Finding innovative ways to address kidney cancer leads to DoD grant

(Press-News.org) Weill Cornell Medicine has received a $1.4 million, four-year grant from the U.S. Department of Defense to investigate a new therapeutic approach for the most common form of kidney cancer.

The grant is one of 10 Idea Awards the department funded this year to support innovative, high-risk, high-reward science that could lead to a paradigm shift in cancer care. The funding will enable principal investigators Dr. Lorraine Gudas and Dr. David Nanus to explore a cellular reprogramming strategy that may improve how patients with clear cell renal cell carcinoma (ccRCC) respond to a form of immunotherapy, called checkpoint inhibitors. Checkpoint inhibitors remove the brakes on T cells, which are a part of the immune system that help fight infection. This allows the T cells to attack cancer cells much like they attack bacteria and viruses.

Kidney cancer is one of the most frequently diagnosed cancers, striking nearly 82,000 Americans each year, according to the National Cancer Institute, and killing more than 14,000. Roughly 8 in 10 of those diagnoses is for clear cell renal cell carcinoma.

“We believe this work could completely change the way kidney cancer is treated,” said Dr. Nanus, the Mark W. Pasmantier Professor of Hematology and Oncology in Medicine and associate director of network integration at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “Today, while checkpoint inhibitors are showing significant treatment benefits for a wide variety of cancers including kidney cancer, most patients with clear cell renal cell carcinoma will become treatment resistant and ultimately die of their disease.”

One current treatment approach for many cancer types is an immunotherapy called chimeric antigen receptor T-cell (CAR-T cell) therapy, which works by removing immune T cells from the body and genetically engineering them to recognize cancer cells based on the antigens they express. The T cells are then infused back into the patient to trigger an anti-tumor response. This approach has not been successful in patients with kidney cancer.

With this grant, the investigators will study an alternative approach: Rather than infusing patients with CAR-T cells, Dr. Gudas and Dr. Nanus will work to reprogram kidney cancer cells to become like immune cells called dendritic cells. These antigen-presenting cells can then train the immune system to target and kill the cancer. They hope that reprogramming the cells, combined with checkpoint inhibitors, can lead to a more effective immune response than what CAR T cell therapy can generate.

“These dendritic-like reprogrammed tumor cells will help to kill the other tumor cells around them, in part by bringing to the tumor T cells that are already in the patient,” said Dr. Gudas, chair of the Department of Pharmacology and the Revlon Pharmaceutical Professor of Pharmacology and Toxicology at Weill Cornell Medicine. “We only need to reprogram a tiny portion of the tumor cell population into dendritic cells to make this treatment strategy successful. “

The researchers plan to use a harmless adenovirus to deliver three genes encoding the proteins necessary to turn the tumor cells into dendritic-like cells. The makeshift dendritic cells can then capture proteins from tumor cells and present them to T cells, which are activated to kill tumor cells. These include cytotoxic T cells or “killer T cells” that destroy tumor cells and memory T cells that act as long-term immune surveillance, staying within the tumor site to recognize and attack future cancer cells.

“It's years away from being in patients, but I think that the concept will be fairly easy to test pre-clinically,” said Dr. Nanus, who is an oncologist and director of the NewYork-Presbyterian/Weill Cornell Medical Center Healthcare Systems Cancer Program. “And since other people are doing similar work on other tumor types, it's something that could be the beginning of a whole new approach to immunotherapy in cancer.”

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