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In immunotherapy of cancer, different vaccination strategies have been developed and evaluated in clinical trials, e.g. monoclonal antibodies, injection of DNA, peptides, proteins, autologous cells (tumoral cells, dendritic cells (DC) or T cells) processed in vitro or even direct injection of modified viral vectors.THERAVECTYS is a Paris-based, privately-owned, fully integrated discovery & clinical development biotech company, developping lentiviral vectors for human vaccination and immunotherapy applications. THERAVECTYS’ vaccine candidates based on a proprietary lentiviral vector technology enable a direct vaccination mechanism in patients by inducing a broad, intense and long-lasting T cell mediated response. Theravectys’ technology presents several advantages compared to these various vaccination approaches: -Our lentivectors encompasse up to 15kb DNA, the resulting polypeptide hence targeting a combination of different antigens which mobilizes different actors of the anti-tumor immune system-No selection of patients is needed according to HLA haplotype since epitopes are physiologically processed in vivo.-Unlike all other vaccination approaches, this technology allows the transduction of non-dividing cells such as DC, the most potent antigen-presenting cells (APC) of the immune system.-Break of immunotolerance: lentivectors not only provide sufficient amounts of antigens to DCs but also ensure an efficient processing and prolonged presentation of the antigens, an efficient maturation of DCs that possess all the stimulating abilities to induce an efficient activation of T cells-Non replicative and non persistent lentivectors-antigen expressing cells and transduced cells are eliminated by the immune response elicited after injection.-Direct injections in patients, without ex vivo process of autologous cells.-Different pseudotypes of lentivectors are developed to avoid specific immune reaction against the vector during boost injection(s).-Vaccination with lentiviral vectors are more potent and efficient than DNA or peptide or protein vaccination.The phase I/II clinical trial with our first vaccine candidate has been completed in HIV-infected patients. The vaccine is safe, as demonstrated by the clinical trial ongoing in 38 patients (no Serious Adverse Events have been reported during the trial). The interim analysis of the immunological data from the first two cohorts of patients performed by THERAVECTYS demonstrates the ability of the vaccine candidate to elicit multi-specific and poly-functional CD4+ and CD8+ cellular immune responses in vaccinated patients, even at the lowest dose.The interim analysis of this trial supports the potential of the lentiviral vector platform developed by THERAVECTYS for the future development of therapeutic vaccines and immunotherapies in oncology and infectious diseases. As a second indication, THERAVECTYS is developing an anti-HTLV-1 vaccine candidate to treat patients who have developed a virally-induced adult T cell leukemia. This vaccine candidate should enter into the clinics in mid-2015. Other indications in the pipeline are urogenital cancers, triple-negative breast cancer, EBV-induced nasopharyngeal cancers, HPV-induced cancers (cervix, oropharyngeal and anal cancers) and multiple myeloma.

Chimeric antigen receptors (CAR) modified T cells have shown very promising clinical results in hematological malignancies. CAR are usually composed of a scFv antigen binding domain linked to a spacer and intracellular signaling domains. CAR introduction into T cells leads to cells with optimal effector functions and with a new antigen binding ability. This strategy is well suited to skirt immune escape mechanisms.Despite their efficacy, CAR-T cells still show toxicity due to a cytokine storm, even if it is manageable. Improving the safety while maintaining or even improving the anti-tumor efficacy of CAR-T cells is therefore a crucial therapeutic challenge.Based on our proprietary lentiviral vector technology, we are developing a CAR-T cell platform aiming at producing innovative CAR-T cells. The development conducted by Theravectys are: -Development of proprietary lentiviral vectors coding for CAR of the second (containing the CD3ζ and the 4-1BB cosignaling domains) and third generations (containing the CD3ζ, the CD28 and the 4-1BB domains) directed against CD19 (for CD19+ leukemias and lymphomas), LMP-1 and -2 (for EBV-induced leukemias). Our lentiviral vectors will allow optimal expression of CAR therefore leading to a better efficacy of CAR-T cells. Hematological malignancies will be used as a benchmark.-Development of an inducible RUSH (Retention Using Selective Hook) system which is based on the streptavidin anchored to the membrane of the endoplasmic reticulum (ER) through a hook, and on the SBP (streptavidin binding protein) introduced into the CAR structure. The interaction between the streptavidin-hook and the SBP-CAR allows the CAR retention inside the ER. The addition of biotin displaces the equilibrium of binding of streptavidin towards biotin instead of SBP, thus leading to the release of the CAR from the ER and its expression to the cytoplasmic membrane. View Large Image | Download PowerPoint SlideThe release of the CAR will stop with drug exhaustion (or antagonist) and remaining cells can be easily reactivated through reintroduction of biotin. This system will increase safety of CAR-T cells. A CD19-CAR RUSH will be used as a proof-of-concept of the RUSH system.Most of the scFv used to date are of murine origin. Neutralizing antibodies against these murine scFv can limit the efficacy of CAR. As an alternative, we are screening and engineering specific humanized camelid nanobodies to be used as binding domains since they are highly homologous to the human VH domain of antibodies and they display high antigen binding capacities. The proof-of-concept will be made with a second generation CAR containing a nanobody directed against Her2 as a binding domain.Theravectys’ technological platforms allows flexibility and reactivity in the CAR design, production and evaluation, thus leading to the fast generation of safe and optimized CAR-T cells.