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Clinical practice: chimeric antigen receptor (CAR) T cells: a major breakthrough in the battle against cancer

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Abstract

Chimeric antigen receptor (CAR) T cell therapy has come of age, offering a potentially curative option for patients who are refractory to standard anti-cancer treatments. The success of CAR T cell therapy in the setting of acute lymphoblastic leukemia and specific types of B cell lymphoma led to rapid regulatory approvals of CD19-directed CAR T cells, first in the United States and subsequently across the globe. Despite these major milestones in the field of immuno-oncology, growing experience with CAR T cells has also highlighted the major limitations of this strategy, namely challenges associated with manufacturing a bespoke patient–specific product, intrinsic immune cell defects leading to poor CAR T cell function as well as persistence, and/or tumor cell resistance resulting from loss or modulation of the targeted antigen. In addition, both on- and off-tumor immunotoxicities and the financial burden inherent in conventional cellular biomanufacturing often hamper the success of CAR T cell-based treatment approaches. Herein, we provide an overview of the opportunities and challenges related to the first form of gene transfer therapy to gain commercial approval in the United States. Ongoing advances in the areas of genetic engineering, precision genome editing, toxicity mitigation methods and cell manufacturing will improve the efficacy and safety of CAR T cells for hematologic malignancies and expand the use of this novel class of therapeutics to reach solid tumors.

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Acknowledgements

This work was supported by the Bob Levis Funding Group (JAF). Additional funding comes from P01 CA214278 (JJM and JAF), R01 CA241762 (JJM and JAF) and U54 CA244711 (JAF) grants from the National Cancer Institute, a U01 AG066100 (JAF) grant from the National Institute on Aging, the Gabrielle’s Angel Foundation (JAF) and the Alliance for Cancer Gene Therapy (JAF). The design of figures was aided by licensed materials from ScienceSlides (https://www.visiscience.com) and the Parker Institute for Cancer Immunotherapy.

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  1. Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA

    Stefan Lundh, In-Young Jung, Alexander Dimitri, Anish Vora, J. Joseph Melenhorst, Julie K. Jadlowsky & Joseph A. Fraietta

  2. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    In-Young Jung, Alexander Dimitri & Joseph A. Fraietta

  3. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    In-Young Jung, Alexander Dimitri, J. Joseph Melenhorst & Joseph A. Fraietta

  4. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    J. Joseph Melenhorst & Joseph A. Fraietta

  5. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA

    J. Joseph Melenhorst & Joseph A. Fraietta

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  1. Stefan Lundh
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Correspondence to Joseph A. Fraietta.

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JJM and JAF hold patents related to CAR T cell therapy and receive associated royalties. The remaining authors have no competing interests.

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Lundh, S., Jung, IY., Dimitri, A. et al. Clinical practice: chimeric antigen receptor (CAR) T cells: a major breakthrough in the battle against cancer. Clin Exp Med 20, 469–480 (2020). https://doi.org/10.1007/s10238-020-00628-1

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