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Front. Immunol. | doi: 10.3389/fimmu.2018.02740

CAR T cell therapy of non-hematopoietic malignancies - detours on the road to clinical success

 Kristen B. Long1,  Regina M. Young2, Alina C. Boesteanu2,  Megan M. Davis2, J J. Melenhorst2,  Simon F. Lacey2, David A. Degaramoda1, Bruce L. Levine2 and  Joseph A. Fraietta2*
  • 1Mansfield University of Pennsylvania, United States
  • 2University of Pennsylvania, United States

Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient’s own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted FDA approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma. Human trials of CAR T cells targeting CD19 or B cell maturation antigen in multiple myeloma have also reported early successes. However, a clear and consistently reproducible demonstration of clinical efficacy of CAR T cells in the setting of solid tumors has not been reported to date. Here, we review the history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies. In addition, we summarize recent strategies and innovations that aim to augment the potency of CAR T cells in the face of multiple immunosuppressive barriers operative within the solid tumor microenvironment. Advances in the field of CAR T cell biology over the coming years in the areas of safety, reliability, and efficacy against non-hematopoietic cancers will ultimately determine how transformative adoptive cell therapy will be in the broader battle against cancer.

Keywords: CAR (chimeric antigen receptor) T cells, Immunothearpy, Cancer, Solid tumor, Microenviroment, adoptive cell therapy, Non-hematopoietic neoplasm

Received: 16 Aug 2018; Accepted: 07 Nov 2018.

Edited by:

John -. Maher, King's College London, United Kingdom

Reviewed by:

Hinrich Abken, Center for Molecular Medicine Cologne, University of Cologne
David M. Davies, King's College London, United Kingdom  

Copyright: © 2018 Long, Young, Boesteanu, Davis, Melenhorst, Lacey, Degaramoda, Levine and Fraietta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Joseph A. Fraietta, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, United States, jfrai@upenn.edu