Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

Abstract

The concepts for T-cell redirecting bispecific antibodies (TRBAs) and chimeric antigen receptor (CAR)-T cells are both at least 30 years old but both platforms are just now coming into age. Two TRBAs and two CAR-T cell products have been approved by major regulatory agencies within the last ten years for the treatment of hematological cancers and an additional 53 TRBAs and 246 CAR cell constructs are in clinical trials today. Two major groups of TRBAs include small, short-half-life bispecific antibodies that include bispecific T-cell engagers (BiTE®s) which require continuous dosing and larger, mostly IgG-like bispecific antibodies with extended pharmacokinetics that can be dosed infrequently. Most CAR-T cells today are autologous, although significant strides are being made to develop off-the-shelf, allogeneic CAR-based products. CAR-Ts form a cytolytic synapse with target cells that is very different from the classical immune synapse both physically and mechanistically, whereas the TRBA-induced synapse is similar to the classic immune synapse. Both TRBAs and CAR-T cells are highly efficacious in clinical trials but both also present safety concerns, particularly with cytokine release syndrome and neurotoxicity. New formats and dosing paradigms for TRBAs and CAR-T cells are being developed in efforts to maximize efficacy and minimize toxicity, as well as to optimize use with both solid and hematologic tumors, both of which present significant challenges such as target heterogeneity and the immunosuppressive tumor microenvironment.

Antibody Structure and Function: The Basis for Engineering Therapeutics

“…As the field evolves, more exploration into novel formats with different potency and kinetics of target engagement will expand possibilities for T cell therapeutics [539]. There is ongoing clinical development to understand how best to employ T cell redirection molecules versus chimeric antigen receptors [542].…”

Human macrophages engineered to secrete a bispecific T cell engager support antigen-dependent T cell responses to glioblastoma

“… 9 These disadvantages require frequent high-dose systemic administration to achieve efficacy, which can be associated with off-target toxicities. 10 Reducing treatment frequency and toxicities through sustained local delivery may therefore be of benefit to improving outcomes and quality of life for patients treated with BiTEs.…”

A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia

“…In addition, targeting epitopes closer to the membrane reportedly results in the exclusion of the negative regulatory protein CD45 in the synapse between T cells and target cells, 26 translating into increased potency of the T-cell response and killing. 27 As such, binding the membrane proximal CD33 C2 epitope for a CD3 redirection bispecific antibody may offer an additional benefit over the membrane distal V domain epitope.…”