Radiopharmaceutical plus CAR-T therapy converts immune-resistant solid tumors into treatable targets in neuroblastoma models
核心洞察
A preclinical study combining CAR T cell therapy with the radiopharmaceutical [67Cu]Cu-LLP2A (搜索) produced greater tumor regression in neuroblastoma (搜索) models than either treatment alone.
Adding CAR T cell therapy to radiopharmaceutical therapy increased tumor shrinkage and complete response rates by 80% in preclinical models.
The combination worked through two mechanisms: priming radiation-sensitive tumors for immune attack and remodeling radiation-resistant tumors to allow CAR T cell infiltration.
Researchers at the University of Pittsburgh, UPMC Hillman Cancer Center (搜索) and the National Cancer Institute have demonstrated in preclinical models that pairing CAR T cell immunotherapy with a targeted radioactive drug produces greater tumor regression in neuroblastoma (搜索), an aggressive childhood cancer, than either treatment alone. The findings, published in Cell Reports Medicine, offer a potential new path for expanding CAR T cell therapy to solid tumors, where the approach has shown limited efficacy to date.
The study combined CAR T cell therapy with the radiopharmaceutical [67Cu]Cu-LLP2A (搜索), a radioactive drug delivered through the bloodstream that targets a receptor called VLA-4 (搜索) found on both tumor and immune cells. Unlike external beam radiation, which targets a fixed location, the drug circulates and can reach tumors wherever they have spread.
"Radiopharmaceuticals have typically been used on their own, and combinations are still being explored. Using them with CAR T cells is a new approach," said senior author Ravi Patel, M.D., Ph.D., director of radiopharmaceutical therapy in the Department of Radiation Oncology at UPMC Hillman Cancer Center (搜索).
Two mechanisms depending on tumor radiation sensitivity
The researchers found the combination worked differently depending on a tumor's sensitivity to radiation. In radiation-sensitive tumors, the drug damaged cancer cells directly and triggered an inflammatory response that primed the tumor to respond to CAR T cells. In radiation-resistant tumors, a common and difficult-to-treat phenotype, the drug did not kill cancer cells directly. Instead, it remodeled the tumor microenvironment, reducing suppressive immune cells and enabling CAR T cells to infiltrate. Researchers describe this as converting a "cold" tumor into one more open to immune attack.
The combination outperformed each treatment alone, including complete tumor regression in a substantial portion of cases. Compared to radiopharmaceutical therapy alone, adding CAR T cell therapy increased tumor shrinkage and complete response rates by 80% in the preclinical models.
"In some of the studies, we had a cure rate as high as 5 out of 7. And then in one study, we had 8 out of 10. So that's pretty high tumor control and cure rate," Patel said.
Addressing a barrier in solid tumors
CAR T cell therapy is a form of cancer immunotherapy in which a patient's own T cells are collected, genetically engineered to recognize and attack cancer cells, and returned to the body. The approach has transformed outcomes in certain blood cancers but has shown limited effectiveness in solid tumors like neuroblastoma (搜索). It is FDA-approved only for treatment of blood cancers.
The tumor microenvironment — the network of cells, signaling molecules and structural tissue surrounding a solid tumor — often suppresses immune activity and prevents engineered T cells from entering or functioning. This is a central barrier to CAR T therapy in solid tumors.
"In this study, we used CAR T cell therapies that have been tested in clinical trials at the National Cancer Institute for children with recurrent neuroblastoma (搜索)," Patel said. "However, current cellular therapy approaches have limited efficacy in solid tumors such as neuroblastoma. Our results may offer a way to improve the therapeutic effect of these CAR T cell therapies in solid tumor cancers."
Neuroblastoma (搜索) is one of the most common solid tumors diagnosed in children. Outcomes for those with relapsed or high-risk disease remain poor despite aggressive treatment, and effective options are extremely limited. High-risk neuroblastoma, which comprises about half of neuroblastoma cases, carries a five-year survival rate of 63%, according to the Mayo Clinic.
Next steps toward human studies
The research is preclinical, tested in laboratory models rather than patients, and researchers cautioned that the findings have not been demonstrated in humans yet. Patel said researchers are at least two years away from a clinical trial.
The team's next steps include identifying biomarkers to determine which patients are most likely to benefit, exploring how imaging could guide more precise treatment decisions, and establishing safe dosing and toxicity profiles before the approach can move into human studies. Because the combination works through different mechanisms depending on tumor radiation sensitivity, biomarker identification could help determine in advance which patients would benefit from each pathway, a step toward more personalized treatment.
"The goal is to potentially get a cure, but, No. 1, extend survival," Patel said. "Right now, few patients are being cured of metastatic cancer. So, if we come up with strategies where we can eradicate even residual sites of tumor, that's something that can be very beneficial. Obviously, a lot of work (must be done) before we get to even testing that kind of approach."
If validated in future clinical studies, the approach could offer new options for children with hard-to-treat solid tumors where neither therapy alone has succeeded, and potentially for other cancers featuring solid tumors, such as breast and lung cancers.