T-cell-based Immunotherapies for Haematological Cancers, Part A: A SWOT Analysis of Immune Checkpoint Inhibitors (ICIs) and Bispecific T-Cell Engagers (BiTEs)

Abstract

Haematology has been at the vanguard of cancer immunotherapy. Immune checkpoint inhibitors (ICIs), bispecific T-cell engagers (BiTEs), allogeneic haematopoietic stem cell transplantation (allo-HSCT) and donor lymphocyte infusion (DLI), as well as adoptive T-cell therapies outside the setting of allo-HSCT, have been approved for distinct haematologic malignancies producing durable responses in otherwise untreatable patients. Despite recent advances, immunotherapies do not benefit most patients, due to resistance or lack of response, and are only approved in specific settings. Moreover, immunotherapies are expensive and may produce severe immune related adverse reactions. Combination therapy complicates the picture and requires further evaluation. This review considers the current status and future perspectives of ICIs and BiTEs approved for haematological malignancies by analysing their strengths, weaknesses, opportunities and threats (SWOT). The biological rationale for anti-cancer mechanisms, clinical data for specific haematological cancers, efficacy, toxicity, response and resistance profiles, novel strategies to improve these characteristics as well as the potential targets to enhance or expand the application of ICIs and BiTEs are also discussed. Cancer immunotherapy has revolutionised oncology care, prolonging survival in rapidly fatal diseases. The number of patients eligible for immune-based cancer treatments is increasing, with immunotherapies being adopted in first line setting (1). Novel targets and combination therapies are set to expand cancer immunotherapy applications. Haematology has been central to these advances. Allogeneic haematopoietic stem cell transplantation (allo-HSCT) was the first clinical application of cancer immunotherapy (1957), while monoclonal antibodies (mAb) were the next success story with the approval of rituximab (anti-CD20 mAb) for B-cell malignancies (1997). These breakthroughs contributed valuable advances to the evolution of cancer immunotherapies. Immune checkpoint inhibitors, developed through mAbs, target T-cells and upregulate anticancer immunity, producing remarkable success in solid and haematologic malignancies. Bispecific T-cell engager (BiTE) antibodies, which redirect T-cells to tumour cells to perform target cell killing, were originally approved for B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), with blinatumomab gaining approval in 2014. Development of novel adoptive T-cell (ATC) therapies in haematology, such as chimeric antigen receptor (CAR)-T-cells, has generated great interest with potential for disease cure. Yet, despite these advances, several challenges remain. Limited breadth of application, unpredictable efficacy, and limiting toxicity profiles attest the need to drive forward change. This review discusses the strengths, weaknesses, opportunities and threats (SWOT) associated with immune checkpoint inhibitors (ICIs) and BiTEs, providing an up-to-date review of licensed agents for haematological malignancies. The biological rationale for a...

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