Tumor-targeted immune cells cure prostate cancer without causing systemic immune suppression

In a major breakthrough in cancer gene therapy, a Northwestern University researcher has endowed immune cells with the ability to specifically target metastatic prostate cancer in mice without causing the toxic immune suppression that has been associated with earlier forms of cancer gene therapy.

Chung Lee, John T. Grayhack, M.D., Professor of Urology at Northwestern University Feinberg School of Medicine, and his laboratory group described the adoptive transfer gene therapy technique in the March issue of Cancer Research.

Lee is also a researcher at The Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The researchers first rendered immune cells known as CD8+ T cells insensitive to transforming growth factor beta (TGF-beta), a powerful, naturally occurring substance in the body that enables cancer cells to evade surveillance by the body's immune system. The immunosuppressive effect of TGF-beta in cancer progression is well established.

After inserting a mutated form of the TGF-beta receptor into CD8+ T cells, Lee and associates transplanted the tumor-specific immune cells into mice that had been given a particularly aggressive form of prostate cancer, called TRAMP-C2.

TRAMP-C2 prostate cancer cells produce large amounts of TGF-beta, and possess such potent immunosuppressive power that regular CD8+ T cells are unable to infiltrate tumor tissues, Lee explained.

The mice received a single injection of tumor-reactive TGF-beta-insensitive CD8+ T cells, tumor-specific TGF-beta-sensitive CD8+ T cells or untreated CD8+ T cells at three (early cancer), seven or 21 days (advanced cancer) after they had been injected with the prostate cancer cells.

Lee and co-researchers found that the tumor-reactive TGF-beta-insensitive CD8+ T cells infiltrated prostate cancer tumors and effectively destroyed the TRAMP-C2 cells.

Moreover, results showed that the CD8+ T cells showed five-fold more tumor-killing activity than that of TGF-beta-sensitive CD8+ T cells and 25-fold more tumor-killing activity over that of untreated CD8+ T cells.

Mice that received adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells following injection of tumor cells showed no or little evidence that cancer had spread in the body.

Importantly, mice that received TGF-beta-insensitive CD8+ T cells did not develop systemic autoimmune disease, as had been the case in earlier studies by Lee and other researchers.

"To the best of our knowledge, studies to test this concept have not been attempted before," Lee said.

In summary, these CD8+ T cells were specifically reactive against tumor tissues. Second, they were insensitive to TGF-beta. The two properties endowed the CD8+T cells with the ability to infiltrate tumor tissues and function as potent effectors against tumor cells. Finally, these cells were able to persist in tumor-bearing hosts but not in those that are cancer free.

The findings of the Northwestern study provide a proof of principle that an adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells may warrant consideration for the treatment of advanced tumors, Lee said.

Researchers from Northwestern University; the National Cancer Institute; Massachusetts Institute of Technology; the Fred Hutchinson Cancer Research Center; and Peking University collaborated on the study, which was supported by grants from the U.S. Department of Defense and the National Institutes of Health.