TH17 Cells Generate Long-lasting T Cells for Adoptive Cell Immunotherapy
by Katharine Hendrix
The March 2017 issue of JCI Insight published ground-breaking findings by a team of MUSC researchers showing that Th17 T cells are superior to the commonly used CD8+ T cells for adoptive cell therapy (ACT). The Th17 T cells not only provided highly potent antitumor activity but also circumvented long-standing problems associated with rapid expansion.
ACT is highly effective in activating the body’s immune defenses to fight cancer. This immunotherapy involves extracting, expanding and enhancing autologous T cells before reinfusing them into the patient where they can induce a complete and durable antitumor response. For example, approximately 54 percent of metastatic melanoma patients achieve an objective response with ACT, and 24 percent achieve complete remission.
The patient’s cells are extracted and treated with a rapid expansion protocol (REP) to generate the very large number of T cells needed for a successful antitumor response. Even when state-of-the-art REPs are used, patients wait up to three months before enough tumor-reactive T cells are produced. Furthermore, CD8+ T cells — which are commonly used for immunotherapy — quickly lose their cancer-fighting potency when they are extensively expanded outside the body.
Because Th17 cells have stem-cell-like properties (i.e., stem memory) and durable efficacy in vivo, MUSC investigators, under the direction of Chrystal Paulos, Ph.D., associate professor of microbiology and immunology and Peng Endowed Chair of Dermatology, hypothesized that they would retain their potent antitumor effectiveness after long-term expansion. Using murine and human CD4+ T cells polarized to a Th17 phenotype, they demonstrated for the first time that this T cell subset multiplies faster and resists degradation better during expansion than other commonly used cells. They found that, even without being restimulated, Th17 cells robustly expanded for 21 days in vitro — producing approximately 5,000 times the original number of CD4+ cells. Furthermore, their stem memory signaling remained intact.
“In contrast to CD8+ T cells, we found Th17 cells can be expanded to large numbers without compromising their therapeutic quality,” Paulos explains. “Th17 cells have a natural propensity to logarithmically expand without restimulation. And restimulation didn’t dramatically impair the antitumor response as with CD8+ T cells. Our findings have major implications for the field of cancer immunotherapy.”
The Th17 cells resisted degradation (senescence) and remained capable of eliminating melanoma in mice after two weeks of in vitro expansion — something that Th1 and CD8+ T cells could not accomplish. In addition, Th17 cells expanded for 14 days showed the same ability as those expanded for only seven days to persist in the tumor-bearing host after reinfusion. “Cytotoxic CD8+ or Th1 cells were less effective at clearing tumor, whereas the Th17 cells persisted much longer. The durability of Th17 cells is due, in part, to their resistance to apoptosis and senescence,” says Paulos.
Treatment with Th17 cells that were expanded for only two or three weeks rapidly and completely eradicated aggressive tumors in mice. “In just two weeks, we expanded enough Th17 cells to eradicate very large tumors, and they mediated durable responses,” explains Paulos. “When we came back again 100 days later and gave the same mice lung tumors, they were all still protected.” In all experiments, Th17 cells produced antitumor immunity superior to that provided by classic CD8+ cells or CD4+ subsets such as Th1 cells.
These findings are important for immunotherapy product development because Th17 cell durability provides a larger window for obtaining potent T cells through in vitro expansion. Th17 cell resilience could also simplify clinical trial protocols — making ACT T cell preparation easier for cancer centers around the world and, thus, extending the benefits of ACT to more patients.