[Aug. 30, 2023: Krista Conger, Stanford Medicine]
Activating the immune system at the site of a tumor can recruit and stimulate immune cells to destroy tumor cells. (Credit: Creative Commons)
Activating the immune system at the site of a tumor can recruit and stimulate immune cells to destroy tumor cells. One strategy involves injecting immune-stimulating molecules directly into tumors, but this method can be challenging for cancers that are not readily available.
Now, Stanford researchers have developed a new synthetic molecule that combines a tumor-targeting agent with another molecule that triggers immune activation. This tumor-targeted immunotherapy can be administered intravenously and makes its way to one or multiple tumor sites in the body, where it recruits immune cells to fight the cancer.
Three doses of this new immunotherapy prolonged the survival of six out of nine laboratory mice suffering from aggressive triple-negative breast cancer. Three of the six were cured of their cancer during the months-long study. A single dose of this molecule induced complete regression of tumors in five out of 10 mice. The synthetic molecule showed similar results in a mouse model of pancreatic cancer.
“We’ve essentially cured some animals with only a few injections,” said Jennifer Cochrane, PhD, Shriram Chair of the Department of Bioengineering. “It was very surprising. When we looked inside the tumours, we saw that they shifted from a highly immunosuppressive microenvironment to one filled with activated B and T cells – the same as when an immune-stimulating molecule is injected directly into the tumour. So, we’re getting results with intra-tumoral injection but with IV delivery.”
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A paper describing the study will be published online in Cell Chemical Biology. Cochran shares senior authorship with Carolyn Bertozzi, PhD, Baker Family Director of Stanford CHEM-H, Anne T. and Robert M. Bass Professor and Professor of Chemistry in the School of Humanities and Sciences; and Ronald Levy, MD, Robert K. and Helen K. Sumi is a professor at the School of Medicine. The lead authors are graduate student Kaitlyn Miller and medical instructor Idit Sagiv-Barfi, PhD.
building on previous research
The treatment builds on a previous study co-authored by Levy and Sagiv-Barfi in which a single immune-activating agent and a different agent were injected directly into the tumor site. That study showed that the combination could eliminate tumors as well as distant metastases in mice. It blocked tumor growth in mice genetically engineered to automatically develop mammary tumors. That discovery sparked an ongoing clinical trial in people with non-Hodgkin lymphoma.
“The surprising result of the new research was that the sculpting of the tumor microenvironment by this intravenously administered molecule was achieved by injecting immune stimulating agents directly into the tumor,” said Levy. “This is a huge advantage because there is no longer a need for an easily or safely injectable tumor site.”
Much more research is needed to determine whether the molecule, called PIP-CpG, will be ready for testing in humans. But because the tumor-targeting part of the molecule — PIP — recognizes certain proteins called integrins found at high levels on the surface of many types of cancer cells, the research suggests the possibility of an off-the-shelf treatment for patients in the future. gives. cancer diversity.
“PIP is a truly versatile tumor-targeting agent because it can localize to many different tumor types,” Miller said. “Moreover, the same molecule is biologically active in mice, non-human primates and humans.”
Along with professor emeritus of developmental biology Matthew Scott, PhD, and the late professor and chair of radiology Sanjeev “Sam” Gambhir, MD, PhD, Cochrane has studied the potential of PIP, which was created in Cochrane’s lab, to He can find and connect with it. Integrates on the surface of cancer cells. Coupling these molecules with probes that can be seen through near-infrared imaging or positron emission tomography allows researchers to track the location of hard-to-see cancers in the body.
In other work in the Cochrane lab, researchers, in collaboration with the Stanford ChEM-H Medicinal Chemistry Knowledge Center, have generated conjugates that seek out cancer cells and deliver a payload of chemotherapy poison to tumors.
Ronald Levy (left) and Idit Sagiv-Barfi lead work on a potential cancer treatment that involves injecting two immune-stimulating agents directly into solid tumors. (Credit: Steve Fish)
“These integrin-targeting molecules act like guided missiles,” Cochran said. “They can deliver toxic drugs or imaging agents. Now we’re using them to deliver a signal that stimulates immune cells to fight tumors.” That signal, the CpG, mimics the pattern of DNA common in bacteria and viruses but rarely found in vertebrates. goes.
Certain types of tumors, including some breast cancers, use natural regulatory pathways to reduce the activity of cancer-killing immune cells that infiltrate the tumor—thereby making them immunologically “cold.”
Miller and Sagiv-Barfi found that PIP-CpG treatment transformed breast cancer tumors in mice into “warm” tumors filled with activated T and B cells. The treatment also reduced the proliferation of another type of immune-suppressing cell called myeloid-derived suppressor cells in the tumour.
The researchers also showed that the treatment could also target multiple tumors in a single animal.
“After more than 10 years of work on PIP, it is rewarding to experience this convergence of expertise from laboratories around Stanford that has allowed us to develop a highly promising new cancer treatment strategy,” Cochran said.
Researchers are now studying the treatment in other types of cancer and in combination with other immunotherapies.
The study’s other Stanford authors are instructor Patrick Neuhofer, PhD; Senior Research Scientist Debra Zerwinski; and Steven Artandi, MD, PhD, professor of biochemistry.
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