"Constructing vaccines against (AVPs) and cancer requires applying non-standard paradigm approaches and even new thinking to succeed."

The failure of Defined Antigen Sequence-based Immunogen Vaccines against AVPs and against cancer is not due to the general lack of immune responses which are present in most cases. 

The failure of the vaccines is due to the progressive deficits in T cell repertoires caused by evolving antigenic diversity leading to the activation of T cells that recognize non-protective epitopes and/or are unable to recognize new epitope variants (immune escape).

Vaccines based on defined antigenic sequence immunogens (DASIs) bearing wild-type or mutated antigen sequences (neoantigens) can activate only a limited pool of lymphocytes. As an alternative, qualitatively new approaches are required. 

Modern vaccinology deals with only the most complicated cases of human diseases and veterinary medicine since the development of effective vaccines against simpler pathogens and diseases that are sensitive to control by the immune system are already available.

Currently, the development of vaccines against the pathogens/diseases with genetic/antigenic variability, such as HCV, HIV, TB, Coronavirus, Ebola, Malaria, Influenza, Dengue/Zika, and other viruses collectively referred to as antigenically variable pathogens (AVPs) and cancer, is hampered due to the immune escape; characterized by the generation of mutated epitopes of these pathogens and cancer cells. The antigenic variation appears to be one of the most significant obstacles to creating these much-needed vaccines.

Remarkably, the high genetic/antigenic instability of cancer cells results in permanent and rapid generation of a vast number of neoantigens bearing new mutated epitopes by various mechanisms during transcription, translation, edition, and/or splicing events, along with point mutations of totally random origin that convert the attempts to define the actual epitope landscape of any given cancer cell; an almost impossible task.

Consequently, to avoid the recognition and elimination by host cytotoxic T lymphocytes (CTLs), the AVPs and cancer cells have developed several escape mechanisms which are also causing the failure of vaccines. Therefore, constructing vaccines against AVPs and cancer requires applying non-standard paradigm approaches and even new thinking to succeed.

CANCER

Whereas there is a striking similarity between AVPs and cancer regarding the nature of T-cell epitopes due to antigenic variability of tumor cells leading to dynamic changes in epitope landscape, representing the main obstacle to the development of vaccines. Cancers have significant added hurdles, such as: escape from immune surveillance by down-regulating tumor antigen expression/presentation, immune tolerance and immune escape mediated by their high epitope mutation rate, immune-suppressive tumor microenvironments, and the generation of new tumor cells from cancer stem cells.

In general, despite the clear evidence that all tumors have a mutator phenotype due to genomic/genetic instability, this issue was not adequately addressed in sufficient detail in cancer vaccine research. The recent data on cancer immunology agrees with our current hypothesis that the rapid turnover of mutated epitopes in cancer cells may hamper the efficacy of defined antigen sequence-based immunogen vaccines (including both wild-type and mutated antigen-based vaccines). The generation of vaccine-induced protective effector T-cells requires a longer period than the time needed for tumor cells to change the epitope landscape; rendering defined antigen sequence-based immunogen vaccines ineffective. Although not appreciated yet, this may represent a significant challenge to cancer vaccines.

Therefore, the simultaneous presentation of a large number of epitope variants carried by VELs is a qualitatively new way that permits the generation of the largest possible pool of effector T-cells capable of dealing with the permanently changing repertoire of neoepitopes in cancer cells.

"VELs are off-the-shelf, universal solutions for fast and efficacious immune-based therapies covering many diseases and cancer."

VELs can potentially reduce the time and cost of vaccine development by 70-80% compared to other methods and take the product research and development phase down from years to months, contributing to the highest possible ROI for commercial partners.

They are off-the-shelf, universal solutions for fast and efficacious immune-based therapies covering many diseases and Cancer and a powerful stand-alone or combination therapy for enhancing immune checkpoint inhibitors (ICI) and adoptive T cell therapy (ACT) cancer treatments.

VELs are compatible and will work universally with virtually all vaccine delivery systems, such as synthetic peptides, DNA, mRNA, viral vectors or nanostructures, and DC-based vaccines.

THE FUTURE OF VACCINES... RIGHT NOW

The simultaneous presentation of a large number of epitope variants by immunization with VEL vaccines may recall past responses, induce responses against antigens present during immunization, and induce T cells capable of recognizing future mutated antigens, thus reducing the chances of immune escape. In this manner, VEL immunogens are in a class all their own.

VEL-based immunotherapeutics are bona fide alternatives to existing paradigms for therapeutic and prophylactic treatment generation. VELs Sciences delivers an innovative immunotherapeutic platform and concept, called Variable Epitope Libraries (VELs), to exploit the high antigenic variability of many significant pathogens and tumor cells as starting points for the construction of a new class of prophylactic immunogens capable of inducing the largest possible repertoire of both B and T cells. We have several published papers relating to VEL-based immunotherapeutic immunogens and our findings.

VELs based on HIV-1-derived B and T cell epitopes were successfully used to generate broadly HIV-1-neutralizing sera in mice (the half of tier 2 HIV-1 primary isolated have been neutralized) and to induce a large pool of epitope-specific T cells, respectively. The VEL immunotherapeutics have been generated based on different antigens, such as survivin, MHC class I molecule, Muc-1, and oncofetal antigen. These immunotherapeutics induced statistically significant tumor growth inhibition and reduction in lung macro-metastasis in aggressive metastatic mouse 4T1 breast tumor model. Our data showed that these antigens could serve as novel molecular targets potentially involved in interactions between tumor cells and the immune system and indicate the feasibility of applying this new class of immunogens as an alternative to current approaches in cancer vaccine development.

The potent, long-lasting immune response elicited by VEL immunotherapeutics makes this technology ideally suited to exert therapeutic activity as a standalone product or can be utilized in combination with other novel immunomodulators. 

COMMERCIALIZATION

VEL prophylactic-therapeutic immunogens are proven effective when used as synthetic peptides, plasmid DNA or recombinant M13 bacteriophages, as documented in published papers. 

The further application of VEL immunotherapeutics using recently developed vaccine delivery platforms, such as nanoparticles, mRNA or DNA electroporation methods, or simply applying an adsorption approach using polyethyleneimine in a mesoporous microrod to enhance peptide vaccines potency dramatically, are expected to deliver continued impressive VELs immunotherapeutic efficacy data in animal models and clinical trials.

Additionally, as a qualitatively new class of immunotherapeutics, VELs may make a decisive contribution to the success of vaccine clinical trials that have failed previously.

Due to their universal nature, we expect VELs to be utilized in urgently needed treatments against many pathogens and cancer.