Smart CARs engineered for cancer immunotherapy

Abstract

Purpose Chimeric antigen receptors (CARs) are synthetic immunoreceptors that can redirect T cells to selectively kill tumor cells, and as “living-drugs” have the potential to generate long-term anti-tumor 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, as well as 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.

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy

“…7,8 This study provides proof-of-principle data that confirm IL13Rα2 as a useful immunotherapeutic target in glioblastoma and establish that CAR T cells can mediate profound antitumor activity against a difficult-to-treat solid tumor.…”

“…4–6 However, extension of the use of CAR therapy beyond hematologic cancers and the efficacy of this therapy against solid tumors remain to be established. 7,8 …”

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

“…Chimeric antigen receptor (CAR)-based T-cell immunotherapy is being actively investigated for the treatment of solid tumors (6,7), including HER2 þ cancers. Unfortunately, the first CAR T-cell clinical experience with targeting the HER2 antigen resulted in the death of a patient with HER2 þ metastatic colon cancer due to "on-target, off-tumor" toxicities (8).…”

Next frontiers in CAR T-cell therapy

“…12,13 Newick et al . 9 highlight the lack of a “dispensable antigen” in solid tumors and discusses tumor-selective versus tumor-specific antigens that are being targeted in clinical trials.…”