Redirecting T cells to hematological malignancies with bispecific antibodies

Abstract

There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need, because it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibodies (BsAbs) is an attractive strategy. BsAbs are an "off-the-shelf" product that is easily scalable in contrast to adoptive T-cell therapies. Among these, the bispecific T-cell engager blinatumomab has emerged as the most successful BsAb to date. It consists of 2 single-chain variable fragments specific for CD19 present on B-cell malignancies and CD3 expressed on almost all T cells. Blinatumomab has shown potent antitumor activity as a single agent, particularly for acute lymphoblastic leukemia, resulting in its US Food and Drug Administration approval. However, although successful in inducing remissions, these are normally short-lived, with median response durations of <1 year. Nevertheless, the success of blinatumomab has reinvigorated the BsAb field, which is bustling with preclinical and clinical studies for not only B-cell-derived lymphoblastic leukemia and lymphoma but also acute myeloid leukemia and multiple myeloma. Here, we will review the successes and challenges of T-cell-targeted BsAbs for the immunotherapy of hematological malignancies with special focus on conducted clinical studies and strategies to improve their efficacy.

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…Another promising strategy is to modulate affinity of Fc fragment for APCs capable of recruiting T cells, leading to epitope spreading and immunization against tumor [93]. Future directions include also combinatory therapies, such as concomitant administration with ICIs [73 && ] to remove inhibitory stimuli from the recruited host T cells or DLI to maximize GVT while reducing GVHD [94].…”

Epidemiology, outcome, targeted agents and immunotherapy in adolescent and young adult non‐Hodgkin and Hodgkin lymphoma

“…It has shown impressive clinical results for CD19‐positive B‐cell precursor ALL. Therefore, the FDA approved its use for the treatment of adult and, in 2018, paediatric patients with B‐ALL (Velasquez et al , ) (Table ). The anti‐tumour effects of blinatumomab in B‐NHL patients have been further confirmed in a phase I/II trial for DLBCL, MCL and FL, achieving an ORR of 69% in all NHL subtypes and 55% for DLBCL with a substantial duration of response of > 13 months (Goebeler et al , ).…”

Current developments in immunotherapy in the treatment of multiple myeloma

“…29 Furthermore, new experimental therapies, such as CAR T cells, bispecific antibodies to redirect T cells toward myeloma cells, and tumor vaccines, are on the verge of clinical development and hold substantial promise for future therapyturning approaches to MM. 67,69,73,[83][84][85]…”