Review Article | Published:

Towards personalized, tumour-specific, therapeutic vaccines for cancer

Nature Reviews Immunology volume 18, pages 168182 (2018) | Download Citation

Abstract

Cancer vaccines, which are designed to amplify tumour-specific T cell responses through active immunization, have long been envisioned as a key tool of effective cancer immunotherapy. Despite a clear rationale for such vaccines, extensive past efforts were unsuccessful in mediating clinically relevant antitumour activity in humans. Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific. As a result of the diversity of tumour neoepitopes between individuals, the development of personalized cancer vaccines is warranted. Here, we review the emerging field of personalized cancer vaccination and discuss recent developments and future directions for this promising treatment strategy.

Key points

  • Cancer vaccines can both generate new antigen-specific T cell responses and amplify existing responses and thereby focus the host immune response against tumour cells. Because of this ability to induce and direct a potent and tumour-specific immune response while minimizing autoimmunity, a cancer vaccine may be an effective combinatorial partner with immune checkpoint blockade or other immune therapeutics.

  • A successful cancer vaccine has four key components, each of which is crucial to its effectiveness: tumour antigens, formulations, immune adjuvants and delivery vehicles. For each of these components, various approaches have been tested preclinically and in hundreds of clinical trials in patients, with limited therapeutic success so far.

  • Neoantigens have emerged as targets of effective tumour-directed T cell responses. Increased neoantigen load is associated with improved patient outcomes, and neoantigen-reactive T cell populations expand in settings of effective immunotherapy and mediate tumour cell killing in preclinical models and patients.

  • Three clinical trials of neoantigen-based vaccines in patients with melanoma, using dendritic cells loaded with short peptides, long peptides or RNA, have shown the safety, feasibility and robust immunogenicity of this approach.

  • A crucial aspect of a vaccine targeting neoantigens is the selection of epitopes that can be presented in vivo by tumour or antigen-presenting cells. HLA-binding prediction, high-resolution mass spectrometry and understanding of antigen processing are important research areas for further discovery.

  • Optimal neoantigen delivery — use of the most effective formulations, immune adjuvants, delivery vehicles and dosing — in combination with complementary therapies will be crucial for maximum therapeutic effectiveness.

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Acknowledgements

This work is supported by grants from the US National Institutes of Health (NCI-1RO1CA155010-02 and NHLBI-5R01HL103532-03) (to C.J.W), the Francis and Adele Kittredge Family Immuno-Oncology and Melanoma Research Fund (to P.A.O.), the Faircloth Family Research Fund (to P.A.O.) and the Dana-Farber Cancer Institute Center for Cancer Immunotherapy Research fellowship (to Z.H.). C.J.W. is a Scholar of the Leukemia and Lymphoma Society.

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Affiliations

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

    • Zhuting Hu
    • , Patrick A. Ott
    •  & Catherine J. Wu
  2. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

    • Patrick A. Ott
    •  & Catherine J. Wu
  3. Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Patrick A. Ott
    •  & Catherine J. Wu
  4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Catherine J. Wu

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Contributions

Z.H., P.A.O. and C.J.W. contributed to researching data for the article and discussing the content in addition to writing, reviewing and editing the manuscript before submission.

Competing interests

C.J.W. is a founder of Neon Therapeutics and member of its scientific advisory board. P.A.O. has advised Neon Therapeutics. Patent applications have been filed on aspects of the described work entitled as follows: Compositions and Methods for Personalized Neoplasia Vaccines (C.J.W.), Methods for Identifying Tumour Specific Neo-Antigens (C.J.W.) and Combination Therapy for Neoantigen Vaccine (C.J.W.). Z.H. declares no competing financial interests.

Corresponding author

Correspondence to Catherine J. Wu.

Glossary

Adoptive cell transfer

(ACT). A form of immunotherapy in which naturally occurring or genetically engineered tumour-specific lymphocytes, which may be autologous (patient's own) or allogeneic (donor), are activated and selected in vitro for tumour reactivity and expanded to reach high numbers for reinfusion into the patient.

Chimeric antigen receptors

(CARs). Engineered receptors that are formed by fusing the antigen-recognition domain of a specific antibody to an intracellular signalling domain. They can be used to modify effector T cells or natural killer cells.

Immune checkpoint blockade

(CPB). The reversion of T cell exhaustion using monoclonal antibodies that inhibit the function of inhibitory immune receptors on the cell surface, such as programmed cell death protein 1 (PD1), PD1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4).

Objective response rate

A common efficacy end point used in clinical trials of cancer therapies in solid tumours; it is usually defined as the percentage of patients who experience at least a 30% decrease in tumour diameter on an imaging scan.

Neoantigens

Antigens arising from mutation of the tumour genome that causes tumour cells to express specific proteins that are not expressed on normal cells.

Adaptive immune resistance

A mechanism of resistance to the antitumour immune response whereby cancer cells are recognized by the immune system but protect themselves by adapting to the immune attack.

Tumour heterogeneity

Cancer cells within the same tumour tissue can have distinct phenotypical and functional profiles as a consequence of genetic changes, environmental differences and reversible changes in cell properties.

Epitope spreading

Broadening of the immune response from the initially targeted epitope to other epitopes on the same antigen or different antigens.

Central tolerance

The clonal deletion of autoreactive B cells and T cells in the thymus during ontogenesis to create a state in which immune cells are unresponsive to autoantigens.

Whole-exome sequencing

Sequencing of the expressed genes in a genome (known as the exome) using high-throughput DNA sequencing technology.

Immune escape

The escape of a tumour from attack by the immune system through various mechanisms such as antigen loss.

Immune adjuvant

A component that is designed to improve the immune response to a vaccine antigen.

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DOI

https://doi.org/10.1038/nri.2017.131