Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: bispecific T-cell engagers and chimeric antigen receptors

Abstract

Recent advances in antibody technology to harness T cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), have led to innovative methods for directing cytotoxic T cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T cells and cancer cells. Another approach infuses ex vivo-engineered T cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR). Both bispecific antibodies and CARs circumvent natural target cell recognition by creating a physical connection between cytotoxic T cells and target cancer cells to activate a cytolysis signaling pathway; this connection allows essentially all cytotoxic T cells in a patient to be engaged because typical tumor cell resistance mechanisms (such as T-cell receptor specificity, antigen processing and presentation, and major histocompatibility complex context) are bypassed. Both the bispecific T-cell engager (BiTE) antibody construct blinatumomab and CD19-CARs are immunotherapies that have yielded encouraging remission rates in CD19-positive r/r ALL, suggesting that they might serve as definitive treatments or bridging therapies to allogeneic hematopoietic cell transplantation. With the introduction of these immunotherapies, new challenges arise related to unique toxicities and distinctive pathways of resistance. An increasing body of knowledge is being accumulated on how to predict, prevent, and manage such toxicities, which will help to better stratify patient risk and tailor treatments to minimize severe adverse events. A deeper understanding of the precise mechanisms of action and immune resistance, interaction with other novel agents in potential combinations, and optimization in the manufacturing process will help to advance immunotherapy outcomes in the r/r ALL setting.

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…1 Breakthroughs were achieved by the bispecific T cell engager (BiTE) antibody blinatumomab and chimeric antigen receptors for genetic engineering of T cells (CAR T cells). 2 Promising results were also obtained with novel CD19 antibodies that were optimized by Fc engineering to enhance their therapeutic efficacy in recent years. 3 , 4 These antibody modifications aimed to improve the antibody's affinity to activating Fcγ receptors (FcγR) on various effector cells and thereby boost its ability to elicit effector cell-mediated killing of leukemia cells.…”

“…1B). 2 In addition, CD19 antibody drug conjugates (ADC) are tested in clinical trials. 18-20 In our opinion, Fc engineered antibodies may offer certain advantages over blinatumomab or CD19 CAR T cells because Fc engineered antibodies are easy to apply and show only limited toxicity.…”

“…1A). 2 The first scFv is specific for CD19 while the second one engages the CD3 trigger molecule on T cells. Blinatumomab proved highly efficient in adult BCP-ALL and B-cell lymphoma patients as well as in pediatric BCP-ALL.…”

“…Blinatumomab proved highly efficient in adult BCP-ALL and B-cell lymphoma patients as well as in pediatric BCP-ALL. 2 , 21 , 22 It has been approved by the FDA for the treatment of relapsed or refractory adult and pediatric ALL patients and current trials are in planning employing blinatumomab in the upfront non-relapsed setting in pediatric ALL also. Likewise, impressive effects in both adults and children were achieved by administration of genetically modified T cells which express a CD19 specific CAR consisting typically of a CD19 scFv fused to intracellular signal transduction domain of CD3ζ for activation and at least one costimulatory domain, e.g.…”

“…1A). 2 , 23-24 For generation of autologous CAR T cells, T cells are isolated, expanded ex vivo, and transduced with the CD19 specific CAR construct using viral transduction methods, and re-infused into the patient. Costimulatory domains included in the CAR were shown to be necessary to achieve CAR T cell expansion in the patient and for long persistence, which provides ongoing control of the disease.…”