Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer

• Published in: Cancer immunology research Vol. 5; no. 12; p. 1152
• Main Authors: Tchou, Julia, Zhao, Yangbing, Levine, Bruce L, Zhang, Paul J, Davis, Megan M, Melenhorst, Jan Joseph, Kulikovskaya, Irina, Brennan, Andrea L, Liu, Xiaojun, Lacey, Simon F, Posey, Jr, Avery D, Williams, Austin D, So, Alycia, Conejo-Garcia, Jose R, Plesa, Gabriela, Young, Regina M, McGettigan, Shannon, Campbell, Jean, Pierce, Robert H, Matro, Jennifer M, DeMichele, Angela M, Clark, Amy S, Cooper, Laurence J, Schuchter, Lynn M, Vonderheide, Robert H, June, Carl H
• Format: Journal Article
• Language: English
• Published: United States 01.12.2017
• Subjects: Adult; Aged; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Biomarkers, Tumor; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cell Line, Tumor; Cytotoxicity, Immunologic; Disease Models, Animal; Female; Gene Expression; Humans; Immunotherapy; Mice; Middle Aged; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Recombinant Fusion Proteins; RNA, Messenger - genetics; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-17-0189

Chimeric antigen receptors (CAR) 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 nontumor 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 × 10 or 3 × 10 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T 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. .