UCSF

Synthetic biomaterial guides cancer therapy to hidden tumors

It may sound like science fiction, but since 2017, scientists and oncologists have genetically engineered patients’ own immune cells to successfully track down and destroy tumor cells. The approach, called CAR T-cell therapy, is currently used to treat just a small number of cancers of the blood and lymphatic system.

A synthetic, DNA-based biomaterial, developed at the UCSF School of Pharmacy, promises to open up the treatment to many more types of cancer and help guide CAR T-cells directly to solid tumors.

The biomaterial, made up of small nanoparticles coated with particular chemical signals, can be injected in the vicinity of a solid tumor, attracting CAR T-cells away from the bloodstream and to the cancer, spurring a strong and localized immune response.

“CAR T-cell therapies have been very impactful in the clinic, but there remain several challenges to using them,” said Tejal Desai, PhD, senior author on the study, which was published in Nature Nanotechnology on December 14. “This biomaterial harnesses the full potential of the therapy, which could make it effective in treating a truly broad range of cancers.”

Priming the immune system to fight cancer

T-cells are white blood cells that patrol the body for threats, like bacteria or cancer. They are dotted with receptors on their surface, and when those receptors lock on to an antigen on a threat, the T-cell is activated, leading to an immune response. Each T-cell possesses just one type of many millions of types of T-cell receptors.

In CAR T-cell therapy, doctors remove T-cells from the body and modify them to have the right receptor needed to target specific cancer cells. But these modified T-cells can’t easily reach tumors hidden inside of the body’s organs, and they sometimes attack healthy tissue.

The UCSF group’s biomaterial solves some of these longstanding limitations of CAR T-cell therapy, according to Desai, who is a faculty member and chair of the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

“These new materials make these cells more efficient, better aimed at their target, and safer, by only activating the immune response when the cells reach the right place, a tumor,” she said.

Biomaterial marks internal tumors for immune destruction

This advance is based on an understanding of what makes regular T-cells so effective in fighting off threats. T-cells are not the only cells that recognize foreign threats—they are joined by additional immune cells that send signals encouraging the T-cells to attack and to even multiply.

Desai’s group wanted to design a material that was safe to put into the body and would withstand degradation. But most importantly, it needed to be able to ferry in the multiple chemical signals that, in conjunction with CAR T-cell therapy, would provoke a full-fledged immune assault on a tumor.

Xiao Huang, PhD, a postdoctoral researcher in the Desai Lab and first author on the paper, had tinkered with short synthetic DNA strands in prior research, and realized that such DNA strands could be used to tether immune signals to synthetic particles, which could then be safely injected into a tumor site.

“The great thing about DNA is that we can design every strand to be exactly what we want it to be,” said Desai. In this case, using different DNA strands would ensure that each particle carried the right assortment of chemical signals to promote an effective immune response.

In addition to helping the CAR T-cells find solid tumors inside of organs, “the CAR T-cells get activated only when they see both the [biomaterial] particles and the tumor,” said Desai, preventing healthy tissue from being attacked. Following testing on cancer cells in petri dishes, the biomaterial also successfully drew CAR T-cells to a tumor in an animal model of cancer.

Helping the body help itself

While this work may most directly benefit cancer patients receiving CAR T-cell therapy, Desai sees broader applications for the biomaterial and is eyeing a form of diabetes as the next target for this approach.

“We’re interested in using biomaterials like this to either activate or calm the immune system, depending on what you want to do, and doing that in a way that's both scalable and manufacturable,” she said. “A healthy immune system is capable of so much on its own, and bioengineering solutions like this just give the body the signals it needs to take care of itself.”

More

DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation (Nature Nanotechnology)

Behind the paper: Surface DNA-scaffolds equip multifunctional biomaterials for precise immune cell modulation (Nature Bioengineering Community)


About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.