Chimeric antigen receptor (CAR) T-cell therapy has been extremely successful in treating relapsed/refractory B-cell malignancies, with six CAR T-cell products now FDA approved. Unfortunately, very limited success has been seen in translating CAR T-cell therapy for T-cell malignancies, primarily due to the lack of a cancer-specific target antigen on malignant T cells. This has resulted in several challenges in translating this innovative immunotherapy for T-cell disease: (i) CAR T cells designed against a T-cell antigen undergo fratricide (self-killing) due to the shared antigen expression on normal and malignant T cells, leading to difficulty in CAR T-cell expansion; (ii) off-tumor on-target toxicity from T-cell antigen directed CAR T cells can result in life-threatening immunosuppression from T-cell aplasia and (iii) the inability to isolate healthy T cells from a patient with a T-cell malignancy can result in product contamination, wherein malignant T cells may be inadvertently genetically modified to express the CAR, thereby making them resistant to CAR therapy. To the best of our knowledge, no tumor-specific antigen has yet been identified with universal expression on cancerous T cells, thereby hindering the development CAR T-cell therapy for this disease. Numerous approaches have been tested to address each of these challenges, such as (i) disrupting target antigen expression on CAR-modified T cells, (ii) targeting antigens with limited expression on T cells, and (iii) using third party donor cells that are either non-alloreactive or have been genome edited at the T-cell receptor α constant (TRAC) locus. In this presentation, we will discuss CAR-based approaches that have been explored both in preclinical and clinical studies targeting T-cell antigens, as well as examine other potential strategies that can be used to successfully translate this therapy for T-cell disease.

Learning Objectives: 

1. Discuss the specific challenges involved in targeting T-cell malignancies with CAR T-cell therapy.

2. Review the different strategies utilized by investigators to overcome these barriers.

3. Discuss clinical trials testing CAR T-cell therapy for T-cell malignancies.