemorrhage, and inflammatory cell infiltration at the intratumoral injection site. A phase 1 trial with systemic dosing is underway.
Chimeric antigen receptors (CARs) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ~50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the non-tumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 x 107 or 3 x 108 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in two and four patients, respectively. mRNA c-Met-CAR T cells cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors.
Author Info: (1) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania julia.tchou@uphs.upenn.edu. (2) Department of Pathology and Laboratory Medicine, Perelman School
Author Info: (1) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania julia.tchou@uphs.upenn.edu. (2) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania. (3) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (4) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania. (5) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (6) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (7) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (8) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (9) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (10) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (11) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (12) Department of Surgery, Perelman School of Medicine, University of Pennsylvania. (13) Department of Surgery, Perelman School of Medicine, University of Pennsylvania. (14) Immunology, H. Lee Moffitt Cancer Center and Research Institute. (15) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (16) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (17) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (18) Experimental Pathology, Program in Immunology, Fred Hutchinson Cancer Research Center. (19) Experimental Pathology, Program in Immunology, Fred Hutchinson Cancer Research Center. (20) Hematology-Oncology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania. (21) Hematology-Oncology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania School of Medicine. (22) Hematology-Oncology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania. (23) Division of Pediatrics, The University of Texas MD Anderson Cancer Center. (24) Hematology-Oncology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania. (25) Hematology-Oncology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania. (26) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania Perelman School of Medicine.
