Wound-healing platelets may also help combat cancer

Wound-healing platelets may also help combat cancer
April 5, 2017

Imagine being able to fight cancer with the same weapons our body uses to fight colds and infections. Scientists have been working on ways to turn the power of the immune system against tumors.

Platelet PlugCancer cells are extremely similar to normal human cells, though, and they have tricks to evade the killer cells of the immune system. Now researchers from the UNC School of Pharmacy and North Carolina State University are combining immune medications with another of the body’s protective cells, the blood platelet, to get around cancer’s defenses

The research also addresses another major issue in fighting cancer: the ability for tumors to regrow and spread after surgery. In mice, the researchers' modified platelets (which naturaly flock to wounds including surgery sites) dramatically decreased cancer recurrence and spread after surgery. The research was published in the journal Nature Biomedical Engineering.

When surgeons cut out a solid tumor, they usually cannot remove every last cancer cell at the surgery site, so there are usually small numbers of tumor cells floating in the patient’s bloodstream. These leftover tumor cells—called residual microtumors if they stay put or circulating tumor cells if they move through the bloodstream—multiply, causing cancer to return, often more aggressively than before surgery.

Oncologists frequently use chemotherapy and radiation to try to wipe out those leftover cells, but both of those therapies can be harmful and uncomfortable to patients. Immunotherapies aim to accomplish the same eradication of the remaining cancer, but by enhancing the body’s immune system with antibodies, molecules and cells that help it target and attack cancer.

Melanoma

One way to do that is to add immune checkpoint inhibitor molecules to the bloodstream. The immune system’s targeted security cells, called T-cells, work by recognizing proteins on the surface of an unfriendly cell and killing it. Friendly cells have a surface protein called PD-1 that acts like a security badge. PD-L1 proteins on the T-cells read the PD-1 protein and the T-cell shuts down. Cancer cells have the PD-1 security badge just like healthy cells so the immune system leaves them alone.

What immune checkpoint inhibitors do is block the T-cell PD-L1 from reading the PD-1 security badge on the cancer cells. Without that clearance, the T-cells will go ahead and attack the cancer. The only problem is that healthy cells cannot prove their innocence either and they get killed along with the cancer—a condition called autoimmune disease. Once the immune checkpoint inhibitor hits the blood stream, it can spread that autoimmune dysfunction throughout the body.

Zhen Gu, a biomedical engineer with dual appointments at UNC School of Pharmacy and NC State, and senior author of the study, used blood platelets as a potential solution to that specificity problem.

When the body suffers a bleeding wound, platelets in the bloodstream clump up at the site of the wound to form a plug that stops the bleeding. Removing a solid tumor causes plenty of damage and every milliliter of blood contains several hundred million platelets, so when it comes time to recover after surgery, billions of platelets will converge on the surgical wound to plug everything up and protect the tissue inside the wound, including the residual microtumors.

Gu and his colleagues had the idea of attaching an immune checkpoint inhibitor to blood platelets. The platelets might then act like a drug delivery system, bringing the inhibitor directly to the site of the microtumors, where T-cells can readily attack the leftover cancer cells.

The natural function of the platelets also enhances the cancer-fighting effects of the inhibitor. Platelets form wound-sealing clots by releasing particles and proteins that mesh together into a tight wad. When the platelets release those particles, the immune checkpoint inhibitor goes with them, ensuring the wound gets a thorough covering. Further, when platelets clump together, they attract T-cells and other immune cells to fight the inhibitor-soaked microtumors.

Breast CancerGu tested the modified platelets in mice with melanoma and breast cancer whose tumors had been surgically removed. For the melanoma mice, the inhibitor platelets attracted ten times as many T-cells into the remaining tumor tissue as normal platelets and three times as many as inhibitor by itself. Three-fourths of the mice treated with inhibitor platelets were alive 60 days after treatment, while none of the mice treated with inhibitor by itself or just platelets lived beyond 30 days.

Three-fourths of the breast cancer mice also survived to the 60 day mark after being treated with the modified platelets. None of the mice treated with regular platelets lived beyond 40 days and none of those treated with inhibitor alone survived for 60 days. Beyond that, the inhibitor platelets cut down on the number of metastases the researchers found in the mouse lungs. They found a median of two metastases in the modified platelet mice compared to 16 in the inhibitor mice and 30 in the platelet mice. The inhibitor platelets also greatly reduced metastases in mice that had been injected with tumor cells, demonstrating that these modified platelets can even fight cancers in the bloodstream.

This therapy is remarkable in that it is effective in targeting and fighting multiple types of cancers. The fact that the platelets also clump around circulating tumor cells means that liquid tumors, like those in leukemia, are also potential targets.

Modified platelets are a long way from regular use in a clinic. These platelets need safety testing, to make sure they don’t cause a serious autoimmune reaction in a wound that is trying to heal. And the immune checkpoint inhibitor used in this study, a drug called atezolizumb, is not currently FDA approved.

That said, atezolizumab and other immunotherapy drugs are on the fast-track to FDA approval, and if the modified platelets continue to produce promising, safe results, they might soon follow.

—Daniel Lane

Daniel Lane covers science, medicine, engineering and the environment in North Carolina.

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