CAR‐T cell therapy in melanoma: A future success story?

Abstract

Chimeric antigen receptor (CAR)‐T cells are one of the impressive recent success stories of anti‐cancer immunotherapy. Especially in haematological malignancies, this treatment strategy has shown promising results leading to the recent approval of two CAR‐T cell constructs targeting CD19 in the United States and the European Union. After the huge success in haematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings. A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features. However, the first results of CAR‐T cell therapy in solid tumors did not reveal the same impressive outcomes that were observed in haematological malignancies, as engineered cells need to cope with several challenges. Obstacles include the lack of migration of CAR‐T cells from blood vessels to the tumor site as well as the immunosuppressive tumor microenvironment within solid tumors. Another hurdle is posed by the identification of an ideal target antigen to avoid on‐target/off‐tumor toxicities. Regarding immune escape mechanisms, which can be developed by tumor cells to bypass immune recognition, the observation of antigen loss should also be considered. This article gives an overview of the challenges displayed in CAR‐T cell therapy for the use in solid tumors and discusses different new strategies and approaches that deal with these problems in order to improve CAR‐T cell therapy, particularly for its use in melanoma.

Non-Melanoma Skin Cancers: Biological and Clinical Features

“…Several patients developing SCC are immune depressed by transplantation, whereas others are affected by HIV-1 infection or hematological disorders, and thus are often excluded from immunotherapy trials. In this context, adoptive cell transfer using chimeric antigen receptor T-cells (CAR-T cells) seems to represent a novel alternative strategy to be potentially pursued in this niche of patients [ 123 , 124 , 125 ].…”

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

“…Chimeric antigen receptor T-cells (CAR-T) are another therapeutic approach that involves the use of engineered T cells to promote their ability to recognize cancer cells. Although this therapeutic field has made great strides and achieved unique results in the treatment of hematological malignancies, it has not produced the same positive effects in melanoma and other solid tumors, due to the presence of a highly immunosuppressive microenvironment in these contexts [ 74 ]. New treatment scenarios involve the development of vaccines that can stimulate the patient’s immune system against tumor-associated antigens.…”

Viral Vector-Based Melanoma Gene Therapy

“…However, with tumors, the transition might be limited by therapeutic barriers such as CAR-T cell expansion, persistence, trafficking, and fate. In the context of melanoma, the first results from CAR-T cell therapy could not reproduce the findings from the treatment of hematological diseases [135]. Issues to be addressed include the lack of migration of CAR-T cells from blood vessels to the tumor site, as well as the immunosuppressive tumor microenvironment within solid tumors, before this technology can be successfully applied for melanoma treatment.…”