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Antitumor activity of CD56-chimeric antigen receptor T cells in neuroblastoma and SCLC models

Abstract

The CD56 antigen (NCAM-1) is highly expressed on several malignancies with neuronal or neuroendocrine differentiation, including small-cell lung cancer and neuroblastoma, tumor types for which new therapeutic options are needed. We hypothesized that CD56-specific chimeric antigen receptor (CAR) T cells could target and eliminate CD56-positive malignancies. Sleeping Beauty transposon-generated CD56R-CAR T cells exhibited αβT-cell receptors, released antitumor cytokines upon co-culture with CD56+ tumor targets, demonstrated a lack of fratricide, and expression of cytolytic function in the presence of CD56+ stimulation. The CD56R-CAR+ T cells are capable of killing CD56+ neuroblastoma, glioma, and SCLC tumor cells in in vitro co-cultures and when tested against CD56+ human xenograft neuroblastoma models and SCLC models, CD56R-CAR+ T cells were able to inhibit tumor growth in vivo. These results indicate that CD56-CARs merit further investigation as a potential treatment for CD56+ malignancies.

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Acknowledgements

We thank the flow cytometry and cellular imaging core facilities at MD Anderson. This study was funded by Cancer Center Core Grant (CA16672); RO1 (CA124782, CA120956, CA141303, CA141303); P01 (CA148600); SPORES (CA100632, CA136411, CA00632); Albert J Ward Foundation; Alex’s Lemonade Stand Foundation; Burroughs Wellcome Fund; Cancer Prevention and Research Institute of Texas; Charles B. Goddard Foundation of Texas; CLL Global Research Foundation; Energy Transfer Partners; Estate of Noelan L. Bibler; Gillson Longenbaugh Foundation; Harry T. Mangurian, Jr., Fund for Leukemia Immunotherapy; Khalifa Bin Zayed Al Nahyan Foundation; Kleberg Foundation; Leukemia and Lymphoma Society; Lung Cancer Research Foundation; Lung Cancer Moon Shot; Lymphoma Research Foundation; Miller Foundation; Mr. Herb Simons; Mr. and Mrs. Joe H. Scales; Mr. Thomas Scott; National Foundation for Cancer Research; NIH Cancer Center Support Grant (CA016672) Pediatric Cancer Research Foundation; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy; University of Texas MD Anderson Cancer Center Sister Institution Network Fund and Moon Shot Fund; The University of Texas Southwestern Medical Center and The University of Texas MD Anderson Cancer Center NIH Lung SPORE Grant (5 P50 CA070907); William Lawrence and Blanche Hughes Children’s Foundation. Publication under the Creative Commons CC-BY license is not required.

Authors contributions

DLC and WLD designed and conducted experiments, performed data interpretation, and manuscript preparation; MHH provided manufacture assistance with the SB plasmids and CAR T cells; HS and SO assisted with the molecular work; TM and KS assisted with the animal experiments; LJC, KAD, BSG, and JVH provided concept and design of work and supervision of scientific work. LJC and JVH provided manuscript editing and review of this work.

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Correspondence to John V. Heymach.

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Conflict of interest

The technology described in this report was advanced through research conducted at MD Anderson by LJC. In January 2015, the technology was licensed by MD Anderson for commercial application to ZIOPHARM Oncology, Inc., and Intrexon Corporation, in exchange for equity interests in each of these companies. LJC and some co-authors are eligible to receive equity as a result of the licensing of this technology. On May 7, 2015, LJC was appointed as the Chief Executive Officer at ZIOPHARM. LJC is also a Visiting Scientist at MD Anderson, where he continues to help supervise the development of this technology. The information being reported in this publication is research in which MD Anderson has an institutional financial conflict of interest. Because MD Anderson is committed to the protection of human subjects and the effective management of its financial conflicts of interest in relation to its research activities, MD Anderson has implemented an Institutional Conflict of Interest Management and Monitoring Plan to manage and monitor the conflict of interest with respect to MD Anderson’ s conduct of this research. JVH reports receiving commercial research support from AstraZeneca and is a consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, and Synta. The remaining authors declare that they have no conflict of interest.

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Crossland, D.L., Denning, W.L., Ang, S. et al. Antitumor activity of CD56-chimeric antigen receptor T cells in neuroblastoma and SCLC models. Oncogene 37, 3686–3697 (2018). https://doi.org/10.1038/s41388-018-0187-2

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