Engineering a New Approach to Pancreatic Cancer Immunotherapy
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and often fatal cancer with few effective treatment options. One major challenge in treating the disease is its highly fibrotic and immunosuppressive tumor microenvironment, which acts as a barrier to effective drug delivery and immune checkpoint blockade.
A collaborative team led by Marcus Ruscetti, PhD, and Prabhani Atukorale, PhD, a biomedical engineer at UMass Amherst who holds a dual appointment at UMass Chan, is working to overcome these challenges. The researchers have received an R01 grant from the National Cancer Institute to advance an innovative nanoparticle-based immunotherapy designed to transform the pancreatic tumor microenvironment and help the immune system recognize and eradicate tumors.
The project builds upon the team’s recent work published in Science Translational Medicine. Their approach combines two complementary strategies. One builds on Ruscetti’s earlier work demonstrating that a combination of the MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib can remodel the tumor microenvironment, increasing tumor vascularization and enhancing drug delivery and infiltration of cancer-fighting cytotoxic T cells. The second, developed in the Atukorale lab, uses lipid-based nanoparticle to deliver STING and TLR4 agonists to activate innate immune responses within the tumor. Together, these approaches work synergistically to produce a potent innate and adaptive immune response, leading to tumor regression and long-term survival in mouse models of PDAC.
With support from the new NCI grant, Ruscetti and Atukorale will further develop this potent combination therapy and make its delivery more precise and effective.
The researchers will engineer targeted nanoparticles designed to deliver these therapies more precisely to tumor cells and antigen-presenting dendritic cells within the pancreatic tumor microenvironment. They will evaluate how different nanoparticle designs affect drug biodistribution, immune activation, safety, and efficacy. They will also test whether the approach can be combined with anti-PD-1 immune checkpoint blockade to generate a stronger and more durable anti-tumor cytotoxic T-cell response in mouse and human preclinical PDAC models.
Ultimately, the team hopes to develop a more targeted and effective immunotherapy approach for PDAC, one that can overcome the tumor microenvironment and harness the immune system to produce lasting anti-tumor responses. In the long term, their work could help expand treatment options for patients facing this devastating disease.
