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Combining immunotherapy and targeted therapies in cancer treatment

Key Points

  • The so-called targeted therapies and cancer immunotherapies are two novel treatment modalities that have recently begun to enter the oncology clinic. Targeted therapies and immunotherapy offer a number of possible synergies in treatment when used together; however, these combinations have not been well studied.

  • Many targeted therapies against tumours affect pathways that are also crucial for immune development and function, which suggests the possibility that targeted therapies may help to optimize anti-tumour immune responses from immunotherapies. Similarly, immunotherapies may serve to consolidate impressive clinical responses from targeted therapies into long-lasting clinical remissions.

  • Targeted therapies promote effective dendritic cell (DC) maturation, T cell priming, activation and differentiation into long-lived memory T cells, which suggests possible combinations of cancer vaccines along with targeted therapies to bolster vaccine responses, as well as effector T cell function.

  • Targeted therapies may sensitize tumour cells to immune-mediated killing by increasing the expression of death receptors or 'distress' ligands while simultaneously diminishing the expression of pro-survival signals, which increases the efficiency of immune-mediated tumour clearance once immune cells are activated in vivo.

  • Targeted therapies might diminish tumour-mediated immunosuppression by abrogating the production of tumorigenic inflammation and by inhibiting immunosuppressive cell types. Impairing immunosuppression improves effector T cell function and increases immune destruction of tumour targets, suggesting possible synergy with immunotherapies that are designed to generate anti-tumour T cells or to bolster their effector function.

  • Important considerations regarding optimizing dose, sequence and timing of targeted therapies will be required when rationally designing future clinical trials in order to maximize anti-tumour efficacy while minimizing any immunosuppressive side effects.

Abstract

During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.

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Figure 1: The generation of potent anti-tumour immune responses requires multiple steps.
Figure 2: Targeted agents may boost DC priming and the activities of tumour-specific T cells.
Figure 3: Targeted agents may antagonize immunosuppression in the tumour microenvironment.
Figure 4: Crucial variables in combining targeted agents and immunotherapy.

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Acknowledgements

Glenn Dranoff is supported by grants from the US National Cancer Institute, the Leukemia and Lymphoma Society, the Melanoma Research Alliance, the Alliance for Cancer Gene Therapy, the Research Foundation for the Treatment of Ovarian Cancer, and Novartis Inc.

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Correspondence to Glenn Dranoff.

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G.D. is a consultant and receives sponsored research support from Novartis Inc.

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Glossary

Complete cytogenetic responses

The lack of any detectable tumour burden by conventional cytogenetic studies, such as karyotype analysis or fluorescence in situ hybridization (FISH).

Dendritic cell (DC) vaccine

A process by which DCs are removed from the patient, loaded with tumour or tumour antigens, matured and then re-infused back into the patient to stimulate immune responses in vivo.

Oncogene addiction

A process by which a single mutated gene or signalling pathway drives tumour proliferation; inhibition of that gene or pathway results in rapid tumour response.

Vaccination in situ

As tumour cells die and release 'danger' molecules, tumour antigens are phagocytosed and presented by dendritic cells to prime anti-tumour immune responses.

Regulatory T (TReg) cells

A T cell subtype that releases suppressive cytokines and serves to silence immune responses.

Myeloid-derived suppressor cells

MDSCs. A myeloid cell subtype that silences responses of cytotoxic CD8+ T cells and helper CD4+ T cells while simultaneously promoting the formation of regulatory T cells.

Major histocompatibility complex

MHC. Proteins that are responsible for displaying varied peptide antigens on the cell surface.

CD8+ T cells

A T cell subtype that recognizes a specific peptide on target cells and kills those cells.

CD4+ T cells

A T cell subtype that recognizes peptides on target cells and secretes signalling molecules (called cytokines) to direct an appropriate immune response.

Anergy

A state in which T cells do not respond to antigenic stimulation even when presented in the appropriate context.

Exhaustion

After chronic stimulation, T cell responses become diminished or non-existent to repeated antigenic encounters.

Epitope spreading

After peptide vaccination, T cells are generated that respond to peptides that were not in the original vaccine formulation, indicating that a secondary round of T cell priming has occurred with antigens taken directly from tumour cells.

T helper 1

(TH1). A helper T cell response that is characterized by interferon-γ (IFNγ) production and stimulation of CD8+ cytotoxic T cells.

Natural killer (NK) cells

A cytotoxic cell of the innate immune system that does not recognize target cells in an antigen-specific manner and kills its targets using similar mechanisms to those of the cytotoxic T lymphocyte.

Opsonization

The phagocytosis of opsonized antigens, most commonly by antibodies and/or complement, from the external environment by dendritic cells or by other antigen-presenting cells.

Antibody-dependent cellular cytotoxicity

(ADCC). The destruction of target cells that are coated with antibodies by innate immune cells expressing Fc receptors, such as natural killer cells, monocytes or macrophages, using cytotoxic substances, such as perforin and granzymes, reactive oxygen species and reactive nitrogen species.

Complement-dependent cytotoxicity

(CDC). The destruction of target cells coated with antibodies by a series of serum proteins that undergo a cascade of enzymatic cleavage and culminate in the formation of pores within the target cell membranes, permeabilizing the cells.

Memory T cells

T cells that have undergone antigenic stimulation at least once and that are capable of rapidly responding to additional antigen encounters.

Central memory T (TCM) cells

Long-lived memory T cells that reside in peripheral blood, lymph nodes and spleen that are capable of undergoing rapid differentiation into effector T cells on antigenic stimulation.

Adoptive transfer

The infusion of cells into animals or patients that have been taken directly from another source or expanded and modified ex vivo.

Lytic pathway

The release of cytotoxic molecules such as perforin and granzymes from cytotoxic T lymphocytes to kill their cognate targets.

Unfolded protein response

A stress response in the endoplasmic reticulum that is triggered by the accumulation of misfolded proteins that initially results in increased protein chaperone synthesis and decreased total protein synthesis in an attempt to remove the misfolded proteins. If misfolded proteins persist, continued activation of this pathway ultimately results in apoptosis.

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Vanneman, M., Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 12, 237–251 (2012). https://doi.org/10.1038/nrc3237

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