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Combination cancer immunotherapy and new immunomodulatory targets

Key Points

  • Tumours actively inhibit the antitumour immune response.

  • The programmed cell death protein 1–programmed cell death 1 ligand 1 (PD1–PDL1) pathway has a natural role in regulating peripheral tolerance and restraining over-exuberant immune responses.

  • PDL1 is a critical dominant immunoinhibitor in many tumour types, leading to immune evasion by the tumour. PD1 pathway blockade unleashes a previously exhausted immune response that is focused on tumour neoantigens.

  • Immunotherapies that increase the antitumour immune response, such as interleukin-2, or blockade of cytotoxic T lymphocyte antigen 4 (CTLA4), PD1 or PDL1 can benefit a moderate number of patients with cancer, with a durable clinical benefit in some.

  • Many patients fail to develop tumour shrinkage when blocking only one immune checkpoint, and increasing response rates is a major and achievable goal.

  • Given the tolerability and efficacy of PD1 pathway blockade in clinical trials it is a good foundation for combination therapies seeking to increase response rates.

  • Once PD1 or CTLA4 are blocked, many other therapies can augment their efficacy, including blockade of other immunoinhibitory pathways, stimulation by activating pathways such as tumour necrosis factor receptor superfamily members, some chemotherapies, radiation, epigenetic modifiers, targeted therapies, angiogenesis blockade, augmentation of natural killer cell activity, chimeric antigen receptor T cell therapies, and vaccines.

  • Therapeutics may work by blocking immunoinhibitory targets or stimulating immunoactivating targets not only on lymphocytes but also on macrophage, natural killer and stromal cells to overcome failure to respond to single checkpoint blockade.

Abstract

Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.

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Figure 1: T cell activation is a multiple-signal process.
Figure 2: Tumours can express co-inhibitory and co-stimulatory ligands.
Figure 3: Immunoregulatory receptors expressed on the cell surface of regulatory T cells.
Figure 4: Activating and inhibitory receptors on natural killer cells.
Figure 5: Immunosuppressive factors in the tumour microenvironment.

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Acknowledgements

G.J.F. acknowledges research support from grants P50CA101942, U54CA163125, P01AI054456 and R01AI089955. K.M.M. acknowledges research support from the Claudia Adams Barr Program for Innovative Cancer Research, an American Association for Cancer Research Basic Cancer Research Fellowship (14-40-01-MAHO), and an American Society of Clinical Oncology Young Investigator Award supported by the Kidney Cancer Association.

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Correspondence to Gordon J. Freeman.

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Competing interests

G.J.F. has patents pending royalties on the programmed cell death protein 1 (PD1) pathway from Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, and Novartis. G.J.F. has served on advisory boards for CoStim, Novartis, Roche, and Bristol-Myers Squibb. K.M.M. and P.D.R. declare no competing interests.

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Glossary

Immunoediting

Immunological processes that identify and eliminate cancer cells. Also known as immune surveillance.

Cytotoxic T lymphocyte antigen 4

(CTLA4). An immune checkpoint that competes with CD28 for its B7 ligands on antigen presenting cells.

Neoantigens

Novel protein sequences that arise during cancer-associated mutagenesis and that can be processed into peptide antigens that are presented by MHC and recognized as foreign by T cells.

Programmed cell death ligand 1

(PDL1). An immune checkpoint ligand expressed on immune cells, some normal tissues and many tumours. PDL1 binds to programmed cell death protein 1 on lymphocytes to inhibit T cell receptor signalling and activation.

T cell exhaustion

A state of T cell non-responsiveness due to chronic activation.

Programmed cell death protein 1

(PD1). An immune checkpoint receptor expressed on activated lymphocytes and highly expressed on exhausted T lymphocytes.

Interferon-γ

(IFNγ). This cytokine triggers diverse cellular responses including macrophage activation and propagation of an immune response, as well as the expression of negative regulatory factors such as programmed cell death 1 ligand 1 and indoleamine 2,3-dioxygenase.

Immune checkpoints

Inhibitory pathways that regulate the adaptive immune responses.

