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.

Nanobodies in cell-mediated immunotherapy: On the road to fight cancer

“…Since then, there have been multiple clinical trials on CD7- and CD38-targeting CAR-T cells to treat a number of different blood and bone marrow cancers ( 125 ). Moreover, a phase I/II trial was conducted to evaluate the safety and efficacy of anti-CD7 CAR-NK cells in CD7 + leukemia and lymphoma patients (NCT02742727).…”

Education and Empowering Special Forces to Eradicate Secret Defectors: Immune System-Based Treatment Approaches for Mature T- and NK-Cell Malignancies

“…Furthermore, idecabtagene vicleucel (Abecma TM ) and ciltacabtagene autoleucel (Carvykti TM ) have been established in the therapy of r/r multiple myeloma [149,150] and brexucabtagene autoleucel (Tecartus TM ) in the therapy of r/r mantle cell lymphoma as well as r/r ALL [151]. In the following, we will summarize preclinical and clinical efforts of CAR T cell therapies in MTCL/L and will focus on challenges, that arise during the therapy of a T cell employing a T cell, and how to overcome them [152,153].…”

Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?

“…The most promising therapeutics are immunotherapies, which are increasingly being incorporated into clinical trials and daily clinical practice. Since the current frontline treatment and chimeric antigen receptor (CAR)-based immunotherapy for T-ALL were recently reviewed [ 1 , 137 ], we, here, exclusively discussed the small-molecule inhibitors and mAbs targeting aberrant pathways or themselves that are associated with T-LICs and leukemic niches, with the other agents omitted in this review unless specified otherwise.…”

“…In this regard, identification of all the components of γ-secretase complexes and their respective substrates are of particular importance for targeted therapeutic development. In addition, CAR-based therapy provides an alternative strategy to target leukemia cells, but there are many obstacles to their use including cytokine release syndrome, fratricide killing, and early exhaustion [ 137 ]. In contrast, developing mAbs specifically against T-LICs or leukemic niches (e.g., anti-NOTCH1 and anti-IL7Rα), along with chemotherapy, will open a brand-new era for the treatment of T-ALL in the very near future.…”