Boosting immunotherapy by targeting cells’ recycling centers

Immune cells
Memory T cells can be boosted with a drug normally used to prevent transplanted organs from being rejected, UCSD researchers found.

A subpopulation of cells in the immune system called CD8+ T cells are vital for the proper functioning of both vaccines and cancer immunotherapy treatments. When these cells divide, they become one of two types of pathogen-destroying soldiers: those that kill right away or those that remember the offender and provide long-term protection. Finding a way to boost the second variety of immune cells, called “memory” CD8+ T cells, could improve both vaccines and immunotherapies.

A team of researchers at the University of California San Diego School of Medicine has discovered an existing drug that does just that. The drug is cyclosporine, which is typically prescribed to organ transplant patients to prevent rejection. Cyclosporine tips the balance in favor of memory CD8+ T cells by activating the proteasome, machinery in the cell that recycles unneeded proteins, according to a press release. The research was published in the Journal of Clinical Investigation.

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Working with mice and cell models, the UCSD team discovered that if they treated CD8+ T cells with cyclosporine after exposure to infection, they could generate twice as many memory cells than they could with a mock booster. Senior author John Chang, M.D., associate professor at UC San Diego School of Medicine, said in the release that “this approach could one day be used as an adjuvant therapy—a one- or two-dose immune booster given alongside a vaccine or cancer immunotherapy to help the intervention work better and last longer."

Immunotherapy continues to dominate the oncology headlines, but the treatments don’t work for every patient, leading to a worldwide search for solutions. UCSD is one of the major players in the search for causes of immunotherapy resistance. Last December, a UCSD team published research focused on a pathway known as Hippo, and two kinases within it, LATS1/2. Inhibiting the enzymes seemed to improve the ability to stimulate an immune response to cancer, they discovered.

A group of researchers in Switzerland is working with Novartis to investigate the potential use of an interleukin-2 (IL-2) antibody in cancer treatment. The antibody inhibits regulatory T cells, which interrupt the work of more beneficial memory cells.

And earlier this year, researchers from the Emory Vaccine Center and Winship Cancer Institute suggested a way to improve responses to immunotherapy drugs like Merck’s Keytruda (pembrolizumab), which acts against the immune checkpoint PD-1. They determined that boosting levels of the cell-surface marker CD28 might enhance the activity of PD-1 blockers.

Combining immune treatments, as the UCSD researchers are suggesting with cyclosporine, is another popular approach. Multiple combination trials are already underway, including one that combines Keytruda with Amgen’s Imlygic, a melanoma treatment that’s derived from herpes virus.