Practical considerations for chimeric antigen receptor design and delivery

ABSTRACT

Introduction: The development of chimeric antigen receptor (CAR)-modified immune cells has become a highly active field of research since the introduction of this approach in 1989. New ideas are constantly being proposed and tested, resulting in CARs that are more effective and specialized.

Areas covered: Many aspects of CAR design and administration can be varied in order to achieve the best possible outcomes; optimization of this therapeutic schema is an active area of research. Here, the authors summarize the work that has been carried out thus far to assess different adaptations for each portion of the CAR itself. They also discuss the various methods used for CAR transgene transfer into effector cells.

Expert opinion: While the field has made significant advancements in terms of expansion and testing of the variations available for CAR therapy, it remains difficult to ascertain which options are truly superior and under what conditions. Continued research in this area, as well as in aspects such as improving the safety profile and the anti-tumor potency of CARs, will be required to bring this therapy from early-phase clinical trials to standard of care as an effective treatment for a broad range of tumor types.

KEYWORDS:

• Cancer
• chimeric antigen receptor (CAR)
• gene therapy
• immunotherapy
• T cell

Article highlights

• Many different options have been tested for use in CARs, though comparisons between the efficacy of different domains are often lacking.

• CD3ζ is the most commonly used intracellular signaling domain.

• 4-1BB or CD28 are frequently chosen as costimulatory domains.

• CD8α and CD28 are typically used for the hinge and transmembrane domains.

• scFv-based ARDs are most often used, but other modes of antigen binding are also being developed.

• LV or γ-retrovirus transduction are the most popular methods for CAR gene transfer into effector cells, however other methods are also being explored.

• Future developments in CAR therapies will improve upon specificity, safety and potency by combining CARs with other elements such as safety elements, immune effector molecules, and gene editing techniques.

This box summarizes key points contained in the article.

Acknowledgements

We thank Dr Mary Faber (of the Medical College of Wisconsin) for critically reviewing this manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the Midwest Athletes Against ChildhoodCancer (MACC) Fund, Children's Hospital of Wisconsin, and the Medical College of Wisconsin.