Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

Abstract

The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape, which has accelerated the progress of immunotherapy. Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers, including stem cell transplantation, immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success. Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed. To provide clinicians with timely information on these revolutionary therapeutic approaches, the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy. Here, we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies. We further discuss the specific mechanisms of action, summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies, as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.

Fig. 1

The development of immunotherapy for hematologic malignancies. a Types of immunotherapies for treating hematologic malignancies. b The journey of the history of immunotherapy for hematologic malignancies

Fig. 2

Mechanisms of action of four kinds of immunotherapy drugs. a The monoclonal antibodies (mAbs), when combined with their targets, can kill cancer cells by direct induction of apoptosis through programmed cell death, antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent macrophage-mediated phagocytosis. b The BiTE ((bispecific T cell engager) molecule usually targets one CD3 molecule and one tumor antigen simultaneously. Thus, in addition to the anti-cancer role of the tumor antigen-targeted antibody, it can promote the activation and recruitment of CD3 + T cells. c After bound to the tumor surface antigen, the antigen undergoes endocytosis and the antibody-drug conjugates (ADCs) will be internalized into the tumor cell and subsequently transported to the lysosome to release the cytotoxic payload, which can induce apoptosis and kill surrounding cancer cells through bystander effects. d The blockade of PD-1 or its ligands PD-L1 and PD-L2 can help to restore the anti-tumor immunity of the body and simultaneously enhance the lysis effect of cytotoxic T cells to achieve the effect of tumor eradication. CTLA-4 inhibitors can block the binding between CTLA-4 molecule and B7 during T cell activation, increase the level of the recognition of T cells to tumor-associated antigens (TAAs) and enhance the anti-tumor responses of the body’s immune effector cells

Fig. 3

The evolution of CAR design and the process of CAR-T therapy in clinic. a The design of the CAR has undergone several updates throughout the evolution of CAR-T therapy. To date, there have been five generations of CAR structures. b CAR-T cell therapy is a multi-step process that involves selecting eligible patients, collecting cells, manufacturing CAR-T cells, lymphodepletion and infusion of CAR-T cells and subsequent longitudinal follow-up

Fig. 4

How immunotherapies work? To promote “Cancer-Immunity Cycle”. The “Cancer-Immunity Cycle” can be divided into multiple steps. Dysregulation of the “Cancer-Immunity Cycle” is the consequence of tumorigenesis and treatment failure. Meanwhile, the TME may also suppress these effector cells engaged in the “Cancer-Immunity Cycle” and resultant cancer immune evasion. Numerous factors that play a part in any step of this cycle offer a wide range of potential therapeutic targets: (i) promoting antigen release, presentation and recognition; (ii) priming and activating the immune response; (iii) overcoming immune evasion; (iv) targeting immune suppression in the TME