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Curated Papers > Highly Cited Authoritative Literature on "Synthetic Biology"

The Principles of Engineering Immune Cells to Treat Cancer. ​

Literature Information ​

DOI10.1016/j.cell.2017.01.016
PMID28187291
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2017
Times Cited536
KeywordsChimeric Antigen Receptor T Cells, Engineered Immune Cells, Cancer Therapy, Synthetic Biology, Precision Therapeutics
Literature TypeJournal Article, Review, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0092-8674
Pages724-740
Issue168(4)
AuthorsWendell A Lim, Carl H June

TL;DR ​

This research highlights the potential of chimeric antigen receptor (CAR) T cells as a novel cancer treatment, while addressing the challenges in ensuring their reliability, safety, and efficacy against various tumors. It emphasizes the role of synthetic biology in enhancing the design and function of engineered immune cells, paving the way for the development of next-generation precision therapeutics.

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Chimeric Antigen Receptor T Cells · Engineered Immune Cells · Cancer Therapy · Synthetic Biology · Precision Therapeutics

Abstract ​

Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools for programming immune cells. We discuss how these tools could be used to design the next generation of smart T cell precision therapeutics.

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Primary Questions Addressed ​

  1. What are the specific challenges faced in the clinical application of CAR T cells for different types of tumors?
  2. How do synthetic biology tools enhance the precision and effectiveness of engineered T cell therapies?
  3. What advancements in immune cell engineering are being explored to improve patient safety and reduce adverse effects?
  4. In what ways can the design of smart T cell therapeutics be tailored to target specific tumor microenvironments?
  5. How does the integration of artificial intelligence in the engineering of immune cells influence treatment outcomes in cancer therapy?

Key Findings ​

Research Background and Objectives ​

The emergence of engineered T cells, particularly Chimeric Antigen Receptor (CAR) T cells, represents a transformative advancement in cancer therapy. This review discusses the engineering principles behind T cells to enhance their efficacy as cancer therapeutics, focusing on safety, precision, and adaptability in targeting various tumor types.

Main Methods/Materials/Experimental Design ​

The review synthesizes current knowledge on T cell engineering, emphasizing the integration of synthetic biology tools to develop advanced T cell therapies. The key areas of focus include:

  • CAR T Cell Design: Utilizing synthetic receptors for MHC-independent target recognition.
  • Combination Therapies: Exploring the use of CAR T cells in conjunction with checkpoint inhibitors and other therapies.
  • Adaptive Engineering: Implementing feedback control systems to modulate T cell activity.

The following flowchart summarizes the technical approaches discussed:

Mermaid diagram

Key Results and Findings ​

  1. Clinical Efficacy: CAR T cells have shown significant success in treating hematological malignancies, with response rates of 70-90% in certain leukemias.
  2. Challenges Identified: Concerns regarding safety, off-target effects, and the development of tumor resistance remain prevalent.
  3. Solid Tumor Targeting: The review highlights ongoing challenges in effectively targeting solid tumors, where T cell infiltration and tumor microenvironment suppression pose significant barriers.
  4. Innovative Engineering Solutions: Advances in combinatorial antigen recognition and affinity-tuned receptors show promise for improving specificity and reducing off-target effects.

Main Conclusions/Significance/Innovation ​

The review emphasizes the need for a multi-faceted approach in T cell engineering to tackle the complex nature of cancer. Innovations in synthetic biology can lead to more effective, adaptable, and safer T cell therapies. By leveraging advanced engineering techniques, it is possible to create "smart" T cells capable of precise tumor targeting while minimizing collateral damage to normal tissues.

Research Limitations and Future Directions ​

  1. Safety and Toxicity: Ongoing clinical trials must continue to address the risks of cytokine release syndrome and other adverse effects associated with CAR T cell therapies.
  2. Long-term Efficacy: Future studies should focus on enhancing the durability of responses, particularly in solid tumors.
  3. Personalized Approaches: The integration of precision medicine with engineered T cell therapies could optimize treatment strategies based on individual tumor profiles.

The review concludes with a call for further research into novel engineering strategies and combination therapies to enhance the efficacy and safety of T cell immunotherapy, paving the way for broader applications beyond cancer, including autoimmunity and infectious diseases.

