Rethink the most important component of cancer vaccines - antigens

As shown in Table 1, cancer treatment can be generally divided into traditional non-immunotherapy and immunotherapy.

Table 1. Overview of cancer treatment methods

Non-immunotherapy of cancer includes chemotherapy, radiotherapy, surgical treatment, etc. Cancer immunotherapy includes: (1) immune checkpoint inhibitors (PD-1 antibodies, PD-L1 antibodies, CTLA-4 antibodies, etc.); (2) T cell-based therapies (all expensive: CAR-T, TILs, TCR-T, in situ editing of T cells, etc.); (3) Therapy based on the Innate immune system (NK cells, γδ T Cell therapy, NK-T cell, CAR-NK, cytokine therapy, etc.); (4) Oncolytic virus; (5) Tumor lytic bacteria; (6) Cancer vaccine (Peptide vaccine, mRNA vaccine, DC vaccine, nanovaccine, and other forms of Cancer vaccine), etc.

Cancer vaccine is one of the important methods of cancer immunotherapy.The three main factors that determine the efficacy of cancer vaccines are antigen, adjuvant, and vaccine formulation.Antigens can induce specific immune responses, adjuvants can amplify specific immune responses, and the formulation determines whether the vaccine can be effectively engulfed by antigen-presenting cells (APCs) and efficiently activate antigen-specific T cells.Among the three factors that determine the efficacy of cancer vaccines, antigen is the most important factor.

To develop an efficient cancer vaccine, the key is to optimize several parameters, especially the tumor antigens for cancer vaccines. Because antigen is the most important and decisive parameter for developing a powerful tumor vaccine,antigen selection is the most important step in designing tumor vaccines.

Figure 1: Various cancer vaccines based on different antigens

In order to enable cancer vaccines to efficiently induce a tumor-antigen-specific immune response, cancer cells themselves are the best source of tumor antigens. Currently, most of the developed cancer vaccine antigens are from tumor cells (except for cancers caused by viruses or bacteria, such as cervical cancer and other cancers definitely caused by viruses).

Professor Liu Mi's team from the College of Pharmaceutical Sciences of Soochow University recently published an article,Rethinking Antigen Source: Cancer Vaccines Based on Whole Tumor Cell/issue Lysate or Whole Tumor Cellin the journal Advanced Science. They summarized the methods and strategies for selecting different types of cancer antigens to prepare cancer vaccines. The Ph.D. candidate Lu Diao is the first author of the article.

In general, the ideal antigen for the cancer vaccine should have, but not limited to, the following characteristics: High immunogenicity; High specificity; Contains a wide range of tumor-specific antigens (all types or at least most types); Easy to obtain quickly, etc. Cancer cell/tumor tissue is the best source of antigens to design and prepare cancer vaccines. Exclude cancers caused by viruses, bacteria, etc. (such as cervical cancer), Professor Liu Mi's team divides tumor antigens into two categories:pre-determined (predefined and sequence are known) antigens and non-identified mixed antigens (types and sequences are anonymous). And both these two major types of tumor antigens originate from tumor cells/tumor groups.

The pre-determined (predefined and sequences are known) antigens are mainly divided into tumor-specific antigens (TSA, neoantigens) and tumor-associated antigens (TAA). The pre-determined antigens can be used to prepare two kinds of cancer vaccines: universal cancer vaccines and personalized cancer vaccines.

Unidentified mixed antigens (with unknown types and sequences) can be classified into three categories: (1) antigens based on a portion of cancer cell components; (2) antigens based on cancer cells/tumor tissue lysates; (3) antigens based on inactivating cancer cells with the intact structure of cancer cells.

Because many other articles have studied and discussed the pre-determined tumor antigens (predefined and sequence known), in this article, this article focused on several strategies and methods for preparing cancer vaccines with unidentified mixed antigens (type and sequence unknown), especially cancer vaccines based on cancer cells/tumor tissue whole cell lysates and cancer vaccine based on inactivated cancer cells with complete structure.

Due to technical limitations, there was no way to use all the lysates of cancer cells as antigens to prepare cancer vaccines before because a large part of the lysates was water-insoluble (also lipid-insoluble) components. Professor Liu Mi's research team utilizes urea to solubilize water-insoluble components and load the whole-cell lysate components of cancer cells/tumor tissue into nanoparticles or microparticles to prepare cancer nanovaccines or microvaccines. The specific process is shown in Figure 2. The cancer vaccines, prepared with whole tumor cell lysates (including water-soluble components and water-insoluble components) as antigen components, can achieve better prevention and treatment effects.

