A new approach targets solid tumors
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for certain blood cancers, but solid tumors—such as prostate, breast, lung, and ovarian cancers—have remained stubborn hurdles. A collaboration between USC Norris Comprehensive Cancer Center and City of Hope has yielded a promising solution: engineering CAR T cells to produce a fusion of two proteins—interleukin 12 (IL-12) and a PD-L1 blocker—so the immune attack is intensified where it is most needed, with reduced risk to the rest of the body.
In preclinical studies, including cell cultures and mouse models of prostate and ovarian cancer, these modified CAR T cells launched a localized assault that shrank tumors without causing notable toxicity elsewhere. The work, published in Nature Biomedical Engineering, represents a strategic shift in CAR T design: rather than delivering a potent immune activator systemically, the therapy concentrates activity in the tumor microenvironment where PD-L1 is often elevated.
How the IL-12–PD-L1 fusion works
IL-12 is a powerful cytokine that can reactivate exhausted T cells and reconfigure the tumor microenvironment to favor an immune response. However, delivering IL-12 systemically can trigger dangerous side effects. The USC–City of Hope team solved this by tethering IL-12 to a PD-L1 blocker, ensuring the cytokine is released primarily in the vicinity of PD-L1–expressing tumors. Since many cancers upregulate PD-L1 to dodge immune attack, the fusion protein naturally accumulates where it is most needed, amplifying anti-tumor activity while minimizing exposure to healthy tissues.
By co-opting the tumor’s own checkpoint pathways, the engineered CAR T cells not only assault tumor cells more effectively but also remodel the surrounding environment to be less hostile to immune infiltration. This dual action—direct tumor killing plus microenvironmental modulation—addresses two of the biggest barriers to solid-tumor CAR T efficacy.
Key findings from the USC Norris and City of Hope study
The researchers demonstrated that the IL-12–PD-L1 fusion–carrying CAR T cells were capable of deep tumor penetration and growth inhibition in ovarian and prostate cancer models. Importantly, the approach yielded tumor shrinkage with minimal systemic toxicity, a critical consideration for moving toward human trials. Senior author Saul Priceman, PhD, emphasized that the strategy makes CAR T therapy both safer and markedly more potent against cancers that typically resist immunotherapy.
First author John P. Murad, PhD, highlighted that the fusion protein directs IL-12 activity to the tumor site by riding along with a PD-L1 blocker, a molecule tumors frequently deploy to silence attacking immune cells. The study received support from the Prostate Cancer Foundation, the Department of Defense, and the National Institutes of Health, illustrating broad backing for translating this concept into clinical testing.
Broad implications and next steps
While the current work focused on ovarian and prostate cancers, the team argues that the concept could be applicable to a wider array of solid tumors, including pancreatic, colorectal, and brain cancers. Priceman notes that no two cancers are identical, so each will require validation, but the underlying strategy could offer a general mechanism to counter the immunosuppressive tumor microenvironment that constrains many therapies.
Looking ahead, the researchers plan to begin clinical trials within the next one to two years, testing the approach in patients. Beyond CAR T cells, the fusion strategy might be adapted to enhance other immune effectors, such as tumor-infiltrating lymphocytes or T-cell receptor T cells, broadening the potential impact of this engineering approach across multiple forms of cancer.
Why this matters for cancer treatment
This work addresses a central challenge in solid-tumor immunotherapy: delivering a robust, localized immune attack without triggering systemic toxicity. By using a PD-L1–driven delivery mechanism for IL-12, the therapy aligns increased potency with improved safety. If clinical trials confirm these findings, patients with solid tumors—many of whom currently have limited options—could gain access to a groundbreaking treatment that leverages the patient’s own immune system in a targeted, safer way.
