A novel dual-carrier ultrasmall nanomedicine for the treatment of stroma-rich pancreatic cancer

EXECUTIVE SUMMARY Cancers rich in dense stromal tissue are more difficult to treat and carry a worse prognosis than cancers without the stroma-rich phenotype. The fibrous stroma surrounding certain tumors effectively excludes many current therapies, including antibody- or cell-based therapies and large (>30nm) nanoparticles. Duo Oncology develops ultrasmall nanomedicines (10nm-30nm) that penetrate and accumulate in stroma-rich tumors but not healthy organs. Specifically, our innovative ultrasmall nanomedicine, DUO-307, penetrates stroma rich tumors and changes the tumor immune microenvironment through the combined actions of its gemcitabine prodrug (PGEM) and co-encapsulated small molecule immunotherapy, chemokine receptor type 2 antagonist (CCR2a; PF-04136309). It is a unique chemo-immunotherapy that is directly cytotoxic to the tumor and increases the expression of programmed death receptor 1 (PD-1), which synergizes with immune checkpoint inhibitor therapy. The proposal funded by the NCI and entitled, “A novel dual-carrier ultrasmall nanomedicine for the treatment of stroma-rich pancreatic cancer”, aims to propel DUO-307 toward commercialization through the completion of three specific aims: • Aim 1, conducted in collaboration with Drs. Lance Munn and Gabriel Duda of Massachusetts General Hospital, will provide an optimized formulation of DUO-307. Our collaborators will grow and harvest human pancreatic cancer patient derived xenografts (PDX) to be used in a vascularized tissue explant (VTE) culture system. Tumor tissue samples will be exposed to increasing concentrations of PGEM to determine the quantity of chemokine ligand 2 (CCL2) produced when maximal GEM-associated apoptosis is achieved. We will then use a human monocyte chemotaxis assay to determine the optimal amount of CCR2a to co-load into our DUO-307 nanomedicine. The optimized formulation will then be characterized for particle size, drug loading efficiency, and stability. Progress has already been made toward the completion of this aim. Qualified PGEM nanoparticles were manufactured and delivered to Dr. Munn’s laboratory. PDX pancreatic tumor samples have been implanted into mice and once they reach the appropriate size will be harvested for experimental use in the VTE cultures. • Aim 2 will evaluate the safety of the optimized DUO-307 formulation. A dose escalation study in naïve mice will be conducted to determine the maximum tolerated dose. A single cycle dosing schedule will be used and terminal clinical chemistry and blood cell counts will be the primary outcomes of interest. • Aim 3 will test the efficacy of DUO-307 in combination with anti-PD-1 therapy in an orthotopic KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mouse model of pancreatic cancer. This aim will be conducted in collaboration with Dr. Song Li at the University of Pittsburgh and will evaluate DUO-307’s ability to inhibit tumor growth, reduce tumor associated macrophage populations, and ultimately increase anti-tumor immunity. Up to this point, we have not encountered administrative, technical, or commercial challenges. In the next two weeks, we will submit a change order to our CDMO so they will be ready to manufacture the optimized DUO- 307 product for the studies outlined in Aims 2 and 3. Duo Oncology’s iCorps team will be compromised of Drs. Sam Rothstein, Katherine Eichinger, and Victoria Manax. Dr. Rothstein is Duo Oncology’s CEO and received a PhD in chemical engineering from the University of Pittsburgh. He has 20 years of experience researching and developing nanoparticle products and founded his first company, a particle CDMO, while in graduate school. Since co-founding Duo Oncology in 2020, Dr. Rothstein has secured more than $4 million in private investment toward the commercialization of Duo Oncology’s lead product. Dr. Rothstein is deeply committed to investigating DUO-307’s commercial landscape. He believes this nanomedicine is uniquely poised to deliver a new, better treatment option for patients with stroma-rich tumors, enhancing their response to anti-PD-1 therapy. Dr. Katherine Eichinger will serve as the Technical Lead/Expert of the iCorps team. She is the PI of the STTR grant and the Director of Operations for Duo Oncology. Dr. Eichinger has worked at three major healthcare institutions as a clinical pharmacist and has earned her PhD in pharmaceutical sciences. Dr. Eichinger has been laying the groundwork for production, preclinical toxicology, and clinical testing of Duo Oncology’s lead product. She is eager to work with Drs. Rothstein and Manax to identify marketplace opportunities for DUO- 307 and efficiently advance it to commercialization. The role of Industry Expert will be filled by Dr. Victoria Manax, an accomplished medical oncologist, who has spent over two decades in the pharmaceutical/biotech industry. Dr. Manax has designed and overseen numerous multimillion-dollar global clinical trial programs and has shaped the clinical trial landscapes through the advocacy of adaptive platform designs. She is well-qualified to help Duo Oncology transition DUO-307 from a novel academic nanomedicine to a global therapy that can transform the lives of oncology patients. Each of the three members of Duo Oncology’s iCorps team are committed to the time requirements of this program and are genuinely invested in refining the commercialization strategy for DUO-307.