Cancer vaccine based on whole cell lysates of cancer cells overcomes many limitations of cancer vaccines based on pre-determined neoantigens, including but not limited to: (1) overcoming the problem of high heterogeneity of cancer cell antigens; contains a wide range of antigens (all or most types), which can induce a wide range of cancer-specific T cells, overcoming the heterogeneity of cancer cells; (2) the preparation process is simple, and the preparation time is short (completed in 1-4 days); (3) low cost and high patient affordability; (4) overcoming the HLA (MHC) restrictions; (5) vaccines contain more diverse neoantigens and combinations of neoantigens, which can induce cross-immune responses across different cancers and lesions, resulting in better therapeutic effects; (6) good safety, non-toxic side effects; (7) compared to in situ vaccines, it can control the dosage and frequency of used antigens and can control the release of antigens; (8) no need to do antigen screening and sequencing, which is time-consuming, labor-intensive, and very expensive; (9) more easily engulfed by antigen-presenting cells (APCs), the co-loaded antigens and adjuvants can more efficiently activate antigen-specific T cells after phagocytosis.

Considering that the current neoantigen-based cancer vaccine needs to do pre-screening and the limitations of neoantigen-based cancer vaccines, developing a cancer vaccine based on cancer cells/tumor tissue lysates (containing whole cancer cell antigens) is a promising direction.

Figure 2, Preparing process of nanovaccines or microvaccines loaded with whole cell lysate components of cancer cells/tumor tissue

In addition to developing cancer vaccine based on cancer cell lysates, scientists are also developing cancer vaccines based on inactivated cancer cells with complete cancer cell structure. The preparation methods for this type of vaccine include methods such as cryosilicification, liquid nitrogen freezing, and in situ vaccines based on methods such as oncolytic viruses. However, this type of therapy also faces potential concerns, such as the large size of cancer cells makes them difficult to be engulfed by antigen presenting cells, and the potential problem of incompletely inactivating cancer cells.

Figure 3. Schematic diagram of cancer vaccine with complete cancer cell structure prepared by low-temperature freezing technology

Given the immunogenicity potential of cancer cells and the multiple specific tumor antigens carried by autologous tumor cells, they are the optimal antigen source for preparing tumor vaccines. In addition to using the whole tumor cell lysates or inactivated complete tumor cells as the antigens to prepare of cancer vaccines, a part of the cancer cell can also be used as the antigens to prepare cancer vaccines. Such as using total RNA components in the cancer cells, cancer cell membranes and the extracellular vesicles (exosomes) of cancer cells. The advantages and disadvantages of using total RNA components in cancer cells, cancer cell membranes and extracellular vesicles (exosomes) of cancer cells as antigen components to prepare cancer vaccines are also discussed in this article. In this article, the author also introduced some limitations of in situ cancer vaccines, such as the need for intratumoral injection, the inability of water-soluble antigen to be uptake by APCs through the cell membrane, the difficulty in controlling the amount of antigens released, the inability of utilizing as a preventive vaccine, the low effective uptake of antigen by APCs, the low amount of antigens reaching lymph nodes, and antigens cannot be uptake by the same antigen -presenting cell together. with adjuvants.

In the preparation of cancer vaccine, how to increase the content of antigens and increase the immunogenicity of antigen is also discussed in this article. In addition, the dendritic cell cancer vaccine activated by a variety of different antigen components was also introduced.

Tumor cells or tumor cell lysis is the best antigen reservoir, so most of the antigens used in cancer vaccine are from tumor cells or tumor tissues. At present, most researchers are committed to finding tumor specific antigenic epitope (tumor-specific antigens or tumor-associated antigens), such as melanoma polypeptides MET, TRMT6 and HNR1110, and then use one or several peptides or mRNA as antigens to prepare vaccines. However, these neoantigen-based vaccines (peptide form, mRNA form or DC vaccine form) have problems such as compllicated preparation process, long preparation time (2-4 months), expensive price, limited efficacy, and inability to overcome the high heterogeneity of cancer cells, etc. However, cancer vaccine based on cancer cells/tumor tissue whole cell lysates or cancer vaccine based on inactivated cancer cells do not need long time to prepare, do not need a lot of labors and are much cheaper, which potentially can become an alternative technology to prepare cancer vaccines.

References：

(1) Lu Diao, Mi Liu*. (2023). Rethinking Antigen Source: Cancer Vaccines Based on Whole Tumor Cell/tissue Lysate or Whole Tumor Cell.Advanced science,e2300121. Advance online publication. https://doi.org/10.1002/advs.202300121

(2) Lu Diao, Lin Ma, Junping Cheng, Yunzhi Pan, Zuofu Peng, Lianjun Zhang, Minghao Xu, Yupei Li, Xuenong Zhang, Honglv Jiang, Guoqiang Xu, Fenghua Meng, Zhiyuan Zhong, and Mi Liu*, Across-cancer specific immune responses induced by nanovaccines or microvaccines to prevent different cancers and cancer metastasis, iScience, 2022, 25,105511

(3) Lin Ma, Lu Diao, Zuofu Peng, Yun Jia, Huimin Xie, Baisong Li, Jianting Ma, Meng Zhang, Lifang Cheng, Dawei Ding, Xuenong Zhang, Huabing Chen, Fengfeng Mo, Honglv Jiang, Guoqiang Xu, Fenghua Meng, Zhiyuan Zhong, Mi Liu*, Immunotherapy and prevention of cancer by nanovaccines loaded with whole-cell components of tumor tissues or cells, Advanced Materials, 2021,43, 2104849