Development of Innovative Personalized Idiotypic mRNA-Based Dendritic Cells and Lipid Nanoparticle Vaccines, for Indolent B-Cell Lymphomas and Chronic Lymphocytic Leukemias

Despite a plethora of approved new drugs, patients with relapsed/refractory indolent non-Hodgkin Lymphomas (NHL) and Chronic lymphocytic leukemia (CLL), are still incurable and have a high impact on the National Health care system. In fact, patients health and quality of life are progressively impaired by multiple disease relapses and lines of subsequent treatments. Therefore, developing efficacious treatment for this disease is considered an unmet need. From a therapeutic point of view, the idiotype (Id) of malignant B cells represents a patient- and tumor-specific Ag, which could be a potential target of personalized treatment. (Id) vaccination has already been attempted proving evidence to be immunogenic but exhibiting failures mainly due to improper design. In this light, the need of innovative and optimized (Id)-based vaccine formulations meets the current breaking advancement in mRNA technology and in the scientific knowledge of tumor biology, opening a new powerful scenario to develop vaccines able to overcome the current limitations and improve the clinical benefit. Recently, we developed a dendritic cell (DC)-based vaccine, namely IFN-DC, which we characterized in preclinical studies and used in a phase I trial in combination with rituximab to treated patients with FL, obtaining a good rate of response by eliciting strong cellular immune responses. Therefore, we aim to improve the efficacy of our DC vaccine and to set up new strategies of treatment to advance chronic B cell lymphomas and leukemias therapy. Specifically, we aim to develop efficacious personalized (Id)-based IFN-DC and (Id)-mRNA-based vaccine formulation, and to design combination treatments with monoclonal antibodies targeting immunomodulatory molecules, such as immune checkpoints, to be used in NHL and CLL. To this end, we will exploits the following scientific and technological approaches: 1) to employ the innovations in mRNA technology, proved to be safe and inexpensive, to deliver (Id) epitopes to IFN-DCs, obtaining (Id)mRNA-IFN-DCs, or to build Lipid Nanoparticle (LNP)-(Id) mRNA; 2) to characterize, phenotypically and functionally, the immune response to (Id)mRNA-IFN-DCs and LNP-(Id)mRNA vaccines; 4) to evaluate the immune profiling of the tumor microenvironment (TME), whenever possible, at molecular and phenotypical levels; 5) to assess the role of macrophages within TME and at the interface of (Id)mRNA-IFN-DCs and LNP-(Id)mRNA vaccines; 6) to assess the efficacy of combination
therapies employing (Id)mRNA-IFN-DCs or LNP-(Id)mRNA vaccines in combination with monoclonal antibodies targeting immunomodulatory molecules (e.g. PD-1, PD-L1, CD37).
Overall our aims will be:

• To generate and characterize personalized (Id)mRNA-IFN-DC and LNP-(Id)mRNA vaccines for NHL and CLL, and to advance their clinical use by performing GMP validation and producing the Investigational Medicinal Product Dossier (IMPD)
• To assess NHL and CLL patient immunoprofiling and potential immune mechanisms inhibiting the efficacy of (Id)mRNA- IFN-DC and LNP-(Id)mRNA vaccine formulations.
• To develop innovative treatments by combining (Id)mRNA-IFN-DC or LNP-(Id)mRNA vaccines with selected monoclonal antibodies targeting immunomodulatory molecules

In conclusion, this study will contribute to develop more efficacious therapeutic options for NHL and CLL by fostering the development of personalized (Id)mRNA-IFN-DC and LNP-(Id) mRNA vaccine formulations.