Haematological malignancies: at the forefront of immunotherapeutic innovation

Abstract

The impressive potency of novel cancer immunotherapies has refocused attention on this class of agents for both solid and haematological cancers, and the robust experience of immunotherapeutic efforts specifically within haematological malignancies offers insights germane to the development of these strategies. From adoptive cellular therapy and antibody-based therapies to active cancer vaccination, early investigations in the blood malignancies provided both initial proofs of principles and informative testing grounds for agents such as allogeneic haematopoietic stem cell transplantation (allo-HSCT), donor lymphocyte infusion (DLI) and rituximab. Unique features of haematological malignancies that enable the development of immunotherapies include their well-known immune responsiveness, ease of tissue sampling to distinguish malignant from normal cells by surface marker expression, the ability to directly examine immune-based antitumour responses after allo-HSCT and DLI, and their shared sites of origin with normal immune counterparts. Lymphoid and myeloid malignant cells subvert physiological immune programmes both to directly drive cancer growth and to indirectly recruit an inflammatory, immune-supportive infiltrate. Clinical and laboratory investigations in haematological malignancies have suggested four major nodes of potential vulnerability in the cancer–immune relationship: direct targeting of surface tumour antigens; boosting immune effector number and function; activating tumour antigen-specific immunity; and overcoming inhibitory immune suppression. An appreciation of the coordination among distinct cells during an effective immune response suggests a multi-pronged combinatorial strategy for inducing potent antitumour immunity; indeed, recent clinical evidence from trials in haematological malignancies supports this paradigm. Moreover, it is becoming increasingly evident that evaluation of both leukaemic and infiltrating immune cells at the site of disease is important to identify biomarkers of immunotherapeutic response and resistance, which in turn enable selection of appropriate treatment options.