Cancer vaccines are one of the most important methods of cancer immunotherapy. The three main factors that determine the efficacy of cancer vaccines are antigen, adjuvant, and formulation. Antigens induce specific immune responses, adjuvants enhance the specificity of immune responses, and the formulation determines whether the vaccine can be efficiently taken up by antigen-presenting cells and activate specific T cells. Among these factors, antigen is the most important.
To develop an effective cancer vaccine, it is crucial to optimize several parameters, especially tumor antigens. Antigen selection is the most important and decisive step in designing potent tumor vaccines because antigens play a vital role in inducing strong immune responses against tumors.
For the efficient induction of tumor-specific immune responses, cancer cells themselves are the best source of tumor antigens. Currently developed cancer vaccines mostly use antigens derived from tumor cells (except for virus- or bacteria-induced cancers, such as cervical cancer caused by viruses).
Recently, Advanced Science published an article titled “Rethinking Antigen Source: Cancer Vaccines Based on Whole Tumor Cell/Tissue Lysate or Whole Tumor Cell”, which reviews the methods and strategies for selecting different types of cancer antigens for cancer vaccine preparation.
Ideally, antigens used for cancer vaccines should possess, but not be limited to, the following characteristics: high immunogenicity, high specificity, a broad range of tumor-specific antigens (all or at least the majority of types), and ease of rapid acquisition.
In general, cancer cells or tissues are the optimal antigen source for developing cancer vaccines, except for virus- or bacteria-induced cancers such as cervical cancer. In this article, the authors categorize tumor antigens into two major classes: pre-screened antigens (predefined and known sequences) and unselected mixed antigens (unknown types and sequences). Both classes of tumor antigens originate from tumor cells or tissues.
Pre-screened antigens (predefined and known sequences) are mainly divided into two categories: tumor-specific antigens (TSA, neoantigens) and tumor-associated antigens. Antigens obtained through pre-screening can be used to prepare universal tumor vaccines and personalized tumor vaccines, two types of cancer vaccines.
Unselected mixed antigens (unknown types and sequences) can be further categorized into antigens based on a portion of cancer cell components, antigens based on cancer cell or tumor tissue lysate, and antigens based on whole cancer cells.
Due to technical limitations, it was previously not feasible to utilize all cellular lysates of cancer cells as antigens for cancer vaccine preparation because most cellular lysates consist of insoluble (non-aqueous and non-lipid soluble) components. The research team led by Liu Mi has successfully solubilized the non-aqueous components by using urea and loaded the whole cell lysate components onto nanoparticles or microparticles to prepare cancer nanovaccines or microvaccines. The use of tumor cell whole cell lysate (including both soluble and insoluble components) as antigen components in cancer vaccine preparation has shown improved preventive and therapeutic effects.
Cancer vaccines based on whole cell lysate overcome many limitations of neoantigen cancer vaccines, including but not limited to:
(1) Overcoming the high heterogeneity of cancer antigens: Such vaccines contain a broad range of antigens (all or most types), which can induce a broad spectrum of tumor-specific T cells and overcome the heterogeneity of cancer cells.
(2) Simple preparation process with short preparation time (1–4 days)
(3) Low cost and high accessibility for patients
(4) Overcoming HLA (MHC) restrictions
(5) Including a more diverse range of new antigens and antigen combinations that can induce cross-cancer
(6) Good safety and no toxic side effects
(7) Compared with in situ vaccines, antigen use, release dose, and injection frequency can be controlled.
(8) No tedious but not necessarily accurate work such as time-consuming, laborious, and costly antigen screening and sequencing is required.
(9) It is easier to be swallowed by antigen-presenting cells, and the co-loading of antigen and adjuvant after phagocytosis can activate cancer-specific T cells more efficiently.
Considering the need for pre-screening of cancer vaccines based on new antigens and the limitations of cancer vaccines based on new antigens, the development of cancer vaccines based on whole tumor antigens is a promising alternative.
In addition to developing cancer vaccines based on cancer cell lysates, scientists are also developing cancer vaccines based on intact cancer cells with undamaged structures. The preparation methods for this kind of vaccine include freezing silicification, liquid nitrogen freezing, and in situ vaccine based on oncolytic viruses and so on. Liquid nitrogen cryotherapy is used to briefly explain how to prepare a cancer vaccine based on the structure of intact cancer cells. Using liquid nitrogen for rapid freezing and its subsequent treatment, cancer cells can be inactivated, and inactivated cancer cells can be used as vaccines. It is used in all cancer cell antigens, so it can activate a broad spectrum of cancer cell specific immune responses. However, this kind of therapy also faces potential concerns such as the large size of cancer cells, antigen-presenting cells are not easy to phagocytose, the inability to completely inactivate cancer cells, and other potential concerns.
In view of the immunogenic potential of cancer cells and autologous tumor cells carry a variety of specific tumor antigens, which are the best source of antigens for preparing tumor vaccines, in addition to using whole tumor cell lysates or complete tumor cells as cancer vaccines, some components of cancer cells can also be used as antigens to prepare cancer vaccines. For example, use all the mRNA components in cancer cells, cancer cell membranes, and extracellular vesicles (exocrine bodies) of cancer cells. Using all the mRNA components in cancer cells, cancer cell membrane, and extracellular vesicles of cancer cells as antigen components to prepare cancer vaccine has its own advantages and disadvantages, which are also described in detail in this paper. In this paper, the authors also introduced some limitations of in situ cancer vaccine, such as the need for intratumoral injection, the inability of water-soluble antigen to be absorbed by antigen-presenting cells through the cell membrane, the difficulty of controlling the amount of antigen release, the inability to be used as a prophylactic vaccine, the less effective uptake of antigen by antigen-presenting cells and lower amounts reaching lymph nodes, and the inability of antigen and adjuvant to be absorbed by the same antigen-presenting cells.
In the preparation of cancer vaccines, how to increase the content of antigen and how to increase the immunogenicity of antigen are also very important. In this paper, the author also introduces some methods to increase the content and immunogenicity of antigens in detail. In addition, dendritic cell cancer vaccines activated by many different antigen components are also introduced in this paper.
Tumor cells or tumor cell lysates are theoretically the best antigen libraries, so most of the antigens in the preparation of cancer vaccines come from tumor cells or tumor tissues.
At present, most researchers are committed to finding tumor-specific antigenic peptides, such as melanoma peptides—MET, TRMT6, and HNR1110, and using one or more new antigenic peptides or mRNA as vaccines to achieve tumor immunotherapy. However, these new antigenic vaccines based on more than 10 to 30 new antigenic peptide epitopes (polypeptide form, mRNA form, or DC vaccine form) have some problems, such as complex preparation, long preparation cycle (2–4 months), being expensive, limited curative effect, and the difficulties in overcoming the high heterogeneity of cancer cells. Cancer vaccines based on whole cells or cancer cell/tumor tissue lysates do not need to be screened, which is time-consuming, laborious, and costly. Therefore, the preparation is fast and cheap, and it is expected to become another technical scheme for the preparation of cancer vaccines.