Researchers use skin-colonizing bacteria to create topical cancer therapy in mice | Information Center

As controls, other mice were treated either without bacteria or with wild-type staphylococcal epidermis (not expressing the ovalbumin peptide) or heat-killed ovalbumin-expressing staphylococcal epidermis, which could not colonize the skin because it was dead.

Six days later, the scientists injected mice with ovalbumin-expressing melanoma tumor cells. While all three types of control mice developed skin tumors rapidly, those treated with genetically modified live staph epidermis developed tumors much more slowly and, in many cases, did not develop tumors at all.

When the researchers looked for an explanation, they found ovalbumin-specific CD8 T cells in draining lymph nodes in the skin, in the spleen, and in slow-growing tumors – which means, according to Fischbach, that the lymphocytes T cells generated by colonizing bacteria must carry the same immune potential as ordinary killer T cells.

“Honestly, I didn’t expect this to work,” Chen said. “All other types of tumor vaccine research involve radiotherapy, chemotherapy or surgery, but we have done next to nothing for these mice. T cells did the work for us.

15 out of 16 tumors disappeared

To find out if their method could treat established melanoma, the researchers tried injecting cancer cells up to two weeks before colonization with the genetically modified staph epidermis.

Even when the melanoma metastasized to the lungs, treatment with the bacteria dramatically reduced the size of the tumors or eliminated them, dramatically improving the mice’s survival times. The method also worked when the researchers used natural melanoma antigens, rather than ovalbumin.

When the researchers combined the new treatment with a second type of immunotherapy designed to boost T cell activity, called “checkpoint blockade”, the benefit was even more pronounced: 15 out of 16 established tumors disappeared. When the mice were reinjected with more cancer cells 30 days later, the tumors still did not grow.

“This appears to be evidence of a memory immune response,” Fischbach said, “similar to what happens after a vaccine.”

Researchers now believe that the host organism produces these T cells to essentially vaccinate itself against colonists, protecting itself against the inevitable cuts and scrapes that could allow bacteria to cross the skin barrier.

“In these experiments, we basically tricked the host into thinking the tumor was infected with bacteria,” Fischbach said, “and then the host attacks that tumor aggressively.”

The scientists also replaced the melanoma antigen with a prostate tumor antigen and tested their method in a mouse model of prostate cancer. Again, the therapy dramatically slowed tumor growth, suggesting that the genetically engineered skin colonizing bacteria may generate a potent immune response against more than just skin cancer.

Transmitting therapy to humans

Researchers are quick to point out that cancer therapies developed in mice don’t always work in humans. But Fischbach says there is cause for hope. First, a precedent study led by co-author Yasmine Belkaid, PhD, chief of the Metaorganism Immune Section at the National Institutes of Health, showed that staphylococcal epidermidis induces the same type of CD8 T-cell response in primates as in mice . Second, while staph epidermis usually clears from mouse skin within weeks, most humans are permanently colonized with a strain of the bacteria.

“Human skin is the natural home for staphylococcal epidermis,” Fischbach said. “In humans, the bug will colonize more efficiently, which could lead to a constant turnover in the supply of tumor-specific T cells.”

Other forms of cancer immunotherapy require taking T cells from a patient, engineering them in the lab to produce a tumor-specific antigen, and then injecting them back into the same individual, often with serious side effects.

“We found that the host vaccinated, day after day, against the organisms that live on the barrier surfaces,” Fischbach said. “If we can direct even a small part of this immune attention to specific cancers – or potentially infectious diseases – we will have a very effective and inexpensive therapy that can simply be applied to the skin.”

Funding for this research was provided by Stanford Microbiome Therapies Initiative, Open Philanthropy, Chau Hoi Shuen Foundation, HHMI Hanna H. Gray Fellowship, Swiss National Fund for Scientific Research, Human Frontier Science Program (Grant LT000493/ 2018-L), the Astellas Foundation Fellowship for Research in Metabolic Disorders, the NIAID Intramural Research Division (Grants 1ZIA-AI001115 and 1ZIA-AI001132), an HHMI-Simons Faculty Scholar Award, the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health (grant DK110174), the Chan Zuckerberg Biohub, Stand Up to Cancer and MAC3 Impact Philanthropies.