With support from the NIH, Assistant Professor Quanyin Hu uses a two-step system to attack triple-negative breast cancer

By Susan Smith

Armed with funding from the National Institutes of Health’s National Cancer Institute, the University of Wisconsin–Madison School of Pharmacy’s Quanyin Hu, assistant professor of pharmaceutical sciences, is poised to expand his work creating engineered cells to help the body fight cancer. Through a new R01 grant, Hu’s Cell-Inspired Personal Therapy (CIPT) Lab will be engineering platelets that can better infiltrate and kill tumors created by triple-negative breast cancer (TNBC).

Hu — who has three times been named a Highly Cited Researcher by Clarivate, representing the top 1% of citations in a field — is combining two technologies developed in his lab to both increase the accumulation of cancer drugs in triple-negative breast cancer tumors and better equip the immune system to destroy cells remaining after surgical treatment.

The problem: Triple-negative breast cancer cells lack receptors for estrogen, progesterone, and human growth factor (HER-2), which means that breast cancer therapies targeting those receptors — and offering fewer side effects in the process — do not work effectively.

“Triple-negative breast cancer tends to have very dismal treatment outcomes for two reasons: because the response rate of the first-line immunotherapy treatments is pretty low, and because triple negative breast cancer has higher aggressiveness in infiltrating the surrounding tissue,” says Hu.

This aggressiveness makes it difficult for surgeons to identify the margin between the cancerous tissue and the healthy tissue, increasing the possibility for cancer cells to be left behind after surgery. These remaining cancer cells will come back aggressively and rapidly, resulting in a cancer relapse.

Triple-negative breast cancer is also regarded as a “cold tumor,” meaning it doesn’t respond well to current immunotherapies. For immunotherapy to work, immune cells, such as T cells, must infiltrate the tumor.

“In triple-negative breast cancer, immune cell infiltration is very low,” says Hu. “The cancer cells create a microenvironment, kind of like a shield surrounding the tumor tissues, that protects the cancer from outside attacks from immunotherapy and drugs.”

The new approach: Hu’s CIPT Lab has long focused on new ways to tackle difficult-to-treat cancers, including a method of targeting tumors with cancer drugs by leveraging the clotting capabilities of platelets and another to use modified platelets to break down the proteins responsible for cancer recurrence. With this grant, Hu’s team wants to bring some of those technologies together.

“Our first goal is to increase the accumulation of the cancer-fighting drugs on the tumor side. To do this, we will use a truncated tissue factor to trigger thrombus and attract immunotherapeutics-conjugated platelets for activating the immune cells to fight the tumor — essentially, we’re modifying a protein to trigger clotting in a specific area, which will amplify the thrombosis signaling to immunotherapeutics-conjugated platelets to accumulate at the tumor site to activate macrophages, T cells, and other immune cells within the tumor site to suppress further tumor growth,” Hu says.

“Our vision is that if we are able to translate these therapeutics to the clinic, they can […] meaningfully improve outcomes for patients with this difficult-to-treat cancer.”
—Quanyin Hu

Secondly, they’ll work to dismantle tumors’ microenvironment “shield” to make cancer drugs more effective, using engineered nanoparticles to deplete the tumors’ own macrophages so they will not be able to hinder infiltrating immune cells.

“In earlier studies, we saw that our platelet-mediated immune checkpoint inhibitor delivery system — using modified platelets and clotting to trigger immune response — can efficiently target the post-surgical tumor site and deliver platelet-derived microparticles that contain PD-1 inhibitors — which block proteins that help cancer evade the immune system — to the tumor site,” says Hu.

Hu’s team has tested these technologies in models of melanoma and triple negative breast cancer, readying them for the next step.

“Now, we are going to test the two-step process in a humanized mouse model, which is a mouse with a human immune system and a human triple-negative breast cancer tumor,” he says. “We hope to establish the clinical, translational potential of this combination strategy.”

The vision: Hu hopes that these technologies can become synergistic tools in the clinic, augmenting existing immunotherapy, chemotherapy, or surgical treatments.

“Our vision is that if we are able to translate these therapeutics to the clinic, they can serve as either adjuvant therapy, given after the primary treatment, or as a complementary therapy to the first-line treatment options that are now available to meaningfully improve outcomes for patients with this difficult-to-treat cancer,” Hu says.