R-CHOP

Acronym for the immunochemotherapy regimen used to treat non-Hodgkin lymphoma: rituximab (R); cyclophosphamide (C); hydroxydaunorubicin (H); Oncovin (O; Genus Pharmaceuticals; vincristine); prednisone (P).

Breakthrough designations

The US Food and Drug Administration (FDA) designation for drugs that, based on preliminary clinical evidence, may substantially improve patient outcomes over available treatments. Breakthrough designation gives access to intensive guidance from the FDA regarding product development.

Objective response rates

Percentage of patients whose tumors decrease in size with therapy. For example, by the RECIST (Response Evaluation Criteria in Solid Tumours) criteria, the percentage of patients whose tumours decrease by 30% or more.

Superagonist

An agent that produces a supra-physiological response, greater than the response seen in normal physiology.

Co-stimulatory signal

A second, non-antigen-specific signal that works with T cell receptor signalling to increase T cell activation.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of myeloid lineage cells with immunosuppresive activities.

Histone deactylase

An intracellular protein that regulates gene transcription by modifying histones and thereby chromosome structure.

BRAF

A serine/threonine kinase often associated with solid tumour oncogenesis and resistance to therapy; mutant BRAF may be an effective target for therapeutics, as seen with vemurafenib in V600E-mutated melanoma.

Cross-presentation

The ability of some antigen presenting cells to take up extracellular proteins or cells and present their antigens in the context of MHC class I.

TNF receptors

(TNFRs). A large family of proteins associated with diverse cellular activities, including the activation of lymphocytes.

TNFR superfamily

(TNFRSF). A group containing approximately 30 type I or type III membrane proteins and several secreted proteins. TNFRSF receptors are characterized by the presence of one to four extracellular, cysteine-rich ligand-binding domains.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). Cell killing mediated by natural killer cells, macrophages, neutrophils and eosinophils through antibodies bound to Fc receptors expressed by these effector cells.

Natural killer T cells

A type of lymphocyte that is thought to have the functions of both activated T cells and natural killer cells.

T cell memory

The process of developing long-lived and self-renewing T cells that retain specificity for an antigen after the antigen has been removed, allowing rapid reactivation of the immune response.

Fc receptor

A type of cell surface receptor that binds to the crystallizable fragment (Fc) region of antibodies to trigger a variety of cellular responses.

Immunoglobulin superfamily

A large group of proteins containing a structural domain related to the immunoglobulin (Ig) domain of antibodies. Ig domains contain 70–110 amino acids with a charcteristic Ig fold giving them a sandwich-like structure composed of two sheets of anti-parallel β-strands.

NY-ESO-1

A tumour antigen that is expressed on various tumours, including some melanoma. It may be used to track the immune response to the tumour by identifying NY-ESO-1-specific T cells using NY-ESO-1 peptide–MHC class I tetramers.

Phosphatidylserine

A phospholipid in the cell membrane, normally found on the inner surface unless the cell is undergoing cell death, in which it can be found on the cell surface and serves as an 'eat me' signal for phagocytes. A ligand for the T cell immunoglobulin mucin 3 immune checkpoint.

Galectin 9

(GAL9). A member of a family of proteins that can bind β-galactoside sugars. Some galectins are overexpressed by tumour cells and some can crosslink extracellular proteins (for example, 4-1BB, T cell immunoglobulin mucin 3) and potentiate their immunomodulatory function.

Poliovirus receptor

(PVR). A protein that is expressed by dendritic cells, but may be overexpressed by some tumours, and can bind T cell immunoglobulin and ITIM domain (TIGIT), a related protein expressed on T cells and natural killer cells.

Human leukocyte antigen

(HLA). The genetic designation for the human MHC

Integrin

A protein that is specialized for cell–cell or cell–extracellular matrix interactions.

Ectonucleotidases

Enzymes, such as CD39 and CD73, that are expressed on the external cell surface and metabolize nucleotides.

Fast track designation

A US Food and Drug Administration (FDA) designation that expedites the FDA review process for a promising medication with the potential to address an unmet medical need for a serious or life-threatening condition with no adequate treatment or cure.

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Mahoney, K., Rennert, P. & Freeman, G. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14, 561–584 (2015). https://doi.org/10.1038/nrd4591

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