Stanford Medicine 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.
The research team included collaborators from the Stanford Cancer Institute and the university’s Department of Bioengineering, and innovation hub Stanford ChEM-H. Results of the study appeared in a paper published online in Cell Chemical Biology on Nov. 12, 2021.
Steven Artandi, MD, PhD, is a study co-author and the Laurie Kraus Lacob Director of the Stanford Cancer Institute. He said, “This study is a promising breakthrough in cancer treatment. Drawing on expertise from laboratories around Stanford, we combined a tumor-targeting synthetic molecule with an immune-activating agent. Administered intravenously, it makes its way to the tumor and activates a powerful immune response.”
The researchers injected the synthetic molecule into laboratory mice with an aggressive triple-negative breast cancer. Results showed that:
- A single dose induced complete tumor regression in five of 10 mice.
- Three doses prolonged survival in six of nine laboratory mice. Of the six, three appeared to be cured of the cancer over the duration of the study.
“We essentially cured some animals with just a few injections,” said co-author Jennifer Cochran, PhD, the Shriram Chair of the Department of Bioengineering. “It was pretty astonishing. When we looked within the tumors, we saw they went from a highly immunosuppressive microenvironment to one full of activated B and T cells—similar to what happens when the immune-stimulating molecule is injected directly into the tumor. So we’re achieving intra-tumoral injection results but with an intravenous delivery.”
The researchers also investigated the synthetic molecule in mice with pancreatic cancer and found similar results. This finding suggests that the new immunotherapy agent may be effective against multiple types of cancer.
The synthetic molecule is called PIP-CpG, which is a conjugate of polyspecific integrin-binding peptide (PIP) and CpG oligonucleotide. The work of putting them together leveraged two areas of previous Stanford research.
PIP is a tumor-targeting agent developed in Dr. Cochran’s lab over 10 years ago. It recognizes proteins called integrins found on the surface of many types of cancer cells. PIP can be coupled with other molecules to:
- Attach probes to cancer cells so doctors can locate hard-to-see cancers in the body using near-infrared or PET imaging
- Seek out cancer cells and deliver chemotherapy medicines to the tumor
“These integrin-targeting molecules act like guided missiles,” Dr. 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.”
CpG oligonucleotide is a single-stranded DNA molecule that amplifies the immune response by activating cancer-specific T cells. CpG and other immunotherapy agents are the research focus of study co-author Ronald Levy, MD, the Robert K. and Helen K. Summy Professor in the School of Medicine.
In past studies, Dr. Levy’s lab has achieved excellent results by injecting CpG directly into the tumor. “This study shows that the sculpting of the tumor microenvironment by PIP-CpG was identical to that achieved by direct injection,” Dr. Levy said. “This is a big advantage because it’s no longer necessary to have an easily or safely injectable tumor site.”
More research is needed to determine whether and when PIP-CpG will be ready for testing in humans. Stanford Medicine researchers are now studying the treatment in other types of cancer and in combination with other immunotherapies.
Dr. Artandi said, “This work reflects Stanford Medicine’s commitment to the highest level of scientific rigor and institutional support. As we move new therapies forward from the lab to clinical trials to clinical practice, Stanford Medicine cancer specialists proceed quickly but cautiously. In doing so, we continue to revolutionize cancer treatment and improve our patients’ quality of life.”
Other Stanford authors of the study are the Baker Family Director of Stanford ChEM-H Carolyn Bertozzi, PhD; instructor of medicine Idit Sagiv-Barfi, PhD; senior research scientist Debra Czerwinski; bioengineering graduate student Caitlyn Miller; and instructor Patrick Neuhofer, PhD.