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Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance.
Literature Information
| DOI | 10.1186/s40425-018-0460-5 |
|---|---|
| PMID | 30514386 |
| Journal | Journal for immunotherapy of cancer |
| Impact Factor | 10.6 |
| JCR Quartile | Q1 |
| Publication Year | 2018 |
| Times Cited | 133 |
| Keywords | Axicabtagene ciloleucel, Chimeric antigen receptor, Leukemia, Lymphoma, Tisagenlecleucel |
| Literature Type | Journal Article, Review |
| ISSN | 2051-1426 |
| Pages | 137 |
| Issue | 6(1) |
| Authors | Michael M Boyiadzis, Madhav V Dhodapkar, Renier J Brentjens, James N Kochenderfer, Sattva S Neelapu, Marcela V Maus, David L Porter, David G Maloney, Stephan A Grupp, Crystal L Mackall, Carl H June, Michael R Bishop |
TL;DR
This review highlights the transformative impact of Chimeric Antigen Receptor (CAR) T cell therapies in treating hematologic malignancies, underscored by recent FDA approvals and ongoing developments in disease applications and CAR designs. It emphasizes the importance of understanding clinical considerations and toxicity management to optimize the implementation of this innovative therapeutic approach for clinicians.
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Axicabtagene ciloleucel · Chimeric antigen receptor · Leukemia · Lymphoma · Tisagenlecleucel
Abstract
Chimeric Antigen Receptor (CAR) T cell therapies - adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.
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Primary Questions Addressed
- What are the latest advancements in CAR T cell therapy designs for treating different types of hematologic malignancies?
- How do the toxicity profiles of various CAR T therapies compare, and what management strategies are recommended?
- What are the long-term outcomes and survival rates associated with CAR T therapies in patients with hematologic malignancies?
- How does the approval process for new CAR T therapies differ between the FDA and other international regulatory bodies?
- What are the potential future applications of CAR T cell therapies beyond hematologic malignancies, and what challenges might arise in those contexts?
Key Findings
Background and Purpose
Chimeric Antigen Receptor (CAR) T cell therapies have emerged as a transformative approach in the treatment of hematologic malignancies. This review by Boyiadzis et al. discusses the development, clinical implications, and ongoing advancements of CAR T therapies, highlighting their success in treating various blood cancers and the evolving strategies to enhance efficacy and manage associated toxicities.
Main Methods/Materials/Experimental Design
The review outlines the evolution of CAR designs, focusing on their structural components and production processes:
CAR Structure:
- Ectodomain: Antigen recognition.
- Transmembrane Domain: Provides stability.
- Endodomain: Signal transduction for T cell activation.
CAR Generation:
- First-Generation CARs: Basic design with CD3ζ for T cell activation, lacking costimulatory signals.
- Second-Generation CARs: Incorporate costimulatory domains (e.g., CD28, 4-1BB) to enhance T cell proliferation and survival.
- Third-Generation CARs: Utilize multiple costimulatory domains for improved efficacy.
Production Process:
- Leukapheresis: Collection of peripheral blood mononuclear cells.
- Genetic Engineering: Use of viral vectors to introduce CAR genes.
- Ex Vivo Expansion: Culturing T cells to achieve therapeutic doses.
Key Results and Findings
- Efficacy: CAR T therapies, particularly those targeting CD19, have shown high response rates in conditions like diffuse large B cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL).
- FDA Approvals: The review discusses three FDA-approved CAR T therapies, emphasizing their clinical trial results, including overall survival and duration of remission.
- Toxicities: Major toxicities such as Cytokine Release Syndrome (CRS) and Neurotoxicity (NTX) are identified, with protocols established for their management.
Main Conclusions/Significance/Innovation
CAR T cell therapies represent a significant advancement in cancer treatment, providing durable responses in previously refractory cases. The review underscores the importance of ongoing research to optimize CAR designs, improve patient outcomes, and manage toxicities effectively. Innovations such as next-generation CAR constructs and alternative antigen targets are highlighted as future directions in enhancing the therapeutic landscape.
Research Limitations and Future Directions
- Limitations: The review notes that while CAR T therapies are promising, challenges remain in terms of toxicity management, treatment accessibility, and the need for personalized approaches based on patient characteristics.
- Future Directions: Ongoing research is directed towards:
- Exploring CAR T applications in solid tumors.
- Developing allogeneic CAR T cells for broader accessibility.
- Enhancing CAR T cell persistence and function through metabolic and genetic engineering strategies.
| Aspect | Current Status | Future Directions |
|---|---|---|
| CAR Design | Evolving from first to third generation | Further optimization and alternative targets |
| Toxicity Management | Established protocols for CRS and NTX | Improved management strategies and predictive markers |
| Clinical Applications | Approved for hematologic malignancies | Expansion into solid tumors and other cancers |
| Accessibility | Limited to specialized centers | Development of allogeneic "off-the-shelf" products |
This structured summary encapsulates the essential elements of the review, providing insights into the current landscape and future potential of CAR T cell therapies in oncology.
References
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Literatures Citing This Work
- Navigating the Fas lane to improved cellular therapy for cancer. - Madhav V Dhodapkar - The Journal of clinical investigation (2019)
- Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells. - Mohamed-Reda Benmebarek;Clara Helke Karches;Bruno Loureiro Cadilha;Stefanie Lesch;Stefan Endres;Sebastian Kobold - International journal of molecular sciences (2019)
- Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer. - Bianca Simon;Dennis C Harrer;Beatrice Schuler-Thurner;Gerold Schuler;Ugur Uslu - Cancers (2019)
- Overview of Targeted Drugs for Mature B-Cell Non-hodgkin Lymphomas. - Stefania Crisci;Raffaele Di Francia;Sara Mele;Pasquale Vitale;Giuseppina Ronga;Rosaria De Filippi;Massimiliano Berretta;Paola Rossi;Antonio Pinto - Frontiers in oncology (2019)
- Effects of interleukin-2 in immunostimulation and immunosuppression. - Jonathan G Pol;Pamela Caudana;Juliette Paillet;Eliane Piaggio;Guido Kroemer - The Journal of experimental medicine (2020)
- TraFo-CRISPR: Enhanced Genome Engineering by Transient Foamy Virus Vector-Mediated Delivery of CRISPR/Cas9 Components. - Fabian Lindel;Carolin R Dodt;Niklas Weidner;Monique Noll;Fabian Bergemann;Rayk Behrendt;Sarah Fischer;Josephine Dietrich;Marc Cartellieri;Martin V Hamann;Dirk Lindemann - Molecular therapy. Nucleic acids (2019)
- The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing Piece of the Puzzle for the Efficient Targeting of these Cells with Immunotherapy. - Shilpa Ravindran;Saad Rasool;Cristina Maccalli - Cancer microenvironment : official journal of the International Cancer Microenvironment Society (2019)
- T Cell Reprogramming Against Cancer. - Samuel G Katz;Peter M Rabinovich - Methods in molecular biology (Clifton, N.J.) (2020)
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- IL-23 and PSMA-targeted duo-CAR T cells in Prostate Cancer Eradication in a preclinical model. - Dawei Wang;Yuan Shao;Xiang Zhang;Guoliang Lu;Boke Liu - Journal of translational medicine (2020)
... (123 more literatures)
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