Stanford scientists develop synthetic molecule that attacks and kills cancer cells

[Mar. 31, 2023: JJ Shavit, The Brighter Side of News]

Stanford University researchers have developed a new synthetic molecule that could potentially revolutionize cancer treatment by targeting tumor cells and activating the immune system, according to a study published in Cell Chemical Biology.

The treatment was able to activate immune cells to attack cancer in mice that were injected with the new synthetic molecule, which combines a tumor-targeting agent with a molecule that triggers immune activation. This 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 cancer.

The new treatment was tested on mice with an aggressive form of triple-negative breast cancer, and the results were promising. Three doses of the new immunotherapy prolonged the survival of six of the nine mice, with three appearing cured of their cancer over the duration of the monthslong study.

A single dose of the molecule induced complete tumor regression in five of ten mice. The synthetic molecule showed similar results in a mouse model of pancreatic cancer. The researchers said the findings were “astonishing” as they achieved results similar to those achieved with intra-tumoral injection but with an IV delivery.

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The lead authors of the study are graduate student Caitlyn Miller and instructor of medicine Idit Sagiv-Barfi, PhD. The senior authors are Jennifer Cochran, PhD, the Shriram Chair of the Department of Bioengineering; Carolyn Bertozzi, PhD, the Baker Family Director of Stanford ChEM-H, Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences and professor of chemistry; and Ronald Levy, MD, the Robert K. and Helen K. Summy Professor in the School of Medicine.

The new treatment builds upon a previous study co-authored by Levy and Sagiv-Barfi, in which the same immune-activating agent and a different one were injected directly into the tumor site. That study showed that the combination could eradicate tumors in mice, including distant metastases. It also blocked the development of tumors in mice genetically engineered to spontaneously develop mammary tumors. That finding launched an ongoing clinical trial in people with non-Hodgkin lymphoma.

The new study found that the sculpting of the tumor microenvironment by this intravenously administered molecule was identical to that achieved by injecting immune-stimulating agents directly into the tumor. This is a significant advantage because it's no longer necessary to have an easily or safely injectable tumor site.

The researchers caution that much more research is needed to determine whether and when the molecule, called PIP-CpG, will be ready for testing in humans. However, because the tumor-targeting portion 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 future possibility of an off-the-shelf treatment for patients with a variety of cancers.

“PIP is a really versatile tumor-targeting agent because it can localize to so many different types of tumors,” Miller said. “Also, the same molecule is biologically active in mice, nonhuman primates and humans.”

The researchers have studied the ability of PIP to seek out and bind to integrins on the surface of cancer cells. Coupling these molecules to probes that can be visualized via 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 Cochran 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 poisons to the tumor.

“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 riles up the immune cells to fight the tumor.”

The team's work is part of a growing field of research known as immuno-oncology, which aims to use the power of the immune system to fight cancer. While traditional cancer treatments like chemotherapy and radiation therapy are effective at killing cancer cells, they can also damage healthy cells in the body, leading to a host of side effects. Immunotherapy, on the other hand, can target cancer cells specifically, potentially reducing these side effects.

The new synthetic molecule developed by the Stanford team represents a significant advance in the field of immuno-oncology. By combining a tumor-targeting agent with an immune-activating molecule, the researchers were able to deliver a powerful one-two punch to cancer cells, recruiting immune cells to destroy them.

But there is still much work to be done before the treatment can be tested in humans. While the molecule has shown promising results in mice, it remains to be seen whether it will be effective in people. The researchers will need to conduct additional preclinical studies to ensure the treatment is safe and effective before moving on to human trials.

If the treatment proves successful in humans, it could represent a major breakthrough in the fight against cancer. Because the tumor-targeting portion of the molecule is versatile and can localize to many different types of tumors, it could potentially be used to treat a wide variety of cancers. And because the molecule can be administered intravenously, it could be easier to administer than other immunotherapies that require direct injection into the tumor.

The researchers are already exploring the potential of the treatment in other types of cancer, and in combination with other immunotherapies. They hope that their work will ultimately lead to new, more effective treatments for cancer patients.

For Jennifer Cochran, the work represents the culmination of more than a decade of research into integrin-targeting molecules. "After more than 10 years of work on PIP, it is rewarding to experience this convergence of expertise from laboratories around Stanford, which allowed us to develop a highly promising new cancer treatment strategy," she said.

The researchers are not the only ones working on new immunotherapies for cancer. Scientists around the world are exploring a wide range of approaches to harness the power of the immune system to fight cancer, from CAR-T cell therapy to cancer vaccines to checkpoint inhibitors.

Despite the challenges that remain, the field of immuno-oncology is rapidly advancing, offering hope to cancer patients who previously had few treatment options. With new treatments like the one developed by the Stanford team, researchers are edging closer to a future where cancer is no longer a death sentence, but a treatable disease.

Other Stanford authors of the study are instructor Patrick Neuhofer, PhD; senior research scientist Debra Czerwinski; and professor of biochemistry Steven Artandi, MD, PhD.

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