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  • Review Article
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Prospects for combining targeted and conventional cancer therapy with immunotherapy

Nature Reviews Cancer volume 17, pages 286–301 (2017)Cite this article

Subjects

Key Points

  • The largely independent research fields of targeted and immune-based cancer therapies are integrating.

  • Research is focused on understanding the impact that targeted and conventional cancer therapies (chemotherapy and radiation) have on the generation of an antitumour immune response. Protective tumour immunity is thought to require innate immune stimulation, a robust cytotoxic T cell response and overcoming an immunosuppressive tumour microenvironment.

  • Insights into the effects of targeted therapies, along with conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical responses in patients.

  • Immune checkpoint inhibitors are emerging as a backbone of cancer therapy and are being combined in clinical trials with many targeted agents.

  • Key future challenges to developing rational combinations include continuing to understand the impact that all cancer therapeutics have on patients' immune systems, optimizing the therapeutic window of treatment through appropriate dosing and temporal sequencing, and prioritizing the rapidly growing number of combination therapy trials.

Abstract

Over the past 25 years, research in cancer therapeutics has largely focused on two distinct lines of enquiry. In one approach, efforts to understand the underlying cell-autonomous, genetic drivers of tumorigenesis have led to the development of clinically important targeted agents that result in profound, but often not durable, tumour responses in genetically defined patient populations. In the second parallel approach, exploration of the mechanisms of protective tumour immunity has provided several therapeutic strategies — most notably the 'immune checkpoint' antibodies that reverse the negative regulators of T cell function — that accomplish durable clinical responses in subsets of patients with various tumour types. The integration of these potentially complementary research fields provides new opportunities to improve cancer treatments. Targeted and immune-based therapies have already transformed the standard-of-care for several malignancies. However, additional insights into the effects of targeted therapies, along with conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical response in patients.

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Figure 1: Stimulation of innate immunity.
Figure 2: Modulation of T cell function.
Figure 3: Modulation of the tumour immunosuppressive microenvironment.
Figure 4: Mechanisms of immunogenic cell death.

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Authors and Affiliations

  1. Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research,

    Philip Gotwals, Daniela Cipolletta, Viviana Cremasco, Britta Mueller, Catherine Sabatos-Peyton & Glenn Dranoff

  2. Translational Clinical Oncology, Novartis Institutes for BioMedical Research,

    Scott Cameron, Adam Crystal, Becker Hewes, Sonia Quaratino & Lilli Petruzzelli

  3. Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, 02139, Cambridge, Massachusetts, USA

    Jeffrey A. Engelman

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  1. Philip Gotwals
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PowerPoint slides

Glossary

Immune checkpoint inhibitors

Therapeutic agents that reverse, for example, programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-mediated repression of cytotoxic T cell activity to enable an antitumour immune response.

Innate immune responses

Refers to the nonspecific immune defence mechanisms that identify and eliminate foreign pathogens. Cells of the innate immune response include natural killer cells, mast cells, eosinophils, basophils and phagocytic cells such as macrophages.

Dendritic cells

(DCs). Immune cells that process and display antigenic proteins in conjunction with major histocompatibility complex proteins on their surface to T cells and are the most potent antigen-presenting cells, regulating both protective immunity and tolerance.

Natural killer (NK) cells

Immune cells that can bind to and kill virally infected cells or tumour cells in the absence of antigen stimulation.

Tumour-immunity cycle

Refers to the sequence of events — tumour-associated antigen loading and activation of dendritic cells (DCs), antigen presentation by DCs to CD8+ T cells and T cell-directed cytolysis of tumours — that are required to drive a potent antitumour response.

Type I interferon

A class of secreted proteins that induce cell-intrinsic antiviral pathways, modulate the innate immune response to promote antigen presentation and natural killer cell function and promote the development of antigen-specific (adaptive) T and B cell memory responses.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells of the myeloid lineage that can potently suppress T effector cell responses and function.

T regulatory (Treg) cells

A subpopulation of T cells that help to maintain tolerance by suppressing the induction, proliferation and activity of T effector cells.

Actinic keratosis

Refers to a rough or scaly skin lesion typically associated with sun exposure.

Endogenous retroviruses

(ERVs). Genomic viral elements that are derived from or resemble exogenous retroviruses. ERVs have been implicated in some cancers and autoimmune diseases.

T cell exhaustion

A state of T cell dysfunction characterized by diminished effector functions and sustained expression of inhibitory receptors that is associated with chronic infection and cancer.

Humoral immunity

The component of the adaptive immune response that is driven by B cell activation (with the help of CD4+ T cells), which results in the secretion of antibodies from plasma cells. It also broadly refers to secreted or soluble factors that are part of an immune response, including complement.

X-linked agammaglobulinaemia

A heritable immunodeficiency caused by a mutation in Bruton tyrosine kinase (BTK) in which patients do not generate mature B cells and hence do not make antibodies.

Waldenström macroglobulinaemia

A type of non-Hodgkin lymphoma characterized by lymphoplasmacytoid cells that secrete large amounts of monoclonal antibodies known as macroglobulin.

TH1 cells

(T helper 1 cells). An effector population of activated, differentiated CD4+ T cells characterized by the secretion of inflammatory cytokines interferon-γ and tumour necrosis factor, as well as interleukin-2.

TH17 cell

(T helper 17 cell). A type of activated CD4+ T cell that promotes neutrophil activation, immunity to pathogens and inflammation.

Immunogenic cell death

(ICD). A form of cell death that is characterized by the release of damage-associated molecular patterns (DAMPs) and results in an immunostimulatory response.

Damage-associated molecular patterns

(DAMPs). Refers to host-derived molecules such as calreticulin, high mobility group box 1 protein (HMGB1), heat shock proteins, ATP and DNA that initiate and maintain an inflammatory response.

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Gotwals, P., Cameron, S., Cipolletta, D. et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer 17, 286–301 (2017). https://doi.org/10.1038/nrc.2017.17

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