Cancer vaccines: anti-tumoral t cell therapy on demand

Cancer immunotherapies exploit the patient´s own immune system to seek and destroy cancer cells. The immune cells involved need activation and instruction to promptly locate and destroy malignancies. Lately those therapies benefitted from novel and revolutionary discoveries such as Immunocheckpoint inhibitors (CPI or ICI) which can unleash anergized pivotal effector cells' cytotoxicity against the cancer cells. Such therapy alone, unfortunately still can help only a subset of patients. Therefore, immunological approaches hold a great potential for cancer treatment, but need strong and solid optimization and better understating. Among them, immune adjuvants and cancer vaccines showed powerful activity not only in clearing the neoplasia but even in giving a long-lasting immune memory avoiding disease recurrence. Despite its great success and its enormous potential in treating patients, cancer immunotherapy lacks successful responses with a broader efficacy, mostly due to immunosuppression and natural immune regulation against self. What is not fully understood is how to make them function properly. There has been a recent surge in interest regarding the combination of these modalities with immune checkpoint inhibitors (CPIs). Despite previous clinical trials with limited success, due to a lack of understanding of immunosuppressive mechanisms, there is now newfound knowledge on how to mitigate suppression. This presents an exciting opportunity for these treatments to be effective. As a result, there is a growing interest in the use of adjuvants for cancer treatment. Among them, microbes and their subunit like viruses, bacteria, toxoids, viruslike particles (VLPs), Lipopolysaccharide (LPS), Poly I:C, DNA or RNA CpGsislands or artificial stimulants like nano materials or polymers showed positive outcome in the fight against cancer. Those immunostimulants are excellent in triggering the immune system to an initial stage but they suffer from lack of specificity for tumor type and miss the long-term efficacy over time to serve as vaccines. Furthermore, the mere activation of the immune system does not suffice to clear out malignancies, for which specialized cancer killer cells are needed. Those cells are generally natural killer cells (NKs) to cytotoxic T cells (CTLs) which upon proper activation they seek and destroy cancer bearing features. The need for both adjuvant and specificity brought us to generate and investigate potential personalized cancer vaccination technologies like loading oncolytic viruses, other microbes or polymers serving as adjuvant, with specific tumor bearing signatures called Tumor Associate Antigens (TAAs) as targets for cancer killing cells. Cytotoxic cells are instructed only upon activation and education from professional antigen presenting cells. Among them, Dendritic Cells (DCs) are needed to bring information about the TAAs by migrating to the lymph node. The results of our new therapies showed a great potential in fighting tumors not only as a therapy in several mouse models, but by establishing immunological memory, which confers long term protection against the disease relapse. We could further generate a specific repertoire of cytotoxic T cells able to clear and control the tumor growth. From this, the next idea was to bring already approved or soon to be approved existing vaccines to a new stage, turning them into powerful anticancer therapies to develop versatile, personalized, and efficient platforms. We focused on Oncolytic Viruses (OVs), Porous Silicon nanoparticles (PSi), Bacillus Calmette Guerin bacteria (BCG) and Measle Mumps Rubella (MMR) vaccine as immune stimulants. No vaccine can exist without antigen presenting cells (APC) and specifically Dendritic cells (DCs), since this immune compartment is the bridge towards the adaptive immunity. For this reason, we investigated DC’s activity when modified and turned into a more migratory phenotype to fight cancer. We monitored the efficacy of such new technologies in vitro with assays directly performed on immunological cells and then in different in vivo murine tumor models to assess the general efficacy in immunocompetent and immune- deficient complex systems. All the technologies were able to induce and potentiate cancer cell killing showing improved efficacy addressing the major drawbacks of immunotherapies. All our work has been carried out up to a preclinical stage. Overall, the work showed the possibility of using the immune system as strong weapon in fighting tumors when properly activated and instructed. Polymer nanoparticle, oncolytic viruses and bacteria are powerful activators of an immune reaction and the physical combination of them with TAAs create a strong tool to act as customizable and personalized vaccines, triggering effector T cells for treatment and long-lasting T cell memory for prevention.non