Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T‐cell therapy for chronic lymphocytic leukemia

Abstract

Studies of chimeric antigen receptor (CAR) T‐cell therapy in chronic lymphocytic leukemia (CLL) have demonstrated the potential to produce deep remissions—and possibly cures—in some patients with heavily pretreated, high‐risk, relapsed, and refractory disease. Unfortunately, most clinical trials of CAR T cells in CLL report complete responses only in the minority of patients, although recent studies have begun to elucidate the factors most predictive of response. These studies have suggested strategies for optimizing CAR T‐cell fitness as well as the pre‐existing host immune response, approaches that will likely lead to improvements in the efficacy of CAR T cells in CLL. Treating patients earlier in the course of their disease or using combination therapies with CAR T cells may further enhance efficacy. In this review, we summarize the existing literature on CAR T cell therapy in CLL, discuss mechanisms of response and resistance, and describe challenges facing the field.

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

“…Despite the high response rate achieved by CAR-T cells in other hematological malignancies, the rate of complete remission in CLL is currently far lower, although at least a large proportion of patients showed a clinical response to CD19 CAR-T cells [142]. The challenge now is to ameliorate and to increase the rate of complete remissions, given also that patients who achieve it have very low risk of disease relapse [143].…”

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

“…Over the past decades, the number of patients referred for allogeneic hematopoietic cell transplantation has dropped significantly, 133 but the procedure should be recommended to young/fit patients in whom BCR/BCL2 inhibitor treatment fails, particularly in those with TP53 aberrations, or in the case of Richter transformation. 134,135 Moreover, although chimeric antigen receptor T cells could also be appropriate in this situation and the results are promising, 136 none of the commercially available products is yet approved for this indication.…”

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

“…However, also using the association of ibrutinib and venetoclax we do not know as yet if any of these patients are cured. In this population, we are hopeful that using novel agents in combination and continued improvements in chimeric antigen receptor (CAR) T‐cell therapy approaches will provide better results …”

“…In this population, we are hopeful that using novel agents in combination and continued improvements in chimeric antigen receptor (CAR) T-cell therapy approaches will provide better results. 67 Finally, ibrutinib has been the first targeted treatment tested in early stage CLL patients at risk to progress towards an active form of disease requiring treatment. Results of the placebo-controlled doubleblinded CLL12 trial allow to conclude that ibrutinib significantly improves event-free survival, PFS, and time to next treatment in patients with treatment-naive early-stage CLL when compared to placebo.…”