Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

Abstract

Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy. Furthermore, there is evidence that BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the BiTE therapy blinatumomab. To overcome these inadequate T-cell responses, BiTEs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of BiTEs in solid malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination therapies and a few other less studied combinations.

KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance

“…Bispecific T-cell engagers (BiTEs) are a class of antibody-like biotherapeutics designed with dual specificity (Figure 3). By linking two distinct single-chain variable fragments (scFvs), BiTEs target both a tumor-associated antigen and a TCR component necessary for T-cell activation, typically CD3 [85]. This configuration allows BiTEs to attract cytotoxic Tlymphocytes to tumor cells, activating the T-cells to eliminate the cancerous targets.…”

Recent advances in cellular immunotherapy for lymphoid malignancies

“…Notably, glofitamab demonstrated favorable efficacy in terms of duration or response in relapsed or refractory DLBCL as 70% of patients continue to be in CR after 18 months [ 51 ]. Therefore, bispecific antibodies represent effective approaches for subsets of relapsed or refractory lymphoid malignancies ( Table 2 ), and bispecific combination approaches targeting various antigens are currently active areas of investigation [ 52 ].…”

Changing Trends in B-Cell Non-Hodgkin Lymphoma Treatment: The Role of Novel Monoclonal Antibodies in Clinical Practice

“…Furthermore, there is evidence that bsAb therapy can increase immune checkpoint expression, which is considered a significant escape mechanism in this type of therapy. To overcome these inadequate T-cell responses, bsAbs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules, or oncolytic viruses [64].…”