Characterization and optimization of Novel Ribonucleoprotein-based Vaccines – RNPVAX

We are studying the immunological purity of a TERT RNP vaccine using reporter lines to identify the TLR receptors involved in adjuvanticity, and we are studying the therapeutic quality in animal models. There the treatment is capable of producing complete cures and we seek to identify the mode of action and the cell populations involved.

Telomerase is a suitable target for cancer immunotherapy: Telomerase (TERT) is a fetal enzyme whose expression is reactivated in 90% of human cancers, due to epigenetic changes or somatic mutations, and allows tumor cells to proliferate indefinitely (2009 Nobel Prize in Physiology and Medicine). Therefore, TERT represents a nearly universal tumor antigen, not expected to induce serious side-effects in normal tissues. Indeed, T-lymphocytes against TERT epitopes can lyse most tumor cells, while sparing normal tissues, also including the few stem cells weakly expressing low level of telomerase. Although the rationale for developing an effective cancer vaccine against TERT remains strong, as highlighted in a statement published in Nature Reviews Clinical Oncology, a breakthrough in vaccine development is also needed to make this strategy efficient.

Although certain genes, such as telomerase, appear to be cancer-specific targets, it does not follow that all epitopes on these targets are target-specific. Some epitopes (fragments of the protein) are shared, which poses vaccine safety problems. We identified these problems in several tumor vaccines, and were able to show that the problem does not arise in telomerase and explain how it can be easily solved. We have even developed software to find out if an antigen presents this risk. A web server has been created and made available

epitopscanner.ircan.org

Thses works have been reported below:

Guillaume Kellermann, Baharia Mograbi, Paul Hofman, Patrick Brest. Shared epitopes create safety and efficacy concerns in several cancer vaccines

J Immunother Cancer. 2025 Jul 11;13(7):e012217. doi: 10.1136/jitc-2025-012217.

pubmed.ncbi.nlm.nih.gov/40645662/

Guillaume Kellermann, Olivier Croce, Baharia Mograbi, Paul Hofman, Patrick Brest. Comprehensive mapping of identical epitopes across human proteins reveals implications for immune recognition and therapeutic design

www.biorxiv.org/content/10.1101/2025.08.31.673368v1.abstract

Following the outstanding success of mRNA vaccine for COVID-19 but their disappointing activity in cancer to date, ribonucleoprotein vaccines (protein-RNA complexes) represent the next-generation technology to extend immunotherapy to all patients. Our preliminary results demonstrate unprecedented efficacy in the field of cancer vaccines and seem to herald a future revolutionary success in the treatment of non-manageable tumors.

Our strategy could provide a new therapeutic opportunity for 90% of all cancers. This would provide a major benefit for human health and have a positive social impact on industry employment.

Finally, this therapy is produced from a very safe fungus (yeast). It does not involve environmental (no toxic waste) or ethical problems (no animals or animal products are needed). It should be noted that this “vaccine” should be less expensive than most current immunotherapies because of the way it is produced. This will result in significant savings for the government health care system, and also facilitate access to cancer therapies for developing countries.

BACKGROUND
Vaccines have been successful in saving lives and improving overall health but have not been effective in treating established cancers due to the difficulty of breaking self-tolerance. Ribonucleoproteins (RNPs) are widely known to break tolerance in autoimmune diseases by inducing dual BCR/TLR signaling in B-cells, leading to a stronger diversification of the immune response against non-tolerized epitopes. RNPs may be a new and effective vaccine for cancer immunotherapy if specific tumor antigens are targeted, such as Telomerase (TERT) which is overexpressed in 90% of human cancers.

OUR IDEA
TERT can associate with RNAs to form ribonucleoprotein complexes, making it a potential vaccine for cancer immunotherapy and a potential vector for other antigens to break immune tolerance. Our preliminary results showed that TERT-RNP is able to induce a broad CD4 and CD8 T-cell immunity, and to display a strong antitumoral activity in mice (TC-1 model) but also on spontaneous tumors in dogs, without any noticeable side effects (mice, dogs and primates).

REMAINING QUESTIONS THAT NEED TO BE SOLVED FOR A NEW THERAPEUTIC APPROACH IN HUMANS
To date, RNP vaccines have been poorly studied and biochemically characterized. Do biochemical parameters such as monomeric/multimeric organization of the RNPs play a critical role in their immunogenicity or therapeutic activity? In RNPs (protein-RNA complexes), the RNA plays the role of the adjuvant, but what would be the optimal RNA structure for an RNP vaccine? Finally, would it be possible to use protein fusion with additional antigens in an artificial RNP to break tolerance against a non-RNP antigen?

PROJECT PLAN
Work Package 1: Characterization of the mode of action of TERT RNP vaccine. Using TERT-RNP efficacy as a proof-of-concept of RNP vaccines, we aim to understand the biochemical properties of the complex required to be efficient and to further characterize its mode of action in vivo. The goal of WP1 is to identify the key parameters associated with the therapeutic efficacy of TERT RNP before moving this novel family of vaccines into future GMP production.
The Expected results of this WP are 1/to define the optimal structure of RNP associated with efficacy; 2/ characterize the processing involved in antigen presentations of RNP and 3/ identify the immune presenting cells and effectors required for this vaccine.
Work Package 2: Development of more optimized RNPs. This WP is based on the previous results obtained with our RNP vaccine. The goal is to define development opportunities for more optimal RNP vaccine candidates that could be translated into the clinic.
The Expected results of this WP are 1/ through the optimization of the RNA component, to identify RNA modification or structures that improve immune responses; 2/ through the development of new TERT protein fusions, to demonstrate that RNP may be useful as a platform for vaccination.

EXPECTED RESULTS AND IMPACT
This project will contribute to a better understanding of RNP trafficking, antigen presentation, the elicited immune response, and the APC involved in the break of tolerance. It will also propose RNPs as a new therapeutic approach for vaccine development by inducing long-term immunity. The project is located at the interface between fundamental research, industry, and clinical research and aims to characterize determinants helpful to understand and optimize RNP vaccine in order to translate this technology to humans. The vaccine may help at term the medical community to propose an alternative for non-responsive patients to current immunotherapies in cancer and other diseases.