Antigenic Essence: Upgrade of Cellular Cancer Vaccines

Simple Summary Early cancer vaccines include whole-cell formulations, which operate on the principle that you should vaccinate with what you want to develop protection against. Such vaccines have been widely tested in various cancers and their advantages described but have not yet managed to pass clinical trials. Antigenic essence technology offers the possibility to revitalize the field of whole-cell-based vaccination, as the essence comprises the entire diversity of native cellular antigens. At the same time, the technology allows for precise control and purposeful change of essence composition as well as purification of essence from ballast cellular substances and also addresses issues of major histocompatibility complex restriction. Antigenic essence technology makes it possible to update many cellular vaccines that have already been developed, as well as to develop new ones, therefore introducing a new direction for anticancer vaccination research. Abstract The development of anticancer immunotherapy is characterized by several approaches, the most recognized of which include cellular vaccines, tumor-associated antigens (TAAs), neoantigens, and chimeric antigen receptor T cells (CAR-T). This paper presents antigenic essence technology as an effective means for the production of new antigen compositions for anticancer vaccination. This technology is developed via proteomics, cell culture technology, and immunological assays. In terms of vaccine development, it does not fit into any of the above-noted approaches and can be considered a new direction. Here we review the development of this technology, its main characteristics, comparison with existing approaches, and the features that distinguish it as a novel approach to anticancer vaccination. This review will also highlight the benefits of this technology over other approaches, such as the ability to control composition, optimize immunogenicity and similarity to target cells, and evade major histocompatibility complex restriction. The first antigenic essence products, presented under the SANTAVAC brand, are also described.

The high similarity between vaccine composition and profile of surface antigens of cancer (or cancer vasculature) cells.

Fundamental limitations
Only a limited number of tumors has enough mutations to apply this technology (e.g., lung cancer and melanoma).
There is no direct connection between a mutation in the tumor genome and the corresponding antigen presence in the tumor. Genes may not be expressed or be expressed only weakly. To confirm that the mutated gene is expressed, a proteome analysis should be done at the stage of neoantigen selection (that is seldomly done in practice).
Tumor sample is required. The large diversity of mutations in tumor cells means that only a personalized approach is possible, not a general one.
Vaccine is prepared based on genomic data of the tumor removed from the body. The vaccine is intended to prevent metastatic (repeat and secondary) tumors, which are highly likely to have their own mutations.
Tumor cells are genetically heterogeneous. Since the neoantigen vaccine is prepared only against a subset of tumor cells, this approach is fundamentally unable to treat a whole tumor. The remaining tumor cells, with additional mutations, will require the creation of a new vaccine (again against only some of the cells).
The cell surface profile of tumor cells changes significantly when exposed to drugs. Identification with or "matching" of the essence composition to these cell surface profiles is at the center of the vaccine design. In cases of tumor relapse, this can lead to the escape of tumor cells from the immune response induced by essence. (However, this limitation is not applicable for SANTAVAC final product that targets the tumor vasculature.) SANTAVAC antiangiogenic vaccines are not suitable for blood cancers (~20% of cancer cases). Some tumors may be resistant to antiangiogenic vaccination. It is expected that some methods of tumor resistance will not work, such as splitting angiogenesis and vascular co-option, while others, such as vascular mimicry, may lead to some degree of resistance.

Type of vaccines
Only personalized (technology restriction).
Any type. Antigenic essences can be autologous (obtained from the patient) as well as allogeneic.
Type of vaccination As adjuvant therapy (tumor sample is required; tumor sample usually obtained during surgical treatment of tumor).
As adjuvant therapy; as neoadjuvant therapy; as preventive vaccination.
Production method A biological sample of the tumor (paraffin section obtained for histological analysis) is used for genome sequencing (NGS of the whole exome).
Optional (but highly recommended) transcriptome and proteome analysis.
Bioinformatic treatment of genome data to predict neoantigens (search for candidates, modeling of immunogenicity and interaction with major histocompatibility complex, or MHC).
Cell culture routines to propagate a primary culture of human microvasculature endothelial cells and produce antigens.
Vaccine production routines using obtained antigens.
Testing neoantigen candidates (capacity to be presented by MНС; presence in the tumor; possibility to induce an immune response).
Vaccine production routines using obtained neoantigens.

Bioinformatic treatment of data
Very complex (time-consuming and required for each individual patient).
Not required (only mass spectrum analysis is required for quality control of the manufactured product).

Number of antigens used for vaccination Several (3-4 peptides) Several hundred
Product nature Chemical (neoantigens are chemically synthesized peptides; strict purification and characterization standards are required).

Universality of antigens
No (neoantigens are strictly specific for the particular tumor of the particular patient) Yes (for antiangiogenic SANTAVAC products)

Relation to MHC
Neoantigens are designed to take into account MHC restrictions SANTAVAC compositions are designed to take into account MHC restrictions

Relation to checkpoint inhibitors Applicable Applicable
Targets Only tumor cells with a high degree of mutation (such as lung cancer and melanoma). Tumors with a low level of mutations, such as gliomas, do not work.
Any cell type: cancer cells; endothelial cells (relate to final products); fibroblasts; etc.

Indications
Only tumors with a high degree of mutations (such as lung cancer and melanoma).

Market size
Limited by the complexity of production, high cost of the vaccine production, restriction in the type of therapy and indications, strong fundamental limitation in efficacy.
Very high due to universality around cancer types, a wide range of production costs (from low to expensive), various available types of therapy, suitability for preventive purposes, and possibility of mass production.

Attractiveness for big pharma
From Low to Average (already well-known and tested on human technology). From Average (not yet well-known technology; preclinical stage) to High.

Conclusions
Antigenic essence (SANTAVAC) vaccines demonstrate many features of mainstream technology but free of some fundamental restrictions, with expected high efficacy, high market coverage, and capacity for bulk production by big pharma.
Neoantigen vaccines are very complex to produce, personalized-only (not only from the points of efficacy, but rather as limitation of the approach), very expensive, very time-consuming to produce, and intended to treat a limited number of tumors. While the fundamentals of this type of vaccine are attractive, limitations of the technology suggest that the overall efficacy of such vaccines is likely to remain elusive.