Chimeric antigen receptor (CAR) T cell therapy, which uses a patient's own immune cells to fight cancer, has emerged as a powerful way to treat lymphoma and other blood cancers. But researchers have struggled to adapt the treatment for solid tumors—including prostate, breast, lung and ovarian cancer—which make up about 90% of all cancer cases.
Now, a research team from the USC Norris Comprehensive Cancer Center , in collaboration with City of Hope, a national cancer research and treatment organization, has found a promising solution. The researchers engineered CAR T cells to produce a fusion of two proteins: interleukin 12 (IL-12) cytokine, which boosts immune activity, and a programmed death-ligand 1 (PD-L1) blocker, an immune checkpoint inhibitor that prevents cancer cells from turning off the immune attack. In mouse models of prostate and ovarian cancer, the modified CAR T cells launched a localized attack, shrinking the tumor without causing toxicity in other parts of the body. The results were just published in the journal Nature Biomedical Engineering .
"By designing CAR T cells that release both IL-12 and a PD-L1 blocker as a fusion protein, we can make the treatment safe and also much more effective, even against tumors that usually resist CAR T cell therapy," said the study's senior author, Saul Priceman, PhD , associate professor in the Department of Medicine at the Keck School of Medicine of USC and founding director of the Keck School of Medicine/Norris Center for Cancer Cellular Immunotherapy Research.
The present study, which was jointly funded by the Prostate Cancer Foundation, the Department of Defense and the National Institutes of Health, focused on ovarian and prostate cancer. But researchers say the findings could be broadly applicable to other solid tumors, including gastrointestinal and brain cancers.
"We believe this new strategy will provide a productive boost to current CAR T cell therapies and can be applicable to multiple cancer types," said John P. Murad, PhD , assistant professor of research in the Department of Medicine at the Keck School of Medicine and the study's first author.
A localized attack
CAR T cell therapy involves altering the genes in a patient's T cells, a type of "fighter" cell in the immune system, to make them destroy cancer. But solid cancers present a challenge, because the area within and around the tumor is hostile toward T cells, preventing them from mounting a strong attack.
Researchers have long eyed IL-12, a powerful cytokine that can reactivate T cells and favorably alter the tumor environment, as a potential solution. But delivering IL-12 on its own can cause dangerous toxicity elsewhere in the body. To work around this, the USC-City of Hope team found a clever way to increase IL-12, but only in the region near the tumor.
To keep IL-12 focused on the tumor and avoid harmful side effects elsewhere, the researchers engineered CAR T cells to localize IL-12 to solid tumors by attaching it to a PD-L1 blocker, a type of immune checkpoint inhibitor. Many cancers evade the immune system by activating "checkpoints," signals that tell T cells to slow down or stop attacking. PD-L1 is one such checkpoint, and tumors often increase PD-L1 naturally or when they detect activated CAR T cells.
When tumors raise PD-L1 levels, PD-L1 blockers naturally gather in the area. By linking IL-12 to a PD-L1 blocker, the researchers ensured that IL-12 was delivered directly to the tumor site, boosting the immune response there while minimizing side effects in other parts of the body, where PD-L1 levels remained low.
The researchers tested the modified CAR T cells in cell cultures and mouse models, finding them to be highly effective in shrinking ovarian and prostate tumors. The approach enhanced the ability of T cells to penetrate tumors and made the surrounding environment less hostile. It was also safe, with minimal toxicity elsewhere in the body, making it an attractive therapy to translate to patients.
Broad applicability
Beyond ovarian and prostate cancers, the findings may be relevant to a range of solid cancers. The research team is now testing the approach in pancreatic cancer and plans to expand soon to colorectal and brain tumors.
"No two cancers are the same, so each needs to be tested and validated as a potential clinical approach. But the new therapy could have broad applicability, because most solid tumors create a surrounding environment that weakens the immune system, which we are capitalizing on with this strategy," said Priceman, who also holds the Norman and Mary Pattiz Endowed Chair in Cancer Research at the Keck School of Medicine.
The researchers aim to move the technique into clinical trials within the one to two years.
The approach may also prove useful beyond CAR T cells, potentially helping to engineer other immune effector cells—the immune system's "fighter" cells that directly attack cancer—including tumor-infiltrating lymphocytes and T-cell receptor T cells.
About this research
In addition to Priceman and Murad, the study's other authors are Reginaldo Rosa, Yuwei Ren, Alyssa J. Buckley, Lupita S. Lopez, Yukiko Yamaguchi, Lauren N. Adkins and Catalina Martinez from the Department of Medicine and the Keck School of Medicine/Norris Center for Cancer Cellular Immunotherapy Research, Keck School of Medicine of USC, University of Southern California; Lea Christian, Anthony K. Park, Jason Yang, Candi Trac, Wen-Chung Chang and Stephen J. Forman from the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Eric Hee Jun Lee from the Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, Georgia; Carl H. June from the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Jun Ishihara from Imperial College London, London, United Kingdom; John K. Lee from the Department of Medicine, David Geffen School of Medicine, University of Southern California, Los Angeles; and Lawrence A. Stern from the University of South Florida, Tampa, Florida.
This work was supported by a Prostate Cancer Foundation Tactical Award [2022TACT3835]; the Department of Defense [W81XWH-21-1-0354]; and the National Cancer Institute of the National Institutes of Health [P30CA014089, P30CA033572].
