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  • Review Article
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Haematological malignancies: at the forefront of immunotherapeutic innovation

Nature Reviews Cancer volume 15, pages 201–215 (2015)Cite this article

Subjects

Key Points

  • 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.

Abstract

The recent successes of cancer immunotherapies have stimulated interest in the potential widespread application of these approaches; haematological malignancies have provided both initial proofs of concept and an informative testing ground for various immune-based therapeutics. The immune-cell origin of many of the blood malignancies provides a unique opportunity both to understand the mechanisms of cancer immune responsiveness and immune evasion, and to exploit these mechanisms for therapeutic purposes.

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Figure 1: Strategies of co-opting physiological immune programmes.
Figure 2: Timeline of major immunotherapeutic advances in haematological malignancies.

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Acknowledgements

P.B. was supported by the US National Cancer Institute under award number T32CA009172. U.E.B. acknowledges support from the German Research Foundation (Deutsche Forschungsgemeinschaft; BU 3028/1-1). C.J.W. is supported in parts by grants NHGRI (U54HG003067), NCI (1RO1CA155010-02) and NHLBI (5R01HL103532-03); the Blavatinik Family Foundation; and the Leukaemia and Lymphoma Translational Research Program. C.J.W. is a recipient of an Innovative Research Grant for Stand Up to Cancer/AACR. The authors thank E. Fritsch, J. Ritz, R. Soiffer and P. Ott for valuable feedback on and discussion of this manuscript.

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  1. Mohini Rajasagi

    Present address: Present address: Bristol-Meyers Squibb, Princeton, New Jersey 08540, USA.,

Authors and Affiliations

  1. Department of Medical Oncology and the Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, 02215, Massachusetts, USA

    Pavan Bachireddy, Ute E. Burkhardt, Mohini Rajasagi & Catherine J. Wu

  2. Broad Institute, Cambridge, 02142, Massachusetts, USA

    Pavan Bachireddy, Mohini Rajasagi & Catherine J. Wu

  3. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Pavan Bachireddy & Catherine J. Wu

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  1. Pavan Bachireddy
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Correspondence to Catherine J. Wu.

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Pavan Bachireddy is a consultant for Jounce Therapeutics.

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Glossary

Professional antigen-presenting cells

(Professional APCs). Professional APCs comprise three major types of immune cells: dendritic cells, macrophages and B cells. Although all nucleated cell types can present intracellularly derived peptides on the ubiquitously expressed major histocompatibility complex (MHC) class I molecule, these three can additionally present antigens derived from the extracellular space, binding them to MHC class II molecules.

High mobility group box 1

(HMGB1). A DNA-binding protein that, when released by dead or damaged cells, stimulates a robust pro-inflammatory response through the binding of Toll-like receptor 4 on dendritic cells, enhancing tumour antigen presentation and driving chemotherapeutic efficacy.

Nurse-like cells

(NLCs). Stromal-like adherent cells that develop in vitro from peripheral blood mononuclear cells of patients with chronic lymphocytic leukaemia (CLL). They are tightly surrounded by CLL cells and promote their survival.

T helper 1 cell

(TH1 cell). A pro-inflammatory subset of CD4+ T cells defined by interleukin-2 and interferon-γ production, which leads to promotion of cellular immunity through CD8+ cytotoxic T cells, macrophages and natural killer cells.

TH17 cells

(T helper 17 cells). An inflammatory interleukin-17-producing subset of CD4+ T cells that is implicated in many autoimmune diseases.

Regulatory T cells

(TReg cells). A CD4+CD25hi T cell subset known to effectively suppress T cell effector functions as well as proliferation and activation of various immune cells, including antigen-presenting cells, B cells and natural killer cells. TReg cell infiltration has been implicated in multiple disease states, ranging from neoplastic growth to autoimmune dysfunction.

