Goal 4. Devise new cell and gene therapy strategies to modulate immune response
Alleviating innate immune activation and preventing adaptive immune response to gene and cell therapies is fundamental to safely establish stable and sustained transgene expression and function. While some gene therapy strategies, such as hematopoietic stem cell gene therapy (HSC GT) following lympho-myeloablative conditioning, may promote tolerance to the therapeutic protein, other ones, such as systemic administration of viral vectors, may instead exacerbate immunity and jeopardize the potential for durable benefit.
We have thus long investigated vector and transgene-directed immune response and effective ways to counteract them, as well as devised careful ad hoc monitoring for prompt capture of the emergence of such responses in early phase clinical trials. Moreover, capitalizing on prior work of several PI’s who identified some novel subpopulations and/or maturation/polarization stages of monocyte/macrophages and dendritic cells with immune suppressive function, we have pursued further characterization of these cellular effectors and the signaling pathways that modulate their activity.
Besides uncovering relevant roles of these cell subsets in pathophysiological processes (such as tissue regeneration, immune homeostasis and autoimmunity, angiogenesis and tumor progression) our research also ventured into genetic manipulation of these cells to open the way to potential new therapies aiming at either:
- achieving antigen-specific immunological tolerance in protein replacement and gene addition therapies and thus ensuring long-term expression of the therapeutic protein;
- or, conversely, enhance adaptive immunity to tumor-associated antigens by reprogramming the immune suppressive activity of myeloid populations within the tumor microenvironment; this would pave the way to the application of our gene transfer platforms to the development of novel treatments for cancer.