Immunology, Transplantation and Infectious Diseases

Targeted Cancer Gene Therapy

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Head of Unit

Luigi Naldini

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Immunotherapy has gained renewed interest for cancer treatment thanks to the efficacy of immune checkpoint blockers and adoptive therapy with genetically engineered T cells. However, many patients fail to respond or develop resistance mainly because of an immunosuppressive tumor microenvironment. We have developed a strategy for targeted gene-based delivery of type I Interferon (IFN) to tumors by tumor-infiltrating monocytes/macrophages, expressing the angiopoietin receptor Tie2 (TEMs), which induces robust tumor responses in several experimental tumor models. Hematopoietic Stem/Progenitor Cells are genetically engineered ex vivo with lentiviral vectors (LV) that target expression to their TEM progeny by a combination of transcriptional and micro-RNA mediated control.

Recently, we showed that targeted delivery of immune stimulatory cytokines by TEMs can effectively reprogram the immune suppressive tumor microenvironment, leading to enhanced recruitment, activation and effector function of immune cells, which in turn induce protective immunity against multiple tumor associated antigens.

Research activity

Our current research aims to:

  1. Develop new conditional lentiviral vectors (LV) and transgenes for endogenously and/or exogenously regulated targeted delivery of immune stimulatory cytokines in the tumor microenvironment;
  2. Characterize the immune cell infiltrate of experimental tumors treated by our gene therapy strategy and identify cellular phenotypes and gene expression signatures providing readouts of the response to our treatment;
  3. Explore new cytokine payloads to be used alternatively or in combination with IFNα, and dissect their role in mediating antitumor responses alone or in combination with immune checkpoint blockers;
  4. Score a panel of human cancers using the above identified signatures to identify cancer types more likely to respond to our strategies.

Regulated expression by newly designed vectors and transgenes, and adoption of emerging strategies for engrafting the engineered progenitors will increase the safety and applicability of this platform to several types of tumors. Therapeutic efficacy of our strategy can be enhanced by synergy with immune checkpoint blockers and selecting candidate target cancers types according to specific features of the immune infiltrate.