Rewriting the Code of CAR T Cells — Annual Report 2025 | The Mark Foundation for Cancer Research

<p>How do you outsmart a tumor?</p> <p>According to Julia Carnevale, MD, a GI oncologist and researcher at the University of California, San Francisco (UCSF), you engineer a CAR T-cell therapy that’s even smarter.</p> <p>As the leader of a 2025 Endeavor Award team backed by The Mark Foundation and the Torrey Coast Foundation, Carnevale is taking on a formidable opponent: gastric and esophageal cancers, which together claim more than 1 million lives worldwide each year. But with a team of multidisciplinary experts, recent technological advances, and dogged persistence on her side, she’s already making gains.</p> <h3>A Complex Foe</h3> <p>Cancers of the stomach and esophagus are among the most aggressive and difficult malignancies to treat, which is why it didn’t take long in GI practice for Carnevale to become frustrated with the lack of therapeutic options available to patients. At the same time, she was watching the historic breakthrough of CAR T-cell therapy change the reality of treating blood cancers. When she had the chance to serve as a site PI for a clinical trial testing a CAR T product that targets Claudin18.2 (CLDN18.2)—a protein abundant in gastrointestinal and pancreatic tumors—she jumped at the opportunity.</p> <p>But applying this technology to solid tumors, which make up more than 90% of all cancer cases, was never going to be easy. While the Claudin product is now approved in China for certain advanced gastric cancer cases, the clinical effects remain limited and lack long-term durability.</p> <p>“There are a lot of ideas out there as to why these solid tumors are not responding to CAR T therapy to the same extent as liquid tumors,” Carnevale explains. “Part of it may be due to kinetics—there is less room for the product to expand and persist. There is also a physical architecture around the tumor that serves as a barrier to entry.”</p> <p>Even if an engineered cell does manage to break through that barrier, it faces a tumor environment actively working to disarm it.</p> <div class="aside-quote"> <p>“Essentially, solid tumors have a host of strategies to shut down any kind of adaptive T-cell response, from metabolic and oxygen deprivation to the recruitment of various immune cells that oppose T-cell activity. Along with all that, we have to thread the needle of finding a really narrow therapeutic window where the therapeutic effects are maximized without off-tumor, healthy tissue toxicity.”</p> </div> <p>To overcome an adversary that complex, tweaking a single variable is a losing game. It requires rewriting the cellular code from scratch—and achieving that requires a collaborative team.</p> <h3>Rewriting the Cell’s Operating System</h3> <p>Carnevale’s Endeavor team is an interdisciplinary powerhouse of colleagues from UCSF and the Gladstone Institutes: Justin Eyquem, PhD; Alexander Marson, MD, PhD; Kole Roybal, PhD; Gregory Allen, MD, PhD; and Karin Pelka, PhD. Together, their expertise spans synthetic biology, immunology, and genomic engineering.</p> <p>Their objective? Execute a comprehensive strategy that programs intelligence into every single phase of a T-cell’s journey.</p> <p>“We conceived of this project as writing the code for the cell to operate, from the outside of the cell all the way through the full journey of what that cell experiences,” Carnevale says.</p> <p>In its first year, the collaboration has already made significant progress across multiple engineering fronts. First, they looked at the cell’s entry point—the binder that locks onto the tumor. By systematically testing subtle variations in how the T-cell attaches to the cancer, they discovered that microscopic structural changes could radically dictate whether a T-cell successfully controls a tumor or fails completely.</p> <p>But getting into the tumor is only half the battle. Once inside, the T-cell must be shielded from the tumor’s chemical warfare. Using precise CRISPR gene editing, Carnevale’s lab has successfully identified central genetic pathways inside human T-cells and modified them to resist attack.</p> <p>“We’ve focused on identifying gene targets that allow the cells to essentially ignore the suppressive cues of the tumor,” Carnevale notes. “We are essentially turning their hearing aids down so they aren’t processing those ‘stop’ signals, which allows them to remain highly functional deep inside the tumor. We’ve also tuned specific molecules to block the tumor’s ability to repel them.”</p> <p>Finally, the team solved a critical safety hurdle. Because solid tumor targets are rarely exclusive to cancer, traditional therapies risk accidentally attacking healthy tissues. To resolve this, the team engineered sophisticated, biological “if-then” logic gates into the cells using synthetic receptors. These internal circuits force the T-cell to verify it has encountered a specific combination of markers before launching its attack, precisely restricting the immune assault to the disease site and sparing healthy organs.</p> <h3>Tenacity Born in the Clinic</h3> <p>No one would claim that Carnevale and her team are playing it safe. That, she says, is because navigating the brutal realities of advanced GI cancers alongside her patients has stripped away any appetite for incremental progress.</p> <p>“Seeing the diseases so intimately completely colors your risk tolerance,” Carnevale says. “A therapy that only briefly delays disease progression is often not in a patient’s best interest when the disease is this challenging. It’s pushed me to examine all of our options and not be too timid in our exploration. Let’s see what levers we can pull. Let’s push that extra mile.”</p> <p>That unrelenting drive is also deeply personal. Carnevale lost her mother to cancer at an early age, a loss that fuels the extraordinary intensity she pours into her work. “It’s a driving force for me. I love this work, and to me, there is no more important, more urgent pursuit in the world.”</p> <h3>Chasing the Slipstream</h3> <p>While her team’s lab work is rapidly advancing—and is currently being tested with complex modeling systems and advanced, lab-grown 3D organoids—Carnevale is also mindful of how the project fits into the broader puzzle of cancer care.</p> <p>Cell therapies are typically reserved for late-stage disease after traditional “first-line” treatments have stopped working. However, scientific data increasingly show that these living drugs perform exponentially better when administered early, before a patient’s immune system is exhausted. But capturing that clinical advantage depends entirely on catching the disease sooner.</p> <p>“The fewer cases of advanced cancer we have to treat, the better,” Carnevale notes. “I am hopeful about the advances we are seeing in liquid biopsy and AI-enhanced diagnosis. Having a reliable blood test, for example, would completely change the field. If we can systematically shift patients away from advanced-stage diagnoses and intercept early disease, we can bring highly intelligent cell therapies into the mix when they have the highest chance of achieving a durable cure.”</p> <p>It is a massive, multi-front challenge, but Carnevale looks to history for proof of what is possible when scientists refuse to settle for marginal gains.</p> <div class="aside-quote"> <p>“When I was in residency and fellowship, a diagnosis of advanced melanoma was an absolute death sentence. Today, because of the immunotherapy revolution, it’s a completely different world. It can feel like we aren’t moving fast enough, but all it takes is finding the right slipstream, and suddenly, you are in a totally different universe than what your last patient experienced. We just have to keep pushing the boundaries.”</p> </div>