CAR-T cell development for Cutaneous T cell Lymphoma: current limitations and potential treatment strategies

Abstract

Chimeric antigen receptor (CAR)-T therapy has demonstrated remarkable outcomes for B cell malignancies, however, its application for T cell lymphoma, particularly cutaneous T cell lymphoma (CTCL), has been limited. Barriers to effective CAR-T cell therapy in treating CTCL include T cell aplasia in autologous transplants, CAR-T product contamination with leukemic T cells, CAR-T fratricide (when the target antigen is present on normal T cells), and tumor heterogeneity. To address these critical challenges, innovative CAR engineering by targeting multiple antigens to strike a balance between efficacy and safety of the therapy is necessary. In this review, we discuss the current obstacles to CAR-T cell therapy and highlight potential targets in treating CTCL. Looking forward, we propose strategies to develop more powerful dual CARs that are advancing towards the clinic in CTCL therapy.

Harnessing the immune system in the treatment of cutaneous T cell lymphomas

“…CARs are recombinant receptor proteins engineered to redirect the function of T lymphocytes ( 81 ). They are composed of an extracellular antigen binding moiety, extracellular hinge region, transmembrane domain, and intracellular T cell activation component ( 82 ). The CAR is anchored to the plasma membrane by the transmembrane domain, which fosters stability of antigen binding.…”

“…Tumor cells attempt to evade the immune system through a variety of mechanisms, such as decreased expression of major histocompatibility complex (MHC) class I molecules, which reduces the antigen presentation capacity ( 83 ). CAR T cells have many advantages in comparison to conventional immune approaches, including higher antigen affinity for binding unprocessed target antigens independent of MHC ( 82 ). Additionally, with their own costimulatory domains, CAR T cells can increase immune responses to apoptosis and lyse target cells ( 82 ).…”

“…CAR T cells have many advantages in comparison to conventional immune approaches, including higher antigen affinity for binding unprocessed target antigens independent of MHC ( 82 ). Additionally, with their own costimulatory domains, CAR T cells can increase immune responses to apoptosis and lyse target cells ( 82 ). Recent advances have led to fourth and fifth generation CARs, which have a transgenic cytokine or intracellular domain of a cytokine receptor to increase cytotoxicity, activate cytokine-driven signaling, recruit innate immune cells for antigen-negative tumor cells, and promote T cell activation ( 84 , 85 ).…”

“…Use of CAR T therapy for CTCL, however, has specific challenges. First, as healthy and malignant T cells share commonalities, this could inadvertently lead to CAR T cells killing healthy T cells, prompting T cell aplasia and immunodeficiency ( 82 ). There is no treatment for quickly remedying T cell depletion, unlike intravenous immunoglobulin for B cell aplasia, which makes this a more concerning adverse event in CTCL patients.…”

“…Additionally, both healthy T cells and circulating tumor T cells may be simultaneously collected when the CAR product is being created. This contamination may promote both tumor outgrowth after ex vivo amplification and resistance ( 82 , 86 ). In a patient with B-ALL, for instance, the CAR gene was accidentally introduced into a leukemic B cell during the T cell manufacturing which can induce resistance ( 87 ).…”