Using CRISPR, PICI scientists create faster, more precise way of engineering cancer-fighting T cells – without the use of expensive viruses
Parker Institute for Cancer Immunotherapy scientists at UCSF and UCLA have unveiled a faster, less expensive and simpler method of gene editing T-cells to fight cancer.
The approach uses CRISPR to cut and paste genes into specific spots in T-cells. Moreover, the method eliminates the need for viruses, which are commonly used to gene edit T-cells but can be time-consuming and costly to manufacture.
The research, published online today by the journal Nature, could significantly impact the landscape of cell therapy and immunotherapy as a whole, according to Fred Ramsdell, Ph.D., vice president of research at the Parker Institute for Cancer Immunotherapy.
“This is a huge advance for the cell therapy and CAR-T field, opening the door for us to create more robust, personalized cancer immunotherapy treatments in less time,” Ramsdell said. “What takes months or even a year may now take a couple weeks using this new technology. If you are a cancer patient, weeks versus months could make a huge difference.”
The recent approval of chimeric antigen receptor T-cell therapy (or CAR-T therapy) by the FDA has revolutionized cancer treatment. To make these cancer-fighting T-cells, scientists rely on viruses, such as lentiviruses or retroviruses, to genetically alter the T-cells so they can better fight tumors.
However, using viruses in the production process of CAR-T can take a long time and a significant amount of resources. It can take up to six months to generate lentiviruses for CAR-T production, while retroviruses may take up to a year. Recent news reports indicate a shortage of these viruses, resulting in backlog that has slowed down cell therapy research.
In addition, the viruses randomly insert the genes with little predictability. This new method using the CRISPR-Cas9 system and electroporation allows scientists to choose where genes will be inserted.
“The biggest advantages are that we can target where genes go into the genome, and we can do it without the use of a virus so the manufacturing is much easier and faster,” said senior author Alexander Marson, M.D., Ph.D., a Parker Institute project member at UCSF.
The researchers also showed they could successfully insert much longer pieces of DNA into T-cells while largely maintaining the cells’ viability. In this paper, they introduced genes encoding a T-cell receptor that recognizes a protein on some skin cancers. Armed with this new receptor, the modified T-cells sought out and killed the cancer cells.
Enabling the insertion of longer DNA pieces into T-cells also opens the door to more sophisticated engineering that can provide T-cells with new or more enhanced disease-fighting power. For example, using this method, researchers could engineer T-cells that do not tire out as easily or produce more of a chemical that harms tumor cells, or both.
“With the ability to rewrite long stretches of DNA – over 1,000 nucleotides at a time – we can start making more significant genetic changes to T-cells and make them more efficient at recognizing cancer and killing cancer,” Dr. Marson said.
Co-author Antoni Ribas, M.D., Ph.D., Parker Institute for Cancer Immunotherapy director at UCLA’s Jonsson Comprehensive Cancer Center, said the work was transformative and marked the beginning of a new era in cell therapy and CAR-T.
“I anticipate that this new technology will revolutionize the field of genetically engineered cell therapy for cancer,” Dr. Ribas said. “In the next three to five years, we will see many more approaches to treat cancer based on this non-viral targeted method.”
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