April 3, 2017 | by Travis Marshall
“If I see the clusters, I’m happy.”
Xiuli Wang, Ph.D., a CAR-T cell researcher at City of Hope, is peering into a microscope in her brightly lit research lab. At the other end of the lens are modified T cells — immune system cells trained to fight tumors — growing in dense, grey clusters.
“One T cell grows to thousands of cells,” said Wang, an associate research professor in the Department of Hematology & Hematopoietic Cell Transplantation. “That’s why they form clusters.”
These cells — so tiny, so seemingly innocuous when suspended against the backdrop of the pale yellow culture — are actually quite powerful. They are what Wang and other CAR-T cell experts at Beckman Research Institute of City of Hope call “soldiers of the immune system.”
CAR-T cell therapy is an innovative and promising approach that recruits the body’s own immune system in the fight against some of the hardest-to-treat cancers, including solid tumors like glioblastoma and blood cancers like lymphoma.
These microscopic fighters could hold the key to launching a real battle against multiple myeloma, a rare and debilitating blood cancer. An upcoming phase 1 clinical trial at City of Hope will look at the effects of CAR-T cells programmed to target a protein called CS-1, which is found on myeloma cells.
Multiple myeloma affects plasma cells, an important part of the immune system primarily found in bone marrow. As it progresses, myeloma can lead to anemia and hinder the body’s ability to fight infections, along with other complications like weakening bones and kidney damage.
Multiple myeloma’s causes and risk factors are not well known. Currently available treatments — including a variety of immunotherapies, chemotherapy and stem cell transplantation — can often be combined to extend patients’ lives upwards of 10 years, but multiple myeloma remains largely incurable.
“There have been advances in new drugs that help extend patients’ lives, but eventually almost 100 percent of them will relapse,” said Maung Myo Htut, M.D., assistant professo in the Department of Hematology & Hematopoietic Cell Transplantation, and the lead investigator on the upcoming CAR-T trial.
“There’s a real need for additional therapies for myeloma, and that’s why we’re looking at CAR-T cell therapy for this type of cancer.”
In theory, CAR-T cell therapy could be customized and applied to almost any cancer. To do so, doctors harvest the patient’s own T cells. The T cells are then reprogrammed in the lab using a harmless virus, which causes the cells to express chimeric antigen receptors (CARs), turning them into smart weapons that seek out a specific target and destroy only those cells.
“We tweak the virus to produce different kinds of receptors based on the tumor, and we can target any type of cancer, as long as it has a protein not expressed by healthy cells,” said Htut. “For myeloma, our target is a protein called CS-1 that is almost universally present on myeloma cells, and that very few other cells in the body express.
“It’s like we’re taking infantry soldiers and training them to be Navy SEALs whose only job is to find and kill these cancer cells.”
Once the T cells are reprogrammed, they are infused back into the patient.
Wang says CAR-T cells hold big advantages over conventional treatments for myeloma. One is their specificity: They target tumor tissue but not normal tissue. Another is, since they are modified versions of the patient’s own cells, there is very little risk of toxicity. And CAR-T cells can survive in patients for long periods of time, whereas chemotherapy and other drugs tend to clear out of the body much faster.
Well-trained CAR-T cells do not clear out — they stay in patients and have memory.
“They play immuno-surveillance,” said Wang. “They monitor the tumor and they kill. Chemotherapy kills not only tumor cells but also normal tissue. CAR-T cells would not touch normal tissue.”
Htut and his colleagues are now writing the protocol for their trial. They’ve done preclinical studies with promising results, and he predicts the phase 1 trial should be active before the end of 2017.
The trial will look at two arms: One will infuse patients with the CAR-T cells after destroying lymphoctes in the blood with chemotherapy, and the other will infuse the CAR-T cells following autologous stem cell transplantation. “This is only a phase 1 trial, so our main goal is to monitor the patients’ safety,” he said.
“You can see the cells are very dense here,” said Wang.
Back in the lab, Htut’s colleague, Wang, is holding up a clear plastic flask. She swishes around the clear pinkish liquid and reveals a silt-like substance collecting at the bottom.
They are T cells that have been transferred from the petri dish to the flask — one step closer to helping patients.
“I am so optimistic for our trial because our preclinical studies are showing that the T cells are very potent and very efficient at killing tumors,” said Wang. “We hope that happens in patients, too.”
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