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Chimeric antigen receptor T cell therapy: 25years in the making. ​

Literature Information ​

PMID26574053
JournalBlood reviews
Impact Factor5.7
JCR QuartileQ1
Publication Year2016
Times Cited113
KeywordsAdoptive immunotherapy, Chimeric antigen receptor T cells
Literature TypeJournal Article, Review, Research Support, Non-U.S. Gov't
ISSN0268-960X
Pages157-67
Issue30(3)
AuthorsSaar Gill, Marcela V Maus, David L Porter

TL;DR ​

This review discusses the evolution of chimeric antigen receptor (CAR) T cell therapy from a theoretical concept to a practical treatment option for cancer, highlighting significant advancements in molecular biology and cell production over the past 25 years. It also aims to provide insights and lessons from the early clinical experiences of CAR T cell therapy to inform practicing clinicians.

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Adoptive immunotherapy · Chimeric antigen receptor T cells

Abstract ​

Chimeric antigen receptor (CAR) T cell therapy of cancer is generating enormous enthusiasm. Twenty-five years after the concept was first proposed, major advances in molecular biology, virology, and good manufacturing practices (GMP)-grade cell production have transformed antibody-T cell chimeras from a scientific curiosity to a fact of life for academic cellular immunotherapy researchers and, increasingly, for patients. In this review, we explain the preclinical concept, outline how it has been translated to the clinic, and draw lessons from the first years of CAR T cell therapy for the practicing clinician.

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Primary Questions Addressed ​

  1. What are the specific molecular biology advancements that have facilitated the development of CAR T cell therapy over the past 25 years?
  2. How have the manufacturing practices for CAR T cell therapies evolved to meet clinical demands and regulatory standards?
  3. What lessons can be learned from the initial clinical trials of CAR T cell therapy that could inform future research and treatment strategies?
  4. In what ways have CAR T cell therapies been adapted for different types of cancers beyond the original indications?
  5. How does the preclinical development of CAR T cell therapies compare to other forms of immunotherapy in terms of challenges and successes?

Key Findings ​

1. Research Background and Objective: Chimeric antigen receptor (CAR) T cell therapy has evolved significantly since its inception 25 years ago, transitioning from a theoretical framework to a tangible treatment option for cancer patients. The objective of this review is to trace the development of CAR T cell therapy, highlighting the advancements in molecular biology, virology, and good manufacturing practices (GMP)-grade cell production. By examining the preclinical concepts and clinical translation of CAR T cell therapy, the authors aim to provide valuable insights and lessons for clinicians involved in cellular immunotherapy.

2. Main Methods and Findings: The review synthesizes a broad range of developments in CAR T cell therapy, detailing the foundational preclinical research that laid the groundwork for clinical applications. Key advancements include the design of CAR constructs, the optimization of T cell activation and expansion processes, and the establishment of GMP protocols for cell production. The authors discuss how these innovations have facilitated the transition from laboratory research to clinical trials, demonstrating the effectiveness of CAR T cell therapy in treating various cancers, particularly hematological malignancies. The review highlights the challenges faced during this translation, including issues related to safety, manufacturing complexity, and regulatory compliance.

3. Core Conclusions: The authors conclude that CAR T cell therapy represents a significant milestone in cancer treatment, offering a novel approach that harnesses the body’s immune system to target and eliminate cancer cells. They emphasize that the lessons learned from the initial years of CAR T therapy, including the importance of rigorous preclinical validation, streamlined manufacturing processes, and careful patient selection, are crucial for the ongoing development and refinement of this therapeutic modality. The review asserts that despite the challenges, the potential of CAR T therapy to improve patient outcomes is increasingly recognized and validated through clinical success.

4. Research Significance and Impact: This review underscores the transformative journey of CAR T cell therapy from concept to clinical reality, signifying a paradigm shift in cancer treatment strategies. The insights provided are essential for clinicians, researchers, and industry stakeholders involved in cellular immunotherapy. The comprehensive overview of the advancements and challenges faced in the field serves not only as a historical account but also as a roadmap for future developments. By elucidating the key factors that have contributed to the success of CAR T cell therapy, this work highlights the potential for continued innovation in the field of immunotherapy, ultimately aiming to improve cancer treatment outcomes for patients worldwide.

Literatures Citing This Work ​

  1. T-Cell Receptor-Engineered Cells for the Treatment of Hematologic Malignancies. - Nasheed M Hossain;Aude G Chapuis;Roland B Walter - Current hematologic malignancy reports (2016)
  2. Chimeric antigen receptor T-cell therapy for solid tumors. - Kheng Newick;Edmund Moon;Steven M Albelda - Molecular therapy oncolytics (2016)
  3. Clinical manufacturing of CAR T cells: foundation of a promising therapy. - Xiuyan Wang;Isabelle Rivière - Molecular therapy oncolytics (2016)
  4. Driving an improved CAR for cancer immunotherapy. - Xiaopei Huang;Yiping Yang - The Journal of clinical investigation (2016)
  5. Current status of engineered T-cell therapy for synovial sarcoma. - Matthew Dallos;William D Tap;Sandra P D'Angelo - Immunotherapy (2016)
  6. Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy. - Zulmarie Perez Horta;Jacob L Goldberg;Paul M Sondel - Immunotherapy (2016)
  7. Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors. - Robert Moot;Sunil S Raikar;Lauren Fleischer;Melissa Querrey;Daniel E Tylawsky;Hirotomo Nakahara;Christopher B Doering;H Trent Spencer - Molecular therapy oncolytics (2016)
  8. Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites? - Valérie Dutoit;Denis Migliorini;Pierre-Yves Dietrich;Paul R Walker - Frontiers in oncology (2016)
  9. Masked Chimeric Antigen Receptor for Tumor-Specific Activation. - Xiaolu Han;Paul D Bryson;Yifan Zhao;Gunce E Cinay;Si Li;Yunfei Guo;Natnaree Siriwon;Pin Wang - Molecular therapy : the journal of the American Society of Gene Therapy (2017)
  10. Autologous lymphapheresis for the production of chimeric antigen receptor T cells. - Elizabeth S Allen;David F Stroncek;Jiaqiang Ren;Anne F Eder;Kamille A West;Terry J Fry;Daniel W Lee;Crystal L Mackall;Cathy Conry-Cantilena - Transfusion (2017)

... (103 more literatures)

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