Dr. Patrick Hwu welcomes Dr. Robert Vonderheide, director of the Abramson Cancer Center and Vice Dean for Cancer Programs at the University of Pennsylvania’s Perelman School of Medicine. Dr. Vonderheide shares his journey from early skepticism about cancer immunotherapy to pioneering work in tumor antigen discovery, vaccine development, and activating the CD40 pathway. He discusses the unique challenges of pancreatic cancer, including its suppressive microenvironment and the role of the KRAS oncogene, and explores strategies combining targeted therapy with immunotherapy to generate effective T-cell responses. Dr. Vonderheide also highlights the promise of early detection and interception, the potential of CD40 agonists, and the importance of mentorship in training the next generation of cancer researchers, emphasizing the collaborative, innovative spirit that continues to drive advances in the field.