Michael Berens, Ph.D., head of the Glioma Research Unit at TGen.
For the past 15 years, scientists at the Translational Genomics Research Institute (TGen) in Phoenix have studied patients’ individual DNA blueprints to identify the most effective treatments for cancer and other complex diseases.
As an affiliate of City of Hope, TGen will use this expertise to chart a path to greater precision in CAR T therapies for cancer patients.
“We are going to add additional experience and techniques to what they do,” explained TGen Professor Michael Berens, Ph.D., head of the Glioma Research Unit. “Our genomics platforms can look at both the weapon — the CAR T cells and their effectiveness — as well as the targets, or the cancer cells, and how they’re shifting and changing.”
CAR T cells are genetically engineered to target tumor-specific, surface protein markers, which stimulate a strong immune response to attack the cancer. The challenge is identifying the most effective markers to target among the thousands that may be present on a tumor.
TGen’s genomics technology can accelerate the identification of these targets. Traditionally, CAR T cells are aimed at proteins that are found at high levels on the surface of tumor cells but are at low levels or absent on healthy cells. In addition to identifying additional targets of this kind, TGen scientists are working on a new assay that allows them to identify a different class of targets – known as neoantigens.
“Neoantigens are exciting because they are found only in tumor cells and nowhere else in the body, making them highly-specific targets for an immune response with less potential for side-effects,” explained John Altin, Ph.D., an assistant professor in the Pathogen and Microbiome and Integrated Cancer Genetics divisions at TGen, who helped to invent the new assay.
Immune responses against neoantigens may be either targeted by the CAR T cells directly, or may be a beneficial side-effect of CAR T therapy. Ultimately, these approaches promise to generate a more successful immune response for cancer patients at City of Hope.
TGen President and Research Director Jeffrey Trent, Ph.D., is collaborating with Christine Brown, Ph.D.
, at City of Hope to use the new assay for CAR T therapies against HER2 breast cancer. The TGen team is also investigating the effectiveness of CAR T against pancreatic cancer, the third-leading cause of cancer death. Pancreatic cancer has proven resistant to other immunotherapy approaches because it has a near-impenetrable physical barrier and an inhospitable environment that thwarts T cells.
In addition to the neoantigen assay, Berens is eager to deploy TGen’s single-cell sequencing technologies to study RNA and the epigenome in CAR T therapy and brain tumors. RNA carries out the instructions coded in the DNA blueprint. The epigenome is the machinery on the DNA helix that turns genes on and off, depending on a cell’s specific function and location in the body.
With single-cell RNA sequencing, “we can now watch how the engineered T cells behave,” Berens explained. “Is it only the CAR T cells that control the tumor, or are they showing the rest of the patient’s immune system what to do?”
The epigenome of a cancer stem cell can convert a cell from being quiet and acquiescent to one that is actively invading the surrounding tissue, even though the DNA does not change, Berens said, which can help oncologists understand how brain tumors escape immunotherapy.
“This is another area where TGen’s genomics can really add value to City of Hope’s CAR T programs,” he said.