Sayeda Yasmin-Karim, MD, PhD
Geraud Richard  Alina-Marissa Ogurek , Amanda Fam, Eric Broyles, Adam Shilling, Jacques Walker, *Sayeda Yasmin-Karim,G Mike Makrigiorgos 1 Brigham and Women’s Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA 2 Northeastern University, Boston, Massachusetts, USA 3 Nanocan Therapeutics Corporation, Princeton, New Jersey, USA
G Mike Makrigiorgos and CoPI: Sayeda Yasmin-Karim
Purpose: Radiation is a common modality for lung cancer treatment. Radiation induces apoptosis, exposing cancer-associated antigens that can be recognized by antigen-presenting cells (APCs) to induce antineoplastic effects by activating cytotoxic T cells. Our prior studies show adding immunoadjuvants like anti-CD40 antibody with radiation can further activate the APCs. Flavonoids like Hesperetin, an ACE2 receptor agonist, were recently shown to induce apoptosis in lung cancer cells where ACE2 receptors are abundant. Here we developed a novel treatment delivery method in a non-small cell lung cancer (NSCLC) model using inhalation of anti-CD40 and Hesperetin-containing nanoparticles (HNP), to enhance the antitumor effect and to reduce systemic toxicity risks.
Methods: We developed syngeneic orthotopic murine lung tumors using a luciferase gene transfected LL/2-Luc2 Lewis lung cancer cell line implanted in wild-type C57BL/6 mice, enabling time-dependent bioluminescence tumor imaging (BLI). We prepared HNP using NanoFabTx™ nano-formulation reagent kits (Millipore-Sigma). We performed in-vivo survival assay analysis after aerosol treatment with HNPs with or without anti-CD40 (abcam).
Results and Conclusion: We were able to successfully develop an aerosol drug delivery system to administer immunotherapeutic anti-CD40 and Flavonoid-loaded HNP in a murine lung cancer model. We found combining aerosol treatment with anti-CD40+HNP (p<0.001) increased survival compared to untreated controls, or anti-CD40 alone (p<0.01). HNP treatment did not result in toxic effects on the vital organs, confirming the potential of this minimally invasive approach for lung cancer treatment.
As lung areas are less accessible for needle insertion, we proposed the novel inhalation formulation to be further tested for lung specific tumors. We aim with this project, building upon the nanoparticle encapsulated smart technology development, concentration, and distribution work, as well as intrabronchial tumor models, testing the different drug and radiotherapy combinations and challenge the hypothesis that we can induce a strong tumor control effect based on inhalation therapy for immune infiltration rather than direct cell death. Achievement of this study milestones will provide sufficient data for IND filling and start Phase I clinical work in aims of offering a novel treatment paradigm for advanced lung cancer patients.