Traditional vaccines are committed to the prevention of a variety of infectious diseases, while cancer vaccines, which have attracted much attention in recent years, aim to focus the strength of the human immune system on the elimination of tumor cells. Cancer vaccine treatment can cause systemic regression of large tumors and prolong the survival time of patients. Although the existing immunotherapies (such as immune checkpoint inhibitors and chimeric antigen receptor T cells) have made remarkable achievements in the field of tumor treatment, tumor vaccines have their unique advantages. For example, tumor vaccines can target intracellular antigens other than tumor-specific surface antigens, and may even trigger new tumor-specific T-cell responses. However, at present, the number of clinical trials of cancer vaccines is limited, and their therapeutic effect as well as detailed and clear principles need to be further explored and confirmed by researchers.
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Types of Cancer Vaccines
Tumor antigens are often divided into tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs). TSA includes viral antigens and new epitopes produced by nonsynonymous somatic cell mutations, while TAA includes tissue-specific antigens and development-specific antigens. Cancer vaccines work by ingesting tumor antigens through APC and presenting them to CD8+ T cells on HLA-I. By activating dendritic cells (DCs) containing tumor antigens, cancer vaccines can induce immune responses to tumor antigens. Different types of cancer vaccines have different ways to co-locate tumor antigens with cross-presented DCs.
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Predefined Antigens
Predefined antigens have a clear definition of tumor antigens before treatment. Predefined antigens can be further classified by the frequency of expression across patient cohorts. Shared antigens are antigens expressed in a sufficient proportion of patients, which enables immunologists to target tumor patients using standard tests, and the resulting shared antigen vaccines can target both TSAs and TAAs. Personalized antigens are unique to the vaccinated patients and are usually composed of new TSA epitopes, which are not common enough for a large group of patients.
2.1 Predefined Shared Antigen Vaccines
Predefined shared antigen vaccines can be regarded as “off-the-shelf” treatments, most of which are the best shared antigens based on clinical and immunological data accumulated in early trials.
2.2 Predefined Personalized Antigen Vaccines
Unlike shared antigens, personalized antigens are unique to only one patient, and are most commonly new-epitope TSAs. The advantage of targeting personalized antigens is that it can achieve high specificity and can be combined with checkpoint blockade therapy to increase T cell reactivity in patients responding to treatment. Advances in next-generation sequencing make the design of personalized antigen vaccines more feasible and effective. Designing personalized antigen vaccines includes variations of DNA and RNA extraction from tumor and germline tissue for exome and RNA sequencing as well as HLA typing. Somatic mutations that exist in tumors but do not exist in germlines, have a low “error detection rate”, and lead to changes in non-synonymous proteins are selected. Using methods similar to the NetMHC algorithm and predicting their binding to patients’ HLA alleles by in silico technology, potential new immunogenic epitopes were selected from somatic mutations.
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Anonymous Antigens ex vivo or in situ
Anonymous antigens are not defined before treatment, the further classification of which can be based on the location of the APC loading, rather than the antigen identity.
- Ex vivo Anonymous Antigen Vaccines, APC Co-localized
The ex vivo anonymous antigen vaccine comes from excised tumor cells (resection biopsies), which are lysed and processed into more antigenic forms and co-localized with APC. The injected tumor cells may be absorbed and delivered to autologous APCs, or the tumor cells themselves will present their antigens to T cells. Studies have shown that the vaccine preparation method based on autologous tumor lysates is more effective than shared antigens, and anonymous antigen ex vivo vaccines have greater potential to present full-spectrum tumor antigens and have been proved to be effective in inducing systemic tumor regression.
- In situ Anonymous Antigen Vaccines, APC Co-localized
In situ anonymous antigen vaccines are similar to ex vivo vaccines, and their functions are to induce APC recruitment and tumor antigen loading and activation, so that APCs can effectively cross-initiate tumor reactive T cells. In situ vaccination combines the immunological benefits of presenting full-spectrum tumor antigens with the practicability of off-the-shelf methods, and can be used for many types of intratumoral administration, including viruses, PRR agonists, and other immune stimulants.
Dendritic Cells
Tumor cells both exclude and inactivate DCs, so researchers tried to replenish DC cells through direct intratumoral administration for subsequent uptake and presentation of tumor antigens. Injection of autologous DCs matured and activated ex vivo in this way can increase the level of intratumoral cytokines associated with disease stabilization and prolonged survival.
Flt3L
Flt3L is the main growth and differentiation factor of hematopoietic progenitor cells, which is responsible for mobilizing DCs, especially the cross-presenting subgroup cDC1. Therefore, Flt3L administration may be a more practical method than direct injection of intratumoral DCs. At present, Flt3L combined with PD-1 blockade to treat cancers such as lymphoma, as well as other Flt3L formulations have entered the clinical stage. Although the progress of Flt3L formulations is hindered by daily administration and available clinical reagents, it still has great potential.
TLR Agonists
TLRs are single-pass transmembrane PRR family receptors expressed on many leukocyte subsets, and can recognize structurally conserved pathogen-related molecular patterns. 10 human and 13 murine TLRs have been identified, each of which has different pathogen-related molecular pattern recognition. Synthetic TLR agonists have been developed to activate several human TLRs and are expected to trigger anti-tumor immune responses.
Oncolytic Viruses and Bacteria for Intratumoral Administration
The preferential replication and cytolysis of oncolytic viruses in tumor cells can produce many therapeutic mechanisms, the main concern of which is that they have a potential systemic vaccinal effect after intratumoral administration. Currently, the only oncolytic virus approved by the U.S. Food and Drug Administration is talimogene laherparepvec (TVEC), a modified GM-CSF-producing HSV1 virus that increases survival after injection and can subside tumors in lesions in neoadjuvant and combination trials with checkpoint blockade. Similarly, attenuated intratumoral injection of Clostridium novyi has been shown to induce tumor-specific T cells and tumor regression and is now being used in combination with PD-1 blockade.