CAR NK Cell Therapy for the Treatment of Metastatic Melanoma: Potential & Prospects

Abstract

Melanoma is among the most lethal forms of cancer, accounting for 80% of deaths despite comprising just 5% of skin cancer cases. Treatment options remain limited due to the genetic and epigenetic mechanisms associated with melanoma heterogeneity that underlie the rapid development of secondary drug resistance. For this reason, the development of novel treatments remains paramount to the improvement of patient outcomes. Although the advent of chimeric antigen receptor-expressing T (CAR-T) cell immunotherapies has led to many clinical successes for hematological malignancies, these treatments are limited in their utility by their immune-induced side effects and a high risk of systemic toxicities. CAR natural killer (CAR-NK) cell immunotherapies are a particularly promising alternative to CAR-T cell immunotherapies, as they offer a more favorable safety profile and have the capacity for fine-tuned cytotoxic activity. In this review, the discussion of the prospects and potential of CAR-NK cell immunotherapies touches upon the clinical contexts of melanoma, the immunobiology of NK cells, the immunosuppressive barriers preventing endogenous immune cells from eliminating tumors, and the structure and design of chimeric antigen receptors, then finishes with a series of proposed design innovations that could improve the efficacy CAR-NK cell immunotherapies in future studies.

Development of Personalized Strategies for Precisely Battling Malignant Melanoma

“…Beyond a high mutation rate, melanoma often rewires its metabolism program through non-genomic regulation to provide a favorable tumor microenvironment (TME) for supporting tumor cell growth and suppressing immune surveillance [11,12,79]. Targeting the vulnerabilities of metabolism may improve melanoma therapy.…”

“…First, selecting an optimal antigen target has the dual goal of inducing an anti-tumor immune response while producing the lowest amount of off-target toxicity and immune side effects for patients. This off-target toxicity is commonly observed when the target antigen is expressed in both healthy tissue and malignant tumor tissue; consequently, multiple targets whose expression is limited to malignant tissues alone have been identified [12,120,121]. For example, CD248 is a type I transmembrane glycoprotein that is either not expressed or minimally expressed in healthy tissues [1,121].…”

“…Cutaneous melanomas have high mutational burdens, making this disease a prime candidate for adoptive cellular therapy (ACT) of either tumor-infiltrating lymphocytes (TILs) or chimeric antigen receptor T (CAR-T) cells [1,[11][12][13][14]. From a treatment perspective, TIL therapy is behind MAPKi targeted therapy and ICI therapy, especially for treatmentrefractory patients.…”

“…From a treatment perspective, TIL therapy is behind MAPKi targeted therapy and ICI therapy, especially for treatmentrefractory patients. CAR-T therapy may be particularly helpful for metastatic and targetedtherapy-resistant melanoma patients [1,11,12]. However, while it has higher specificity than MAPKi targeted therapy, CAR-T therapy has more dangerous potential side effects, such as cytokine release syndrome (CRS) [11,12,14].…”

“…CAR-T therapy may be particularly helpful for metastatic and targetedtherapy-resistant melanoma patients [1,11,12]. However, while it has higher specificity than MAPKi targeted therapy, CAR-T therapy has more dangerous potential side effects, such as cytokine release syndrome (CRS) [11,12,14]. The review aims to recapitulate an up-to-date overview of where we stand regarding the scope of precision oncology techniques, describe what we can expect in terms of the future landscape by challenging what is already known in the field, and provide recommendations for ways to circumvent the crucial dead ends we currently face in the treatment of advanced melanoma.…”