July 13, 2021

By Christopher Vaughan

Researchers at Stanford have shown that blocking the CD47 signal on breast cancer cells increases the effectiveness of a standard antibody treatment for HER2+ breast cancer, even when the cancer has become resistant to the treatment. 

 “These results demonstrate that we can turbocharge existing treatments for HER2+ breast cancer by amplifying an underappreciated mechanism that the body uses to fight cancer,” said Irv Weissman, MD. Weissman is the Virginia and DK Ludwig Professor for the Clinical Investigation of Cancer Research and the director of the Institute for Stem Cell Biology and Regenerative Medicine. The research is published in the Proceedings of the National Academy of Sciences (PNAS). Weissman and Mark Pegram, MD–the Susy Yuan-Huey Professor of Medicine–are senior authors on the paper, and Rosalynd Upton is first author. 

Historically, patients with breast cancer that displayed the HER2 marker, which occurred in about 16% of breast cancer cases, had very low survival statistics. The clinical development of anti-HER2 antibody therapy called trastuzumab (which is sometimes referred to by the trade name Herceptin) led to large improvements in the treatment of HER2+ breast cancer and became a mainstay medication for those with this form of breast cancer. 

Trastuzumab binds to HER2 on the cell surface, and can affect HER2+ breast cancer cells either directly through its inhibitory biological activity, or indirectly by recruiting immune system cells to attack the cancer cell. But though trastuzumab is highly effective to treat early-stage HER2+ breast cancer, the majority of patients with an advanced-stage, metastatic form of this cancer become resistant to the treatment. In such cases, their cancers ultimately progress, even if they initially responded to the treatment. Resistance to treatment occurs even though the cancer cells still display high levels of HER2 protein on their surface and should still be susceptible to antibodies that attack HER2. 

Weissman and his colleagues wondered if the treatment of HER2+ breast cancer could benefit from the activation of an immune cells called scavenger macrophages, which are tasked with engulfing and destroying diseased or damaged cells. The Weissman lab and other researchers had already shown that CD47 could act as a “don’t eat me” signal to macrophages, and that blocking the signal with anti-CD47 antibodies reactivated macrophages’ natural cancer fighting activity. Weissman and his colleagues had shown that many cancers, including breast cancer, express high levels of CD47, which protects them against these immune monitors. 

A recent clinical trial showed that blocking the CD47 “don’t eat me” signal with an anti-CD47 antibody increased the efficiency of another antibody drug called Rituximab when used against another kind of cancer called diffuse large B-Cell lymphoma. This was true even when the lymphoma had acquired resistance to Rituximab alone. 

“We wondered if we might see a similar beneficial effect if we blocked CD47 signaling when administering trastuzumab in the treatment of HER2+ breast cancers,” Weissman said, “especially if cancer cells were resistant to trastuzumab treatment.” 

To test this idea further, researchers from the Institute for Stem Cell Biology and Regenerative Medicine, along with colleagues in the Stanford Cancer Institute, studied mice that had been engrafted with human HER2+ breast cancer cells that had become relatively resistant to treatment. What they found was that while trastuzumab or anti-CD47 antibodies by themselves had some therapeutic effect, the combination of the two therapies inhibited tumor growth significantly more and produced better survival statistics than either treatment alone. 

Most of the research on trastuzumab has focused on the action of immune cells called natural killer (NK) cells to attack the cancer, but this study illuminates how trastuzumab also recruits macrophages to do the job. “Until now, the process of antibody-dependent cellular phagocytosis, in which macrophages engulf and kill cancer cells, has been an understudied mechanism of action of trastuzumab,” said Pegram. “This study is evidence that this mechanism of action can be significantly enhanced by adding anti-CD47 antibodies.”

What was most interesting to Upton, the first author on the paper, was that adding anti-CD47 antibodies made such a qualitative difference in cancer fighting. “That we could take cancer cells that were specifically resistant to trastuzumab, and by adding something else make those cells vulnerable again, was almost like magic.” Upton earned her JD from Stanford Law School at the same time as she was earning her PhD in cancer biology. She is now clerking in the US Court of Appeals for the Federal Circuit.

The results support the further exploration of this approach in human clinical trials, Weissman said. 

This work was supported by the National Institutes of Health (R35CA220434), the DK Ludwig Fund for Cancer Research, the Gunn-Olivier fund, the Israel Science Foundation, and the Mary Kay Foundation.