Camillia S. Azimi, PhD, CRI-Merck Postdoctoral Fellow Icahn School of Medicine at Mount Sinai Area of Research: Solid Cancers Despite significant advancements in cancer immunotherapy, solid tumors, which constitute about 90% of adult cancer cases, remain challenging to treat effectively using immunotherapy. This resistance is often attributed to the suppressive influence of tumor-associated macrophages (TAMs) within the tumor microenvironment. As the first line of defense, macrophages demonstrate immense power and control over the inflammatory state and adaptive cell response. Once influenced by the tumors’ suppressive signals, the TAMs dampen endogenous anti-tumor responses and inhibit T cell-centric therapeutic strategies. To address this hurdle, Dr. Azimi is conducting research to reprogram TAMs directly at the tumor site using innovative lipid nanoparticles (LNPs). These LNPs have demonstrated success in various medical applications, including COVID-19 vaccines, gene therapy, and autoimmunity treatments. Dr. Azimi’s research aims to harness LNPs to deliver specific reprogramming proteins derived to TAMs. This strategy seeks to activate immunostimulatory responses in TAMs, potentially reinvigorating their ability to fight cancer. Dr. Azimi’s research proposes two additional approaches to enhance the specificity of LNP delivery to a specific subset of these suppressive macrophages, called the TREM2+ TAMs which have been shown to widely correlate with pro-tumorigenic conditions and thus poor prognosis across many solid tumors. One approach involves using bispecific antibodies, antibodies that have two ’arms’ that can attach to two different targets, to facilitate targeted LNP transfection. The second approach involves engineering the reprogramming proteins themselves to activate only upon binding to the TREM2 marker. By focusing on specificity, the researchers aim to maximize the impact of reprogramming while minimizing off-target effects. The anticipated outcomes of this research hold tremendous potential. If successful, it could lead to a cost-effective therapeutic approach that reprograms TAMs thereby enhancing the body’s immune response against solid tumors. This innovative strategy not only addresses a critical challenge in cancer immunotherapy but also establishes a platform for the development of future therapies. The research’s far-reaching implications could reshape both the fundamental understanding of cancer treatment and its clinical applications, representing a promising advancement for the field. Projects and Grants LNP mediated in vivo reprogramming of tumor associated macrophages Icahn School of Medicine at Mount Sinai | Solid Cancers | 2023 | Miriam Merad, MD, PhD
