Our Science

Cancer Immunotherapy

Temferon™: our gene therapy product to treat cancer

We develop a lentivirus ex-vivo gene transfer strategy into autologous hematopoietic stem/progenitor cells (HSPCs) to target interferon-αexpression to tumor-infiltrating monocytes/macrophages (Tie2 Expressing Monocytes - TEMs). As a result, a recruitment of tumor-specific cytotoxic Tcells is added to the interferon-α effect. In contrast to antigen-restricted Chimeric Antigen Receptor T cells (CAR-T), Temferon™ generates immune responses to any TEMs positive tumors.
Using a combination of transcriptional and microRNA-mediated control, TEMs become capable to selectively express interferon-αlimited to the tumor micro environment. Based on these mechanisms, TEMs are armed with a specific drug and can systematically break the tumor immune-tolerance reprogramming the micro environment and generate an immune response.
Genenta has been authorized to enter in a Ph I/II clinical trials in early Multiple Myeloma relapsing and newly diagnosed Glioblastoma tumor patients. The demonstration of Temferon™ safety and of the molecular and biological readouts at the base of the predicted clinical efficacy in these two indications should support the potential development of Temferon™ against a broad range of tumors both as first line and as combination therapy.

The immunosuppressive tumor microenvironment represents a major hurdle to cancer therapy. We developed a gene transfer strategy into hematopoietic stem cells (HSCs) to target transgene expression to tumor-infiltrating monocytes/macrophages. Using a combination of transcriptional and microRNA-mediated control, we achieved selective expression of an interferon-α (IFN-α) transgene in differentiated monocytes of human hematochimeric mice. We show that IFN-α transgene expression does not impair engraftment and long-term multilineage repopulation of NSG (NOD/LtSz-scidIL2Rγnull) mice by transplanted human HSCs. By providing a source of human cytokines in the mice, we improved the functional reconstitution of human myeloid, natural killer, and T cell lineages, and achieved enhanced immune-mediated clearance of transplanted human breast tumors when hematopoiesis was engineered for tumor-targeted IFN-α expression.
By applying our strategy to mouse breast cancer models, we achieved inhibition of tumor progression and experimental metastases in an autologous setting, likely through enhanced generation of effector T cells and their recruitment to the neoplastic tissues. By forcing IFN-α expression in tumor-infiltrating macrophages, we blunted their innate protumoral activity and reprogrammed the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity. Overall, our studies validate the feasibility, safety, and therapeutic potential of a new cancer gene therapy strategy, and open the way to test this approach as adjuvant therapy in advanced breast cancer patients.

Copyright © 2014,
American Association for the Advancement of Science


Science Translational Medicine 01 Jan 2014:
Vol. 6, Issue 217, pp. 217ra3
DOI: 10.1126/scitranslmed.3006353






Luigi Naldini

Modified stem cells for therapeutics applications

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Cell & Gene Therapy Insights / Cellular Immuno-Oncology 4.0

Interview

The promise of tumor-targeted gene-based delivery of immune-activating cytokines

LUIGI NALDINI is the Director of the San Raffaele Telethon Institute for Gene Therapy and Professor at the San Raffaele University and Milan, Italy. He has pioneered the development and applications of lentiviral vectors for gene therapy and contributed to advance targeted genome editing in cell and gene therapy. He is member of EMBO, past President of ESGCT, and received the Outstanding Achievement Award from ASGCT in 2014 and from ESGCT in 2015, the Beutler Prize from ASH in 2017 and the 2019 Jeantet-Collen Prize for Translational Medicine.