Programmed cell death protein 1

(PD1). An immune-checkpoint receptor expressed on activated T cells, as well as other immune subsets, that primarily functions in peripheral tissues. Binding to its ligands, PDL1 or PDL2, which are expressed on tumour and stromal cells, induces T cell exhaustion.

Natural killer cells

(NK cells). Lacking the antigen-recognition diversity of T and B cell receptors, NK cells function instead through an array of inhibitory and activating cell surface receptors, of which killer-cell immunoglobulin-like receptors have a prominent role.

Hodgkin Reed–Sternberg cells

(HRS cells). Neoplastic cells of B cell origin that serve as hallmarks of classical Hodgkin lymphoma. These cells have unusual morphology and a unique immunophenotype that does not resemble any normal cell in the body.

Bispecific T cell engagers

(BiTEs). Fusion proteins that are composed of two single-chain variable fragments, which are derived from a T cell-specific CD3-specific antibody and a tumour- targeting antibody, respectively.

Granzyme- and perforin-mediated tumour cytotoxicity

The principal mode of targeted cell killing by cytotoxic T cells (after antigen recognition on the surface of the target cell), whereby intracellular cytotoxic granules within T cells release their stores of perforin and granzymes to trigger apoptosis of the target cell.

Philadelphia chromosome

The defining translocation in chronic myeloid leukaemia between two genes on the long arms of chromosome 22 (BCR) and chromosome 9 (ABL), resulting in a novel fusion protein (BCR–ABL) that can be targeted by ABL kinase inhibitors, such as imatinib.

Chimeric antigen receptor

(CAR). A synthetically engineered receptor composed of a single-chain antibody fragment, to confer tumour recognition, coupled with intracellular signalling domains derived from the T cell receptor and a co-stimulatory molecule, most commonly either CD28 or CD137.

CAR T cells

(Chimeric antigen receptor T cells). T cells that are isolated from patients' peripheral blood, genetically modified with CARs, and then activated and expanded ex vivo and subsequently infused back into the patient a few days after a lymphodepleting chemotherapeutic regimen.

Killer-cell immunoglobulin-like receptor

(KIR). Expressed on natural killer cells, this receptor recognizes self-major histocompatibility complex class I molecules and may be activating or inhibitory; as a result, natural killer cells preferentially kill target cells that lack self-MHC class I molecules (that is, KIR ligands).

Idiotype vaccine

A cancer vaccine that targets the unique antigenic determinant located in the variable region of the B or T cell receptor that is expressed by clonally expanded malignant B or T cells, respectively.

Regulatory B cells

(BReg cells). A newly described subpopulation of B cells that remains incompletely defined in humans. BReg cells have been suggested to functionally resemble chronic lymphocytic leukaemia cells in humans and contribute to rituximab resistance in preclinical models.

Myeloid-derived suppressor cells

(MDSCs). A highly heterogeneous population of tolerogenic myeloid-derived cells often described in either granulocytic or monocytic subtypes. MDSCs have been strongly implicated in the pathogenesis of many blood malignancies, including multiple myeloma, chronic myeloid leukaemia and myelodysplasia.

CTL-associated antigen 4

(Cytotoxic T lymphocyte-associated antigen 4). CTLA4 is exclusively expressed on the surface of activated T cells, where it counteracts CD28 both by outcompeting it for its ligands, CD80 and CD86, on antigen-presenting cells and by triggering intracellular inhibitory pathways. It has an important role in maintaining immune homeostasis.

Smouldering multiple myeloma

Early-stage multiple myeloma preceding the active, clinically symptomatic phase.

NK T cells

(Natural killer T cells). A specialized subset of innate-like T cells that recognize lipid-based antigens presented by the CD1 family of major histocompatibility complex-like molecules and rapidly produce very large amounts of various cytokines without clonally expanding like 'classical' T cells.

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Bachireddy, P., Burkhardt, U., Rajasagi, M. et al. Haematological malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer 15, 201–215 (2015). https://doi.org/10.1038/nrc3907

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