Recent experiments exploring the use of patients’ own genetically reprogrammed immune cells toward the treatment of chronic diseases such as HIV and cancer have had encouraging and sometimes high-profile results. Yet, these studies have only been conducted in a limited number of individuals, and outcomes have been inconsistent, ranging from complete remission to complete inefficacy.
Now, two teams of researchers have demonstrated a method of using patients’ cells to create long-lived immune cells that target specific HIV and cancer antigens, and appear to resist degradation over time. Their work was published today in two separate papers in Cell Stem Cell.
“Our method has realized the functional rejuvenation and unlimited production of mature cytotoxic T cells with desired antigen-specificity for the first time in vitro,” says Shin Kaneko a stem cell biologist at Kyoto University in Japan and a co-author of the HIV-related study.
Difficulties in previous attempts to extract and reengineer T cells from patients are thought to be due in part to a phenomenon known as ‘cellular senescence’, a type of aging process. Naïve, quiescent T cells can survive for decades in the body. But active T cells, particularly those expanded outside the body in the laboratory, can gradually lose the ability to proliferate and be effective. This can lead to insufficient numbers of active immune cells to combat disease.
“Replicative senescence is likely to be a major issue for adoptive cell therapy,” says Carl June, an immunologist at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. “[These papers] address this issue and are exciting demonstrations of the progress in cell and developmental biology.”
The first part for both teams was to extract T cells—one group from an HIV-infected individual and the other group from a person with malignant melanoma—that already could detect the respective diseases. To combat senescence they then guided those cells into an induced pluripotent stem cell-state by exposing them to a harmless virus that introduced four genes in a process developed by last year’s Nobel Prize winner in medicine and physiology, Shinya Yamanaka. After coaxing the induced cells to mature back into T cells, the researchers found that these new cells were characterized by 30 to 50% longer telomere caps on the ends of their chromosomes, leading to longer life spans when grown in a lab dish. Notably, after this manipulation, the cells could still specifically target HIV and melanoma.
Additionally, they demonstrated a 10- to 100-fold increase in the cells’ ability to multiply, a potential solution to insufficient numbers of circulating immune cells. “Eventually, we will accumulate [banks of T cells] against various epitopes of HIV that would allow us to develop a more effective, hopefully curative therapy,” says Hiromitsu Nakauchi, director of the Stem Cell Therapy division at the University of Tokyo and senior author on the HIV study.
Hiroshi Kawamoto, an immunologist at the RIKEN Research Center for Allergy and Immunology in Yokohama, Japan and senior author of the melanoma study, believes it could be possible to transfer induced stem cells back to cancer patients in the future. Directed into the thymus, they could give rise to a constantly replenishing population of mature T cells. “If such [a] patient is appropriately immunized [with the T cells], we can expect long-lasting immunity against cancer,” he says.
Both groups plan to test their souped-up T cells in animal models to study safety and efficacy, as well as exploring other potential components of the virus or cancers the cells might target.
Nicholas Restifo, an immunologist at the US National Cancer Institute in Bethesda, Maryland, cautions that reprogrammed cells may possibility have the ability to become cancerous, so “eventual clinical usage must be very judicious.” However, he’s still a proponent of the therapeutic approach: “This ‘reincarnation’ of T cells for immunotherapy is an exciting idea.”
Image: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus, via Wikimedia Commons