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Originally published May 4, 2026
Last updated May 4, 2026
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At USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC, physician-scientists are rethinking how the immune system can be mobilized against cancer. Rather than targeting a single tumor antigen — a strategy that has historically limited the effectiveness of cancer vaccines — Fumito Ito, MD, PhD, a surgical oncologist with USC Norris Comprehensive Cancer Center, is advancing a fundamentally different approach: activating the body’s immune system directly within the tumor microenvironment to recognize and attack a broad spectrum of cancer signals.
Ito’s work centers on in situ immunomodulation (ISIM), an approach sometimes referred to as “in situ vaccination,” though it differs significantly from traditional vaccine mechanisms.
“When you hear ‘cancer vaccine,’ you typically think about targeting one or two specific antigens,” Ito says. “But tumors are heterogeneous. They express many known and unknown antigens simultaneously. With ISIM, instead of selecting targets in advance, we allow the immune system to identify them.”
The protocol Ito developed is a multistep, combination strategy designed to orchestrate a coordinated immune response. It begins with the intratumoral injection of CDX-301, a cytokine that recruits conventional type 1 dendritic cells (cDC1s) — key orchestrators of antitumor immunity — into the tumor.
“These dendritic cells are like the commander-in-chief of the immune system,” Ito says. “They are essential for initiating a strong T-cell response.”
Next, localized radiation therapy is applied to induce tumor cell death, releasing a wide array of tumor antigens. The recruited dendritic cells then process and present these antigens to T cells. Finally, immune-stimulating agents — including CDX-1140 and poly-ICLC — are administered to activate the dendritic cells and amplify T-cell priming.
The result is a dynamic, multi-antigen immune response that extends beyond the treated lesion. In preclinical models, this approach demonstrated activity not only in injected tumors but also in distant metastatic sites — suggesting the potential for systemic disease control.
In a clinical trial, Ito and his team observed encouraging responses from this protocol in a subset of patients. “We’ve seen tumor shrinkage and, in some cases, complete disappearance of tumors,” he says. “Post-treatment biopsies have occasionally shown no residual cancer.”
But in the initial cohort, not all patients responded as Ito expected.
“After treating the first several patients, we identified a potential limitation involving interleukin-6 (IL-6),” he says. “We hypothesized that IL-6 signaling might be restricting the full immune response.”
As a physician-scientist at an academic medical system, he was able to quickly move back to the lab to figure out the problem. His team tested this hypothesis in preclinical animal models and confirmed that blocking IL-6 significantly enhanced treatment efficacy. This insight led to a protocol modification in a subsequent patient cohort, incorporating an IL-6 receptor inhibitor (tocilizumab) alongside anti-PD-1 therapy to remove the suppression in the full immune response.
“With these additions, we began to see improved responses,” Ito says. “This bidirectional approach — moving from patients to the lab and back again — allowed us to refine the therapy in real time.”
This study demonstrated that the treatment is safe and well tolerated, with limited systemic toxicity. Because the approach relies on direct tumor injection, it is broadly applicable across tumor types that are accessible for intratumoral therapy, Ito says.
While the study was not powered to determine efficacy by cancer subtype, early signals were observed in patients with breast cancer and squamous cell carcinoma. These indications may serve as a focus for future trials, and Ito is optimistic about the potential of this strategy.
“We’re seeing not only clinical responses but also clear evidence of immune activation both within tumors and in the peripheral blood,” he says. “That gives us confidence as we move into the next phase of development.”
He anticipates that full study results will be published in 2027.
“This type of research underscores the importance of clinical trial funding, awareness and collaboration,” Ito says. “Patients who have progressed on standard therapies may still have meaningful options through investigational protocols like these.”
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