Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer immunology research, 2017-12, Vol.5 (12), p.1152-1161

Ort / Verlag

United States

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. .