The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

Abstract

Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first Cerrano et al. CART Research and Clinical Practice FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…Immune effector cells may also be genetically engineered with the aim of improving and specifically directing their killing properties against the tumor. CAR T cells have been under development for more than 30 years (249), and recently entered the therapeutic armamentarium for lymphoproliferative diseases [as reviewed in (250)(251)(252)]. Anti-CD19 CAR T cells are currently approved by FDA and European Medicine Agency for the treatment of patients with aggressive B-cell lymphomas or B-ALL.…”

Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy

“…Another generic modifier affecting the TI is the uncontrolled and unpredictable release of cytokines resulting from non-specific interactions between administered and endogenous cells leading to cytokine release syndrome (CRS) or other off-target toxicities such as neurotoxicity. 17 Finally, the genetic background of the patient and other hidden circumstantial factors related to the host's history play a subtle and unquantifiable role in sculpting CTL function in vivo. 18 A dramatic example of discrepancy between administered dose of effector cells and their on-target deployment was described by Pockaj et al 13 decades ago.…”

Tisagenlecleucel in Acute Lymphoblastic Leukemia: A Review of the Literature and Practical Considerations

“…Various costimulatory domains are now under investigation, including 4-1BB, CD28, CD2, CD27, TLR2, and OX40. 3,25 Whereas tisagenlecleucel incorporates the 4-1BB domain, axicabtagene ciloleucel (Yescarta; Kite Pharma, Inc), an FDA-approved CAR T-cell agent for r/r large B-cell lymphoma, utilizes CD28. 26 The costimulatory variations selected for specific CAR designs may play an important role in their cellular kinetics, cytotoxic function, and safety profile.…”