1. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape
- Author
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Naoki Mizutani, Yasuyuki Igarashi, Jin-ichi Inokuchi, Ke Cao, Soichiro Iwaki, Takayuki Fukui, Chinatsu Arima, Noriyasu Usami, Tetsuo Taniguchi, Kohei Yokoi, Yoko Matsumoto, Keiko Wakahara, Takashi Takahashi, Ryuichi Ueoka, Yuji Komizu, Mamoru Kyogashima, Satoshi Fujii, Kiyoshi Yanagisawa, Yukiko Mizutani, Mei Chee Tai, Akira Satou, Seiichi Kato, Norie Togawa, Kouji Tanaka, Motoshi Suzuki, Yoshinori Hasegawa, Takashi Murate, Keiko Tamiya-Koizumi, Mitsuhiro Nakamura, and Takahiro Shiraishi
- Subjects
0301 basic medicine ,Receptor, ErbB-2 ,T-Lymphocytes ,Mice, SCID ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Metastasis ,Mice ,Interleukin 21 ,0302 clinical medicine ,Clinical investigation ,Cytotoxic T cell ,Transgenes ,Ceramide synthase ,0303 health sciences ,Interleukin-13 ,biology ,Brain Neoplasms ,CD28 ,General Medicine ,Phenotype ,Tumor antigen ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Research Article ,Protein Binding ,Expression of Concern ,T cell ,Receptors, Antigen, T-Cell ,Antineoplastic Agents ,03 medical and health sciences ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Lung cancer ,Antigen-presenting cell ,neoplasms ,030304 developmental biology ,CD40 ,business.industry ,medicine.disease ,030104 developmental biology ,Immunology ,Interleukin-13 Receptor alpha2 Subunit ,biology.protein ,Cancer research ,Tumor Escape ,Neoplasm Recurrence, Local ,Protein Multimerization ,Glioblastoma ,business ,Neoplasm Transplantation ,030217 neurology & neurosurgery - Abstract
In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
- Published
- 2016