Chimeric Antigen Receptor Based Cellular Therapy for Treatment Of T-Cell Malignancies

Abstract

T-cell malignancies can be divided into precursor (T-acute lymphoblastic leukemia/lymphoblastic lymphoma, T-ALL/LBL) and mature T-cell neoplasms, which are comprised of 28 different entities. Most of these malignancies are aggressive with rather poor prognosis. Prognosis of relapsed/refractory (R/R) disease is especially dismal, with an expected survival only several months after progression. Targeted therapies, such as antiCD30 immunotoxin brentuximab vedotin, antiCD38 antibody daratumumab, and anti-CCR4 antibody mogamulizumab are effective only in subsets of patients with T-cell neoplasms. T-cells equipped with chimeric antigen receptor (CAR-Ts) are routinely used for treatment of R/R B-cell malignancies, however, there are specific obstacles for their use in T-cell leukemias and lymphomas which are fratricide killing, risk of transfection of malignant cells, and T-cell aplasia. The solution for these problems relies on target antigen selection, CRISPR/Cas9 or TALEN gene editing, posttranslational regulation of CAR-T surface antigen expression, and safety switches. Structural chromosomal changes and global changes in gene expression were observed with gene-edited products. We identified 49 studies of CAR-based therapies registered on www.clinicaltrials.gov. Most of them target CD30 or CD7 antigen. Results are available only for a minority of these studies. In general, clinical responses are above 50% but reported follow-up is very short. Specific toxicities of CAR-based therapies, namely cytokine release syndrome (CRS), seem to be connected with the antigen of interest and source of cells for manufacturing. CRS is more frequent in antiCD7 CAR-T cells than in antiCD30 cells, but it is mild in most patients. More severe CRS was observed after gene-edited allogeneic CAR-T cells. Immune effector cell associated neurotoxicity (ICANS) was mild and infrequent. Graft-versus-host disease (GvHD) after allogeneic CAR-T cells from previous hematopoietic stem cell donor was also observed. Most frequent toxicities, similarly to antiCD19 CAR-T cells, are cytopenias. CAR-based cellular therapy seems feasible and effective for T-cell malignancies, however, the optimal design of CAR-based products is still unknown and long-term follow-up is needed for evaluation of their true potential.

Keywords: CAR-T cells; T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma; T-cell lymphoma; chimeric antigen receptor (CAR); immunotherapy; therapy.

Figure 1

Desired and undesired effects of CAR-based therapy in T-cell malignancies and selected circumventing approaches. Besides on-target antitumor activity (A) the anti-T-NHL CAR-T cell therapy can be complicated by fratricide – on target killing of CAR-T cells expressing T-cell antigens (B), which can be overcome by limiting superficial T-cell antigen expression using genetic as well as posttranslational modifications; contamination of the final product by transduced tumor cells (C) is another undesired effect observed in anti-T-NHL CAR-T setting and can be overcome by the use of allogeneic CAR-T cells, transduction of NK-cells or by selection and use of ƴδ T lymphocytes. BiP, immunoglobulin heavy chain binding protein; COPI, coated protein I; COPII, coated protein II; ds-DNA, double-stranded DNA; gRNA, guiding RNA; KDEL receptor, K = lysine, D = aspartic acid, E = glutamic acid, L = leucin; PAM, protospacer adjacent motif.