Cellular immunotherapy is beginning to bring new hope to patients with certain blood cancers. Tumors that form solid masses, such as breast and pancreatic cancer, are the next frontier for the strategy — but scientists are still grappling with how to overcome the unique challenges large clusters of tumor cells present to engineered immune cells. In new work published Monday in the Journal of Clinical Investigation, researchers at Fred Hutchinson Cancer Research Center show that a dissolving biopolymer sponge packed with a trio of therapeutic ingredients can shrink tumors and extend survival in laboratory models of cancer.
Loaded with engineered immune cells, molecules that help stimulate those cells’ ability to eliminate cancer and a special ingredient that recruits a patient’s own immune cells for a second round of anti-cancer attacks, the spongey, lattice-like scaffold offers a new strategy for tackling genetically variable and crowded masses of tumor cells.
Current experimental cell-based immunotherapy strategies rely on immune cells that seek out a single target, but solid tumors may be able to slip past such a focused attack if certain cells in the tumor don’t possess that particular target but do have one of many other potential immune targets. The implant draws on the natural ability of the immune system to respond to a wide array of targets and deliver a multi-pronged attack.
“We address the main problem that solid tumors have,” said Fred Hutch’s Dr. Matthias Stephan, an immunobioengineer who led the study.
Cellular immunotherapies currently being tested — and showing promise — in clinical trials are delivered intravenously. This can work well in some patients with blood cancers like leukemia, as the engineered cells fan out to hunt down cancer cells circulating in the blood (or residing in the bone marrow). But because solid tumors like breast cancer present millions upon millions of diseased cells all packed together, they require a concentrated effort. Merely injecting a solution of T cells onto a tumor would result in most of them seeping away without a chance to get a toehold in the tumor, said Stephan.
His approach is to concentrate engineered immune cells known as CAR T cells directly at the site of the tumor using the scaffold. A T cell is a specialized type of immune cell capable of recognizing and eliminating diseased cells. Researchers genetically engineer T cells with a scientist-designed chimeric antigen receptor, or CAR, that gives them the ability to “see” cancer cells with specific targets on their surface.
Stephan’s biopolymer sponge, which lasts for about a week before dissolving harmlessly in the body, gives the CAR T cells a comfortable home base and retains them right where they’re needed. The synthetic T-cell headquarters is well-stocked with molecules that help energize the T cells. Because tumors release a number of molecules that switch T cells to a lethargic state, the immune boosters are necessary to ensure that the scaffold-delivered T cells are on high alert for cancer cells and ready to pounce as they exit the implant, instead of releasing unprepared T cells that may wander away, uninterested in their potential targets. By localizing delivery of a high dose of boosted T cells, Stephan’s scaffold overcomes two hurdles at once.
And indeed, when the researchers tested their strategy in a preclinical mouse model of pancreatic cancer, they found that CAR T cells delivered with immune-boosting nourishment via the scaffold multiplied their numbers and responded robustly to the cancer: The animals’ tumors shrank. In contrast, CAR T cells that were injected into tumors (without activating molecules to support their attack) didn’t expand their numbers and reacted anemically in the face of millions of tumor cells.
These latest experiments confirmed a previous laboratory study in which Stephan’s team demonstrated that T cells delivered via a scaffold rich in immune boosters, but not those delivered intravenously, could shrink ovarian tumors in mice. They also showed that when used after surgery to remove breast cancer tumors in mice, the scaffold-supplied T cells reduced the rate of relapse compared to the same cells infused via IV — and even chased down tumor cells that had spread to nearby lymph nodes.
“We showed that the first version of the scaffold is doing its job; it’s sending out the CAR T cells and you clear all the tumor cells you wanted to target,” said Stephan of their newest results. But they also observed that other tumor cells that carried different genetic alterations that made them invisible to the CAR T cells quickly rebounded and caused relapse.
Adding a mix of CAR T cells — tailored to each patient — to target all those different genetic alterations would be a time-consuming and expensive fix, said Stephan. To tackle this issue, he and his team instead decided to pit the enormous genetic variability of the patient’s own immune system against the enormous genetic variability of tumors.
The researchers added a new, third ingredient to take their scaffold to the next level. Once the CAR T cells have started killing tumor cells, fueled by the energizing support molecules also loaded in the scaffold, the “scaffold can serve a second purpose, which is to release locally, at the right time, a high concentration of a vaccine adjuvant,” said Stephan. An adjuvant is a molecule or compound that gives an enormous boost to the immune system, helping it better recognize in the dying tumor cells the danger still posed by the rest of the cancer.
“Now, your own immune system … gets primed. We create a second wave of anti-tumor response, this time coming from the patient,” he said.
The molecule triggering this second wave is carried within the scaffold by microspheres, ultra-thin layers of waterproof molecules that surround miniscule clumps of the immune activator. The immune system-activating molecule Stephan chose to demonstrate his strategy is called a STING agonist, for STimulator of INterferon Genes, because it prompts release of molecules that galvanize immune cells known as interferons. The STING agonist is just one possible adjuvant that could be used to incite a wider anti-cancer immune response.
If diffused throughout the body, STING agonists are very toxic. But the researchers hypothesized that by adding a STING agonist to their scaffold, and keeping its release confined and tightly controlled, they could spark a patient’s own immune system to fight their cancer without causing serious toxic side effects. They were right: When the microspheres dissolved a few days after the scaffold was implanted, the STING agonist spread into the area right around the tumor, acting as a localized red alert to native immune cells nearby.
In their experiments with pancreatic cancer, a notoriously deadly and difficult-to-treat disease, the researchers found that placing a CAR T- and STING agonist-loaded sponge extended average survival in mice from about two weeks to two months — far longer than any other strategy they tried. They saw similar results when they tested their fully loaded scaffolds in a mouse model of melanoma.
If the scaffold performs the same way in people, its CAR T cells could be “buying the patient’s immune system time to orchestrate this anti-tumor immune response by shrinking the tumor first,” said Stephan. That sets the stage for the patient’s immune cells to mop up the residual tumor cells.
Stephan is now working with industry partners to continue developing the scaffold, but many steps remain before the immunotherapy-delivering scaffold could be used in the clinic. These include a series of human trials and the process of obtaining FDA approval.
If approved, Stephan envisions his technology being used to help shrink inoperable tumors enough that they could be removed surgically. As shown in the team’s prior work, the scaffold could also be placed in the tumor area after surgery to eliminate residual cancer cells and potentially stave off relapse.
Stephan’s ultimate aim is to shrink tumors enough to extend the lives of patients with aggressive and even incurable disease.
“What we’re really trying to do,” explained Stephan, “is buy the patient time.”
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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