“Esophageal cancer is one of the deadliest and least ‘forgiving’ malignancies in the U.S. and around the world,” says Prakash Nallathamby, assistant professor of practice and associate director of the Berthiaume Institute for Precision Health at the University of Notre Dame.

Nallathamby, who is also an affiliate of Notre Dame’s Harper Cancer Research Institute and the Bioengineering Graduate Program, explains that the cancer is becoming more widespread, for reasons that are not fully clear. “We used to associate it mainly with risk factors like smoking,” he says, “but we can now see that rates continue to rise even where tobacco use has fallen.”

One thing is certain, he says, “Given that this cancer has a five-year survival rate of around 20-25%, there is an urgent need for novel treatment platforms that can overcome the biological and logistical hurdles of advanced disease.” And the need is even more urgent for veterans, who are five to ten times more likely than members of the general population to develop esophageal cancer.

So Nallathamby was excited to partner with the U.S. Defense Health Agency’s Peer Reviewed Cancer Research Program (PRCRP), an entity charged by Congress to investigate cancer risks and knowledge gaps that may be relevant to active-duty service members, their families, veterans, and the American public.

Over the next two years, with funding from the PRCRP, Nallathamby plans to apply a new technological breakthrough to make the benefits of CAR-T-cell therapy available to those suffering from esophageal cancer.

CAR-T-cell therapy has been at the center of several major cancer success stories over the past few decades. Among the most famous is that of Emily Whitehead, who, at the age of six, was the first pediatric patient at CHOP to receive CAR-T-cell therapy in 2012 for treating her non-responsive relapsed acute lymphoblastic leukemia (ALL). Today, she remains cancer-free and has gone from a sure death sentence to living the life of an everyday college student.

CAR-T cell therapy has been successful in treating several blood cancers, including leukemia, lymphomas, and myelomas. But the success has been difficult to replicate for most other types of cancer.

“Solid tumors are much tougher to treat with CAR-T-cell therapy than blood cancers,” Nallathamby explains. “Tumors form physical barriers, suppress immune activity around them, and show mixed antigen patterns—all of which make it hard for CAR-T cells to reach, survive, and work effectively. On top of that, manufacturing takes about 4 weeks, and patients usually get only one infusion after chemo preconditioning.”

In a typical CAR-T process, doctors collect a patient’s T cells by Peripheral blood mononuclear cell (PBMC) collection. In the lab, those cells are activated and genetically modified—usually with a viral vector—to display a chimeric antigen receptor (CAR) that recognizes a tumor antigen. The modified cells are expanded to large numbers, tested for quality, and then infused back into the patient after a short chemotherapy regimen. Once inside the body, CAR-T cells are expected to seek out and bind cancer cells via the CAR, multiply in place, and release cytokines that kill the tumor.

Nallathamby plans to develop a modified version of CAR-T-cell therapy using specially designed multispecific “bridge” nanoparticles. The nanoparticles, which are less than 100 nanometers wide, have a silica core and are studded with gold nanodots. The design is based on one that Nallathamby and his team recently patented. The nanoparticles will present antibodies targeting up to four antigens simultaneously on esophageal cancer cells and one antigen on CAR-T cells and T-cells.

The team will administer multispecific bridge nanoparticles together with “off-the-shelf,” orthogonal CAR-T cells in mouse models of esophageal cancer. Once in circulation, the nanoparticles home to tumor antigens and simultaneously anchor the CAR-T cells at the disease site. Because these CAR-T cells are pre-manufactured rather than patient-derived, no leukapheresis or custom engineering is needed; they are activated on demand with a small orthogonal molecule.

This streamlined approach reduces the treatment window from the four- to five-week cycle of conventional CAR-T therapy to just three or four days, making repeat dosing practical. “We hope this gives patients more opportunities,” Nallathamby explains. “If we see a 30 percent response after one round, we will still have time to administer additional rounds safely. When tumors shrink, surgery outcomes become more viable with a smaller resection.”

Nallathamby’s team will specialize in the lab-based development of the treatment, but as he puts it, “We have a clear desire to move this treatment from the lab bench to the patient’s bedside. And that vision is all about leveraging the resources of our regional and state translational research network.”

Nallathamby’s team’s lab-based work will be complemented by contributions from clinicians. Dr. Sazzad Hassan, Assistant Research Professor of Surgery at the Indiana University School of Medicine, and Dr. Urs von Holzen, Surgical Oncologist and Medical Director at the Goshen Center for Cancer Care, will serve as co-principal investigators for the project.

The new funding is the result of a series of efforts that have been developing since 2021, when the Nallathamby group, with support from BIPH, entered into a partnership with the Indiana Clinical and Translational Sciences Institute’s (I-CTSI) Drug Think Tank, facilitated by Dr. Padma Portonovo (Indiana University School of Medicine). Nallathamby also highlighted the early proof-of-concept studies by Emma Tam ND’20 (Da Vinci Fellow) and Jordan Chang ND’22 (NURF) that laid essential groundwork for the current effort.

Contact:

Brett Beasley / Research Content Strategy Program Director
Notre Dame Research / University of Notre Dame
bbeasle1@nd.edu / +1 574-631-8183
research.nd.edu / @UNDResearch

About Notre Dame Research:

The University of Notre Dame is a private research and teaching university inspired by its Catholic mission. Located in South Bend, Indiana, its researchers are advancing human understanding through research, scholarship, education, and creative endeavor in order to be a repository for knowledge and a powerful means for doing good in the world. For more information, please see research.nd.edu or @UNDResearch.