Towards personalized, tumour-specific, therapeutic vaccines for cancer

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.

Figure 1. Manipulating the immune response to tumours.

a | Cancer vaccines can select suitable antigen targets to generate new antigen-specific T cell responses against tumour cells. b | Cancer vaccines can also amplify existing tumour-specific T cell responses. c | Finally, cancer vaccines can increase the breadth and diversity of the tumour-specific T cell response. Together, these effects can result in regression of tumours.

Figure 2. Mechanisms and components of an effective cancer vaccine.

a | The tumour antigen presentation process. As a first step, antigen encounter by antigen-presenting cells (APCs) such as dendritic cells (DCs) occurs at the injection site (or, in the case of DC vaccines, antigens may be exogenously loaded on APCs before injection). The antigen-loaded APCs traffic through the lymphatics to the draining lymph nodes, which are the primary site of T cell priming. In the lymph node, mature DCs present the tumour-derived peptides on MHC class I molecules and MHC class II molecules to CD8⁺ and CD4⁺ T cells, respectively, of both naive and memory phenotypes. The generation of tumour-specific T cell responses is promoted by the delivery of a costimulatory ‘signal 2’ to T cells, such as through CD80–CD28, CD86–CD28, CD70–CD27 and CD40–CD40 ligand (CD40L) interactions. Costimulation is increased by IL-12 and type I interferons (IFNs) produced by DCs. Together, these interactions promote the generation and expansion of activated tumour-specific CD4⁺ and CD8⁺ T cell populations. CD4⁺ and CD8⁺ T cells traffic to the tumour site, and upon encountering their cognate antigens, they can kill tumour cells through cytotoxicity and the production of effector cytokines, such as IFNγ and tumour necrosis factor (TNF). In turn, the lysed tumour cells release tumour antigens that can again be captured, processed and presented by APCs to induce polyclonal T cell responses, thereby increasing the antigenic breadth of the antitumour immune response and leading to the process of epitope spreading. b | There are four key components of cancer vaccines: tumour antigens, formulations, immune adjuvants and delivery vehicles. CpG ODN, CpG oligodeoxynucleotide; GM-CSF, granulocyte–macrophage colony-stimulating factor; MPL, monophosphoryl lipid A; poly-ICLC, polyinosinic–polycytidylic acid with polylysine and carboxymethylcellulose; STING, stimulator of interferon genes protein; TCR, T cell receptor; TLR, Toll-like receptor.

Figure 3. Neoantigens are ideal targets for cancer vaccines.

a | Several lines of evidence support neoantigens as being crucial targets of antitumour T cell responses. b | Potential antigens for use in cancer vaccines differ in terms of tumour specificity and vaccine personalization. Neoantigens are optimal targets for personalized, tumour-specific cancer vaccines. CTL, cytotoxic T lymphocyte; DC, dendritic cell; TCR, T cell receptor.

Figure 4. Neoantigen‑based therapeutic cancer vaccines.

a | The typical workflow for neoepitope selection and vaccine manufacture. DNA and RNA are extracted from single-cell suspensions of tumour cells and matched normal tissue cells. Somatic mutations of tumour cells are discovered by whole-exome sequencing (WES). RNA sequencing (RNA-seq) narrows the focus to mutations of expressed genes. Clinical HLA typing is carried out on DNA from normal tissue. The potential antigenicity of neoepitopes identified by WES and RNA-seq is assessed by predicting the affinity of the neoepitopes for binding to the HLA type of that individual (using NetMHCpan), thereby generating candidate vaccine epitopes. Validated epitopes are selected for incorporation into the personalized cancer vaccine, which is administered to patients in combination with an immune adjuvant. b | The schema of three phase I clinical trials of personalized neoantigen vaccines in patients with melanoma. These trials have used dendritic cells (DCs) pulsed with short HLA-A2-restricted neoantigen peptides (ClinicalTrials.gov identifier: NCT00683670) (top); synthetic long peptides targeting neoantigens admixed with poly-ICLC (polyinosinic–polycytidylic acid with polylysine and carboxymethylcellulose) (NeoVax) (ClinicalTrials.gov identifier: NCT01970358) (middle); or neoantigen-targeting mRNA (IVAC MUTANOME) (ClinicalTrials.gov identifier: NCT02035956) (bottom). These studies show that vaccination is feasible, safe and able to induce robust neoepitope-specific T cell responses. c | Strategies to improve personalized neoantigen vaccines for cancer.