References ​

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  3. Prospects for gene-engineered T cell immunotherapy for solid cancers. - Christopher A Klebanoff;Steven A Rosenberg;Nicholas P Restifo - Nature medicine (2016)
  4. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. - Richard A Morgan;Nachimuthu Chinnasamy;Daniel Abate-Daga;Alena Gros;Paul F Robbins;Zhili Zheng;Mark E Dudley;Steven A Feldman;James C Yang;Richard M Sherry;Giao Q Phan;Marybeth S Hughes;Udai S Kammula;Akemi D Miller;Crystal J Hessman;Ashley A Stewart;Nicholas P Restifo;Martha M Quezado;Meghna Alimchandani;Avi Z Rosenberg;Avindra Nath;Tongguang Wang;Bibiana Bielekova;Simone C Wuest;Nirmala Akula;Francis J McMahon;Susanne Wilde;Barbara Mosetter;Dolores J Schendel;Carolyn M Laurencot;Steven A Rosenberg - Journal of immunotherapy (Hagerstown, Md. : 1997) (2013)
  5. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. - James N Kochenderfer;Wyndham H Wilson;John E Janik;Mark E Dudley;Maryalice Stetler-Stevenson;Steven A Feldman;Irina Maric;Mark Raffeld;Debbie-Ann N Nathan;Brock J Lanier;Richard A Morgan;Steven A Rosenberg - Blood (2010)
  6. Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors. - Leonardo Morsut;Kole T Roybal;Xin Xiong;Russell M Gordley;Scott M Coyle;Matthew Thomson;Wendell A Lim - Cell (2016)
  7. Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. - Evripidis Lanitis;Mathilde Poussin;Alex W Klattenhoff;Degang Song;Raphael Sandaltzopoulos;Carl H June;Daniel J Powell - Cancer immunology research (2013)
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  9. Current concepts in the diagnosis and management of cytokine release syndrome. - Daniel W Lee;Rebecca Gardner;David L Porter;Chrystal U Louis;Nabil Ahmed;Michael Jensen;Stephan A Grupp;Crystal L Mackall - Blood (2014)
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Literatures Citing This Work ​

  1. Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment. - Zhenguang Wang;Yelei Guo;Weidong Han - Protein & cell (2017)
  2. Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV. - Dongfang Liu;Shuo Tian;Kai Zhang;Wei Xiong;Ndongala Michel Lubaki;Zhiying Chen;Weidong Han - Protein & cell (2017)
  3. Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives. - Zong Sheng Guo;Zuqiang Liu;Stacy Kowalsky;Mathilde Feist;Pawel Kalinski;Binfeng Lu;Walter J Storkus;David L Bartlett - Frontiers in immunology (2017)
  4. Molecular Dissection of CD8+ T-Cell Dysfunction. - Chao Wang;Meromit Singer;Ana C Anderson - Trends in immunology (2017)
  5. Adoptive transfer of murine T cells expressing a chimeric-PD1-Dap10 receptor as an immunotherapy for lymphoma. - Adam Lynch;William Hawk;Emily Nylen;Sean Ober;Pierre Autin;Amorette Barber - Immunology (2017)
  6. Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy. - Rigel J Kishton;Madhusudhanan Sukumar;Nicholas P Restifo - Cell metabolism (2017)
  7. NK Cell Exhaustion. - Jiacheng Bi;Zhigang Tian - Frontiers in immunology (2017)
  8. Reprogramming cellular functions with engineered membrane proteins. - Caroline Arber;Melvin Young;Patrick Barth - Current opinion in biotechnology (2017)
  9. Tumor immunity requires border patrol to fight the enemy within. - Derk Amsen;Pleun Hombrink;Rene A W van Lier - Nature immunology (2017)
  10. Adnectin-Based Design of Chimeric Antigen Receptor for T Cell Engineering. - Xiaolu Han;Gunce E Cinay;Yifan Zhao;Yunfei Guo;Xiaoyang Zhang;Pin Wang - Molecular therapy : the journal of the American Society of Gene Therapy (2017)

... (526 more literatures)

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