Injections in Mice Eliminated Local and Distant Tumors, Study Shows

Injections in Mice Eliminated Local and Distant Tumors, Study Shows

Injecting two immuno-enhancing agents in very small amounts directly into a solid tumor eliminated not only the local, and all distant tumors (metastasis), a new mouse study shows.

The effectiveness of the treatment was seen across multiple tumor types, including lymphoma, breast and colon cancer, and melanoma. The results prompted a Phase 1 clinical trial (NCT03410901) to test the strategy in patients with low-grade B-cell non-Hodgkin lymphoma.

The study, “Eradication of spontaneous malignancy by local immunotherapy,” was published in the journal Science Translational Medicine.

This new strategy, called in situ vaccination, is a promising cancer therapy that has several advantages. In in addition to being fast and relatively inexpensive, it uses such small amounts of the drugs that it is unlikely to induce adverse side effects linked to whole-body immunotherapies.

The approach consists of injecting small amounts of two medicines directly into a tumor. One of the components, an OX40 activator, already is approved for human use. It is designed to enhance T-cell survival and activation, while counteracting the immunosuppressive effects of other immune cells.

The other medicine, CpG SD-101, is an investigational immune activator developed by Dynavax, and has been tested extensively in separate human trials. This molecule is intended to increase OX40 expression in T-cells and enhance their transformation into potent anti-tumor cells.

“When we use these two agents together, we see the elimination of tumors all over the body,” lead author Ronald Levy, MD, professor of oncology at Stanford University Medical Center, said in a press release.

“This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells,” he added.

The approach was first tested in mice with lymphoma. Each mouse had lymphoma in two sites of the body, but only one was treated. Interestingly, the therapy didn’t eliminate only the tumor injected with the medicines — out of 90 mice, 87 also had no signs of the untreated tumor.

Tumors came back in three mice, but a second round of the therapy was sufficient to induce tumor regression. Similar results were seen in mice with breast, colon and melanoma tumors.

Researchers then tested the therapy in mice genetically prone to spontaneous breast tumors in all 10 of their mammary pads. When mice developed their first tumor, both agents were injected. As seen before, the therapy prevented the occurrence of tumors in the other mammary glands, which significantly increased the animals’ life span.

In a final experiment, researchers explored the specificity of T-cell response against tumor cells. They transplanted lymphoma cancer cells in two different locations in the mouse body, followed by colon cancer cells transplanted into a third location. Injecting the treatment into one of the lymphoma sites led to the regression of both lymphoma tumors, but had no effect on the colon cancer cells, which continued to grow.

The same specificity of response was seen in the reciprocal experiment where treating only one of two colon tumors led to complete regression of both local and distant colon tumors, but had no effect in the unrelated lymphoma tumor.

“This is a very targeted approach,” Levy said. “Only the tumor that shares the protein targets displayed by the treated site is affected. We’re attacking specific targets without having to identify exactly what proteins the T cells are recognizing.”

A clinical trial will now test this in situ vaccination strategy in about 15 patients with low-grade lymphoma.

If successful, the results should support new trials for other tumor types. In the future, clinicians may inject the two agents directly into a solid tumor before removing the tumor surgically, getting rid of metastasis (even if not visible) and preventing cancer recurrence. This also may be used to prevent the development of future tumors linked to genetic mutations, like BRCA mutations for breast cancer.

“I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system,” Levy said.

“This in situ vaccine maneuver is safe because it uses low doses of the immunoenhancing agents and practical because the therapy can be applied to many forms of cancer without prior knowledge of their unique tumor antigens,” researchers concluded.

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