Intratumoral injections of RNA chimeric antigen receptor (CAR) T cells directed against c-Met (RNA CAR T c-Met) induces tumor necrosis and inflammatory responses in metastatic breast cancer

Chimeric antigen receptors (CARs) are synthetic molecules that redirect T cells to mediate antitumor effects in hematologic malignancies. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to... [ view full abstract ]

Chimeric antigen receptors (CARs) are synthetic molecules that redirect T cells to mediate antitumor effects in hematologic malignancies. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date. In preclinical studies, we found that the cell-surface molecule c-Met was frequently expressed in breast cancer. We constructed a CAR that was specific for c-Met and demonstrated that the CAR T cells had potent antitumor activity in immune-incompetent mice with tumor xenografts. Therefore, we conducted a phase 0 clinical trial (NCT01837602) to evaluate the safety and feasibility of treating metastatic breast cancer with intratumoral (IT) administration of RNA-transfected c-Met CAR T cells. RNA transfection was used to ensure safety by limiting on-target/off-tumor effects. Patients with metastatic breast cancer presenting with accessible cutaneous or lymph node metastases received a single IT injection at one of two dose levels: 3x107 and 3x108 cells. Low level CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues shortly after IT injection in two and four patients, respectively. RNA CAR T c-Met injections were well tolerated in all patients.Tumors treated with IT RNA CAR T c-Met were excised. Examination of resected tumor revealed extensive tumor necrosis at the injection site, including abundant cellular debris with loss of c-Met immunoreactivity, surrounded by macrophages at the leading edge of necrotic zone. We conclude that IT injections of RNA CAR T c-Met are well tolerated and that they evoke an inflammatory response within tumors.