Immunotherapy Coalesces on Platelets as Drug Delivery Mechanism

        Maintaining hemostasis (stop bleeding) is the main function of thrombocytes—commonly referred to as platelets. Yet, what if these cells could be engineered to carry anticancer drugs to wipe out those microtumors? Well, scientists at the University of North Carolina (UNC) and North   Carolina State University (NC State) have developed a way to do just that, reporting successful outcomes in animal studies.

        “Our goal was to study a new and effective way to treat cancer patients after they have surgery,” explained senior study investigator Zhen Gu, Ph.D., associate professor in the joint department of biomedical engineering at UNC and NC State. “There has been tremendous interest in developing new, effective strategies to prevent cancer recurrence after surgery. Among them, cancer immunotherapy has received considerable attention. But immunotherapeutic agents do not directly attack the tumor—they use the body’s immune system to kill cancer cells.”

        After surgery to remove a cancerous tumor—even if the surgery is considered successful—it’s nearly impossible to ensure that all microtumors have been removed from the surgical site. Cancer recurrence is always a major concern, as well as the possibility that tumor cells will circulate through the body after surgery.

        The researchers decided to look for a novel approach that could address these concerns. However, the scientists ran into additional issues they needed to consider during the development process. For instance, immune cells may be blocked by inhibitory molecules, which serve as checkpoints to alleviate or “turn off” the immune system response. Cancer cells can leverage such mechanisms to escape the immune system response. The cancer cells’ defense strategy can be overcome by immune checkpoint inhibitor agents, including anti-programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) antibodies—several of which have already been FDA approved.

        To overcome many of these problems, Dr. Gu and his colleagues used immunotherapy to directly target residual tumors after surgery or surgeries to remove the primary tumor, rather than to nonspecifically bolster the immune system. The research team managed to attach specific cancer-fighting antibodies to the surface of platelets, which then travel to a wound site to kill cancerous microtumors or circulating tumor cells. This way, the negative side effects could be avoided.

        “But challenges remain in order for these inhibitor antibodies to be used effectively in patients,” noted lead study investigator Chao Wang, Ph.D., a postdoctoral researcher in Dr. Gu’s laboratory. “Currently, the antibodies cannot target the tumor site effectively. The off-target antibodies and overdose usage of antibodies can cause side effects such as an autoimmune disorder, which can damage normal tissue cells.”

        The findings from this study were published recently in Nature Biomedical Engineering in an article entitled “In Situ Activation of Platelets with Checkpoint Inhibitors for Post-Surgical Cancer Immunotherapy.”

        “We wanted to utilize platelets’ intrinsic tendencies to accumulate at wounds and to interact with circulating tumor cells, for targeted delivery of immune checkpoint inhibitors,” Dr. Gu remarked. “Interestingly, we found the antibody can be promoted to release from activated platelets in the surgical site, due to the generation of small platelet-derived microparticles upon the platelet activation. Also, aggregated platelets can help attract and boost immune cells to the surgical site.”

        The researchers utilized atezolizumab, an anti-PD-L1 inhibitor antibody, which was recently fast-tracked by the FDA. For the mice that received the treatment—in comparison to their placebo counterparts—the treatment “significantly” prolonged overall survivor after surgery by reducing the risk of cancer regrowth and metastatic spread.

    “It’s going to be a broader technology to treat a variety of tumors. That’s why we applied different cancer types—not just for solid tumors, but for cancers like leukemia,” Dr. Gu concluded. “Leukemia is a liquid, circulating tumor, while breast tumors and melanoma are solid tumors, so this is going to be a very broad technology. We need new approaches to address cancer metastasis and circulating tumors after surgery, and we think we’re on the right track using platelets laced with antibodies to kill various types of cancers.”