Self-Assembling Chemoimmunotherapy Hydrogel Treats 100% of Glioblastoma-Bearing Mice

A Johns Hopkins University research team has developed a “drug-delivered-by-drug” hydrogel that combines the anticancer drug­­­ paclitaxel (PTX) and an anti-CD47 antibody (aCD47) in a solution that self-assembles into an anticancer gel that fills the tiny grooves left after a brain tumor is surgically removed. Tests in live mice showed that the chemoimmunotherapy aCD47/PF hydrogel suppressed tumor recurrence following resection of the tumor, leading to what the researchers stated as a “striking 100% survival rate.” The results, they suggest, offer hope for patients diagnosed with glioblastoma, one of the deadliest and most common brain tumors in humans.

The scientists, led by Honggang Cui, PhD, a Johns Hopkins University chemical and biomolecular engineer, suggest that the gel can also reach areas that might be missed during surgery, and which current drugs may not reach to kill remaining cancer cells and suppress tumor growth.  “Despite recent technological advancements, there is a dire need for new treatment strategies,” said Cui. “We think this hydrogel will be the future and will supplement current treatments for brain cancer.”

In their paper published in Proceedings of the National Academy of Sciences Self-assembling paclitaxel-mediated stimulation of tumor-associated macrophages for postoperative treatment of glioblastoma,” the team stated, “The hydrogel serves as a drug depot for localized, sustained release of both PTX and aCD47, eliciting an immune-stimulating tumor microenvironment (TME) and inducing macrophage phagocytosis of cancer cells.

Glioblastoma multiforme (GBM) is hugely aggressive, with extremely high patient morbidity and mortality, the authors explained. And while progress in immunotherapy has significantly improved clinical outcomes for patients with some types of advanced cancers, “brain tumors continue to be a conspicuous exception to this trend, largely due to the unique immunosuppressive tumor environment in brain and insufficient infiltration of T cells into GBM.”

The use of protein drugs and small-molecule therapeutics in combination can “synergize their biological and pharmaceutical activities to improve treatment outcomes,” the team noted. However, it can be challenging to develop effective systems that can deliver both anticancer drugs and antibodies simultaneously, as the different drug types can have very different molecular characteristics, such as size and water solubility.

The team’s newly reported approach involved developing a gel solution that consists of nano-sized filaments made with PTX. These filaments then provide the vehicle for delivering the aCD47 antibody into cavity left by GBM resection “in situ-formed PTX PFs hydrogel seamlessly filled the cavity left by GBM resection, serving as a reservoir for long-term, localized release of both PTX and aCD47 to residual tumor tissue,” the team noted. By blanketing the tumor cavity evenly, the gel releases medication steadily over several weeks, with the active molecules remaining close to the injection site. Importantly, the developers pointed out. “… the in situ-formed hydrogel increases the therapeutic concentration at the target site while preventing leakage of the drugs into blood stream and major organs, so as to reduce off-target side effects.”

Describing the results of their tests in mouse models of glioblastoma, the investigators reported, “Resection surgery plus aCD47/PF treatment eliminated tumor recurrence, leading to 100% survival … Collectively, these data suggest that site-specific aCD47/PF hydrogel implantation as an adjunct therapy to surgical resection shows promise as an effective treatment approach for GBM.”

Surgery is essential for this approach, they further point out, as administering the gel directly in the brain without surgical removal of the tumor resulted in a lower, 50% survival rate. “The surgery likely alleviates some of that pressure and allows more time for the gel to activate the immune system to fight the cancer cells,” Cui said.

“This hydrogel combines both chemotherapy and immunotherapy intracranially,” said co-author Betty Tyler, associate professor of neurosurgery at the Johns Hopkins School of Medicine. “The gel is implanted at the time of tumor resection, which makes it work really well … We don’t usually see 100% survival in mouse models of this disease. Thinking that there is potential for this new hydrogel combination to change that survival curve for glioblastoma patients is very exciting.”

The team focused on the anti-CD47 antibody to combine with paclitaxel, as a potential way of overcoming one of the toughest hurdles in glioblastoma research, by targeting macrophages, a type of cell that sometimes supports immunity but other times protects cancer cells, allowing aggressive tumor growth. “Macrophages are the main effectors of the innate immune response,” the investigators explained. “Recent studies have shown that cancer cells, including brain tumor, can evade innate immune surveillance via overexpression of the immune checkpoint CD47.”

The gel also seems to trigger an immune response that the mouse body otherwise struggles to activate on its own when fighting glioblastoma. When mice that had survived following  initial treatment were subjected to a subsequent glioblastoma challenge, the animals’ immune systems could beat the cancer without any additional medication. This finding suggested that the gel may not only fend off cancer, but also help to rewire the immune system to discourage recurrence with immunological memory. “These results strongly substantiate that a robust and durable antitumor memory immune response was established by a single localized aCD47/PF hydrogel treatment,” the scientists noted. “We show that this “drug-delivered-by-drug” strategy not only combines the distinct material properties of the two therapeutic agents for their long-acting local release, but also synergizes their biological properties to stimulate tumor-associated macrophages with concurrent T cell-mediated immune response for improved tumor treatment.”

One of the go-to therapies for glioblastoma is a wafer co-developed by a team of researchers at Johns Hopkins and the Massachusetts Institute of Technology in the 1990s, commercially known as Gliadel. The FDA-approved biodegradable polymer also delivers medication into the brain after surgical tumor removal.

Gliadel showed significant survival rates in laboratory experiments, but the results achieved with the new gel are some of the most impressive the Johns Hopkins team has seen, said Tyler, who played a pivotal role in the development of Gliadel.

Co-author Henry Brem, MD, neurosurgeon-in-chief at Johns Hopkins Hospital, co-developed Gliadel in addition to other brain tumor therapies currently in clinical trials. Brem emphasized the challenge of translating the gel’s results in the lab into therapies with substantial clinical impacts. “The challenge to us now is to transfer an exciting laboratory phenomenon to clinical trials.”

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