Project Summary
In this Industry-Academic Partnership R01 application, a multidisciplinary team of investigators from the
University of California at Davis, TargaGenix and Northeastern University are proposing to develop a highly
innovative combination treatment strategy for refractory tumors, such as pancreatic ductal adenocarcinoma
(PDA). The proposed studies will leverage multi-disciplinary expertise of scientists and clinicians to develop
effective PDA treatment paradigm based on the combination of TGX-1214 (a nanoemulsion of our lead next
generation taxoid DHA-SBT-1214) with immune checkpoint inhibition. In preliminary studies, our novel lead
agent DHA-SBT-1214 strongly inhibited pancreatic cancer growth in two preclinical models of pancreatic cancer
(complete tumor regression in both models). In addition, we have recently documented that the combination of
an anti-PD-L1 therapy with our novel chemotherapy drug DHA-SBT-1214 formulated in a nanoemulsion (TGX-
1214), significantly increased CD8+ T-cell infiltration and enhanced the therapeutic effects of the anti-PD-L1
antibody in a pancreatic cancer syngeneic model. It is noteworthy that TGX-1214 alone on combined with an
anti-PD-L1 antibody therapy strongly reduced tumor growth to a higher extent than paclitaxel, nab-paclitaxel
(Abraxane), gemcitabine, or single anti-PD-L1 antibody therapy groups. Moreover, in the clinically relevant KPC
genetically-engineered mouse model of PDA, TGX-1214 reduced tumor fibrosis and increased of CD8+ T-cell
infiltration. Importantly, TGX-1214 appears safe and present a high therapeutic window as indicated by GLP-
toxicity studies in rats and dogs. Thus, these results indicate that TGX-1214 is safe and effective in multiple
preclinical models of PDA; it stimulates the immunogenic potential of PDA and provides synergistic therapeutic
effects with immune checkpoint blockade therapy, warranting further evaluation. Our long-term goal is to develop
safe and effective treatment strategies for PDA to test in clinical trials and ultimately to be used in humans. Based
on these novel findings, we hypothesize that a combination of TGX-1214 and immune checkpoint antibody
therapy will provide superior efficacy with less toxicity. The specific aims of the study are: (1): To evaluate tumor-
specific delivery, biodistribution, tumor stromal density modulation, and immune cell infiltration of TGX-1214 in
clinically relevant animal models of PDA; (2): To determine the therapeutic efficacy and safety of the TGX-1214
along with anti-PD-L1 antibody therapy in two clinically relevant PDA animal models (orthotopically grafted
pancreatic tumor organoids and KPC mice), and (3): To determine the efficacy of TGX-1214 as monotherapy in
patients with treatment-refractory PDA. At the completion of these studies, we expect that TGX-1214 in
combination with cancer immunotherapy, will become part of the personalized medicine revolution that is only
now beginning and will become a significant part of the future treatment paradigms to eliminate the burden of
PDA, providing positive benefits in long-term treatment outcomes.