Smart CARs engineered for cancer immunotherapy

Abstract

Purpose of review: Chimeric antigen receptors (CARs) are synthetic immunoreceptors, which can redirect T cells to selectively kill tumor cells, and as 'living drugs' have the potential to generate long-term antitumor immunity. Given their recent clinical successes for the treatment of refractory B-cell malignancies, there is a strong push toward advancing this immunotherapy to other hematological diseases and solid cancers. Here, we summarize the current state of the field, highlighting key variables for the optimal application of CAR T cells for cancer immunotherapy.

Recent findings: Advances in CAR T-cell therapy have highlighted intrinsic CAR design and T-cell manufacturing methods as critical components for maximal therapeutic success. Similarly, addressing the unique extrinsic challenges of each tumor type, including overcoming the immunosuppressive tumor microenvironment and tumor heterogeneity, and mitigating potential toxicity, will dominate the next wave of CAR T-cell development.

Summary: CAR T-cell therapeutic optimization, including intrinsic and extrinsic factors, is critical to developing effective CAR T-cell therapies for cancer. The excitement of CAR T-cell immunotherapy has just begun, and will continue with new insights revealed in laboratory research and in ongoing clinical investigations.

Figure 1. Key Variables in CAR T Cell Therapy

The diagram depicts the processes (Steps 1-5) of CAR T cell therapy moving in a counter-clockwise direction, starting with patient leukapheresis and ending with infusion of engineered CAR T cells. 1. Leukapheresis and T cell enrichment: The first key variables include T cell isolation, in particular whether the starting population is unselected peripheral blood mononuclear cells or enriched T cell subsets (i.e. memory) with potentially defined CD4:CD8 ratios. 2. Activate T cells: The next key variables in T cell manufacturing are T cell activation, including CD3 antibody stimulation along with CD28 co-stimulation or antigen presenting cells. 3. Engineer CAR T cells: Key variables in CAR design dictate an optimized CAR, and include the antigen-binding domain, the extracellular linker/spacer, and the intracellular signaling domain. 4. Expand CAR T cells: Optimized CARs are then introduced into T cells using various engineering strategies (viral or non-viral delivery). Key variables in T cell expansion include cytokines, immune-modulators, and ex vivo culture time and expansion conditions. 5. Infuse CAR T cells: Finally, key variables in adoptive transfer include patient pre-conditioning regimens, route of T cell administration, as well as T cell dose and frequency of infusions. The tumor microenvironment, antigen expression heterogeneity in tumors, and safety considerations, are also important factors in optimizing CAR T cell therapy (discussed in the body of this review). Cumulative consideration of each key variable is critical in developing the most effective CAR T cell product.