A breakthrough design for solid tumors: CAR T cells deliver IL-12 and PD-L1 blocker
Chimeric antigen receptor (CAR) T cell therapy has transformed treatments for certain blood cancers, but solid tumors such as ovarian, prostate, breast, and pancreatic cancers have posed stubborn challenges. A collaborative effort from USC Norris Comprehensive Cancer Center and City of Hope has produced a promising strategy: engineering CAR T cells to secrete a fusion protein that combines interleukin-12 (IL-12) with a PD-L1 blocker. This approach localizes immune activation to the tumor site, aiming to overcome the hostile microenvironment that often blunts CAR T cell efficacy.
How the fusion protein works
Delivering IL-12 systemically can trigger dangerous toxicity. The new design tethering IL-12 to a PD-L1 blocker ensures that the pro-immune signal concentrates where PD-L1 is upregulated—near solid tumors. PD-L1 is a well-known mechanism tumors use to dampen T cell activity; blocking it reactivates the immune response. By linking the two components, the researchers create a tumor-focused boost that both enhances T cell activity and disrupts the tumor’s defense, while minimizing side effects elsewhere in the body.
Evidence from preclinical models
In cell cultures and mouse models of ovarian and prostate cancer, the modified CAR T cells demonstrated robust anti-tumor activity. They improved T cell infiltration into tumors, reprogrammed the surrounding microenvironment to be less suppressive, and, crucially, caused significant tumor shrinkage without detectable toxicity to distant organs. These findings, published in Nature Biomedical Engineering, suggest the approach can be both highly effective and safer than previous attempts to deliver IL-12.
Why this could be broadly useful
Although the initial focus was ovarian and prostate cancers, the strategy is potentially applicable to a wide range of solid tumors that create a hostile microenvironment. The team is now testing the approach in pancreatic cancer and plans to expand to colorectal and brain tumors. Beyond CAR T cells, researchers see potential for applying the same principle to other immune effector cells, such as tumor-infiltrating lymphocytes or T cell receptor (TCR) therapies, broadening the impact across cancer types.
Next steps and implications for patients
The researchers aim to move toward clinical trials within one to two years, contingent on safety, manufacturability, and regulatory review. If successful, this tumor-focused strategy could complement existing CAR T therapies and offer new options for patients whose solid tumors have resisted current immunotherapies. The approach may also reduce systemic risks by confining cytokine activity to the tumor neighborhood, addressing a major hurdle in translating CAR T cells to solid cancers.
Conclusion
Engineered CAR T cells that co-deliver IL-12 and a PD-L1 blocker represent a promising path forward for solid tumors. By concentrating immune activation at the tumor site, this strategy could enable safer, more effective immunotherapy across multiple cancer types and broaden the reach of CAR T cell therapy beyond hematologic malignancies.
