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  • Review Article
  • Published:

Evolving synergistic combinations of targeted immunotherapies to combat cancer

Key Points

  • Clinical trials have validated immuno-oncology as a new pillar of anticancer therapy.

  • Combinations could involve two (or more) sequential or simultaneous immunotherapies, and/or immunotherapies in combination with conventional cancer therapies.

  • The programmed cell death protein 1 (PD1)–PD1 ligand 1 (PDL1) axis seems to be the most promising immuno-oncology target, and its blockade is likely to become the main foundation for combination strategies in the foreseeable future.

  • The paradigm of immuno-oncology combinations is to block PD1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) simultaneously; this blockade is synergistic and shows clinical benefit in patients with melanoma but has an increased frequency of immune-mediated, albeit clinically manageable, toxic effects.

  • Even if designing rational combinations that provide optimal benefit to patients with cancer is a challenging process, there are a number of different combination immuno-oncology therapies currently in development.

Abstract

Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients.

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Figure 1: Receptor–ligand pairs of the immune system that are amenable to pharmacological manipulation with immunostimulatory monoclonal antibodies.
Figure 2: The rapid evolution of combination immunotherapy.
Figure 3: Schematic representation of the main mechanisms of action postulated to mediate synergistic effects of combined immunotherapies.
Figure 4: Building immunotherapy combinations on the pillar of PD1 or PDL1 blockade, and steps in the development of an immunotherapy combination.
Figure 5: Preclinical and clinical development of combinations of immunostimulatory monoclonal antibodies.
Figure 6: Biomarker discovery for combination immunotherapy and proposed new concepts for clinical management with immunotherapy based on biomarkers.

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Acknowledgements

The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise. The authors wish to acknowledge R. Turner and K. McGlynn of StemScientific, an Ashfield Company, part of UDG Healthcare plc, funded by Bristol-Myers Squibb, for coordinating the writing process and providing editorial support.

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Correspondence to Ignacio Melero.

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D.M.B. and A.J.K. are full-time employees of Bristol-Myers Squibb. I.M, M.A.A, J.-L.P.G. and J.H. declare no competing interests.

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Supplementary information

41568_2015_BFnrc3973_MOESM222_ESM.pdf

Supplementary information S1 (table) | Combinations of PD-1/PD-L1 antagonistic antibodies with conventional anticancer therapy (Source: https://clinicaltrials.gov/ accessed on May 2, 2015) (PDF 117 kb)

41568_2015_BFnrc3973_MOESM223_ESM.pdf

Supplementary information S2 (table) | Combinations of immunoregulatory antibodies (excluding PD-1/PDL1 antagonistic antibodies, see Suppl. Table 1) with conventional anticancer therapy. (Source: https://clinicaltrials.gov/ accessed on May 2, 2015). (PDF 148 kb)

41568_2015_BFnrc3973_MOESM224_ESM.pdf

Supplementary information S3 (table) | Combinations including two or more immunotherapy agents based on PD-1/PD-L1 blockade. (Source: https://clinicaltrials.gov/ accessed on May 2, 2015). (PDF 129 kb)

Glossary

Immune synapses

Transient cell–cell interactions of T lymphocytes that are highly structured to favour the organized interaction of surface receptors and are sustained by adhesion molecules and reorganization of the cytoskeleton and a centriole.

T cell receptors

(TCRs). Antigen-specific surface receptors on T lymphocytes that recognize peptides (antigens) bound to self-antigen-presenting molecules of the major histocompatibility complex. Clonally distributed repertoires of TCRs result from random gene rearrangement and are shaped by processes of positive and negative selection in the thymus.

Fc

Crystallizable fragment of immunoglobulins that corresponds to the constant regions of the heavy chains, which convey biological properties to the antibody but are not involved in antigen recognition.

Regulatory T cells

(TReg cells). A special subset of T cells that function to repress the activation of other T lymphocytes. The main TReg cell subset is characterized by expression of the transcription factor forkhead box P3.

Antigen-presenting cells

(APCs). Cells that have the main function of presenting antigens to T lymphocytes. The most efficient APCs belong to the various lineages of dendritic cells.

T cell exhaustion

A dysfunctional state of T cells characterized by the inability to proliferate and exert effector functions while still viable.

Major histocompatibility complex

(MHC). A genomic locus encoding the main transplant antigen molecules that function to present peptide antigens to T lymphocytes. MHC class I molecules present antigens to CD8+ T lymphocytes, and MHC class II molecules present antigens to CD4+ T lymphocytes.

Autologous

Obtained from the same individual.

Antibody-dependent cellular cytotoxicity

(ADCC). An immune mechanism of cell killing that is mediated by natural killer cells and macrophages and that leads to the destruction of antibody-coated target cells.

Hypophysitis

The anterior pituitary gland (adenohypophysis), when inflamed, can cause dysfunction and require substitutive therapy of the relevant hormones owing to insufficient function (panhypopitituarism).

Abscopal effect

A therapeutic effect of radiotherapy achieved outside the irradiated field in a patient with metastatic cancer. The term is also generalized to other local treatments with systemic effects.

Stereotactic radiotherapy

The precise delivery of ionizing radiation to tumour lesions by means of computer-assisted spatial localization to avoid damage to the surrounding non-tumoural tissue.

Commensal flora

Microbiota (for example, bacteria and fungi) that live on epithelial surfaces of an organism without causing harm or even exerting symbiotic functions.

Ectopic

In the context of this Review refers to the presence or expression of an antigen in an organ or cell type that does not normally express it.

Immune editing

The selection of less immunogenic cancer cell variants as a consequence of the evolutionary pressure of immune surveillance.

Neoantigens

Antigens of tumours that result from a mutation in an exon sequence, thus giving rise to a peptide presented by a self-human leukocyte antigen (HLA) molecule. These antigens are individual to the tumour of each patient and are not shared with other cases.

Epitopes

Minimal elements of an antigen that are recognized by an antibody, or the peptide within a protein sequence that is specifically recognized by a given T cell receptor.

Anergy

An epigenetically induced dysfunctional state in which there is no immune response by T lymphocytes to a specific antigen.

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Melero, I., Berman, D., Aznar, M. et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer 15, 457–472 (2015). https://doi.org/10.1038/nrc3973

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