Cancer Assassins
TGen Provides Boost to City of Hope CAR T Research
One of the most exciting developments in cancer treatment is immunotherapy, and City of Hope is at the forefront of this new frontier through its robust chimeric antigen receptor, or CAR T, cell therapy program.
“Immunotherapy is about waking up the immune system to recognize and destroy cancer,” explained Christine Brown, Ph.D., Heritage Provider Network Professor in Immunotherapy at City of Hope. “We can reprogram T cells to recognize and directly kill those (cancer) cells.”
In CAR T therapy, a patient’s immune cells are removed from their bloodstream, genetically engineered and re-programmed to recognize and attack targets on their cancer cell, and then reintroduced into the body to seek and destroy the tumor.
As an affiliate of City of Hope, TGen will use our expertise to chart a path to greater precision in CAR T therapies for cancer patients.
“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,” explained TGen Professor Michael Berens, Ph.D., Deputy Director and head of the Glioma Research Unit.
The challenge in CAR T therapy 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 PepSeq, 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.
“The PepSeq technology is going to empower what we learn from each patient on a clinical trial, so we can understand why a patient might respond or might not respond,” Dr. Brown said. “It really allows us to improve on that therapy, and hopefully to bring new therapies that are more potent, to patients more rapidly.”
TGen President and Research Director Jeffrey Trent, Ph.D., is collaborating with Dr. Brown 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, Dr. 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,” Dr. 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.
