When the immune system detects an antigen—any molecular structure it can identify as foreign—it goes on the attack. T cells, the white blood cells that drive the body’s adaptive immune response, lead the way. But in the complex game of hide-and-seek that occurs within a cancer patient’s tumor cells, the cancer can use these very same checkpoints to make the T cells stand down, allowing the cancer cells to mutate and multiply. If unchecked, the tumors may spread, and the cancer could metastasize.
Checkpoint inhibitor drugs, the largest and most studied category of available immunotherapies, suppress the checkpoint proteins on cancer cells that enable those cells to fool the immune system into leaving them alone.
In addition to checkpoint inhibitors, other forms of immunotherapy in use include CAR T-cell therapy, a process by which T cells are removed, supercharged, cloned and reintroduced into the body. There are also cancer vaccines. While these therapies, and combinations of them, are currently FDA approved or in clinical trials available for late-stage patients, in the lab researchers have moved beyond them and are seeking the next wave of immune-boosting treatments.
Cancer patients, Luke explained a few days before the ASCO meeting, are divided into two subsets. There are those fortunate few whose immune systems recognize cancer and have an immune response—which cannot beat cancer on its own, but is a response just the same.
These patients have what’s called a “hot,” or “T-cell inflamed,” tumor microenvironment. Their tumors are populated by T cells that are suppressed but that, if given support by immunotherapies, might fight the cancer cells. But most patients’ tumors are “cold,” or devoid of T cells, a situation that Gajewski calls a “failure to recruit,” making the tumor far less likely to respond to immunotherapy.
“We try not to use the c-word,” Luke said, referring to the pursuit of a cure, “because we don’t want to overpromise what we’re talking about, but certainly we have patients who got immunotherapy five years out, 10 years, and longer, with no recurrence and not needing any more treatment. It’s sort of like a vaccine, in the fact that if the immune system figures it out, you don’t need any more treatment program.”
On a midday break during his Friday rounds, Luke wears a white lab coat and has the youthful appearance of an assistant professor. He makes rounds every day, tending to melanoma patients on Tuesdays. His name regularly pops up on melanoma.org’s “find support” message boards. “If I was in the Chicago area this is who I would seek out,” wrote one patient to another in May.
To understand why immunotherapy does not work for the majority of patients, researchers must keep going back to the minority for whom it does. Patients who respond to immunotherapy are “paradigm,” Luke said.
What is it about these patients, their immune systems, their cells, their genes—whatever it might be—that prompts an immune response? One clue could be biomarkers, internal biological molecules whose presence predicts particular clinical outcomes, and for Luke and Gajewski’s purposes might indicate which type of immunotherapy would be most effective in an individual cancer patient. Both are among the researchers now working in the lab to understand biomarkers, comparing tissue samples and blood tests of patients who don’t respond to immunotherapy with those of responsive patients to understand what’s different. Pinpointing biomarkers is the primary focus of a new UChicago clinical trial, begun this past March with Luke as the principal investigator.
Examples of biomarkers include oncogenes, genes that under certain circumstances may transform a cell into a cancerous tumor cell. Another biomarker could be the mutation rate within tumors and its effect on how a patient responds to immunotherapy. “Extrinsic” biomarkers include the presence or absence of certain bacteria in a patient’s gut microbiome.
Gajewski and his team were among the early discoverers of one extrinsic biomarker, a healthy bacteria strain known as Bifidobacterium. In 2015 the team discovered that mice procured for their lab from one supplier tended to have a robust spontaneous immune response to melanoma tumors implanted under the skin. Mice from a different supplier had a much weaker response. When the researchers mixed the mice from both cages together, they found that both sets of mice had a robust response. The team traced the change to Bifidobacterium, which was present in the intestines of the immune-responding mice who shared it with their new neighbors. The anticancer effects of the gut bacteria were comparable to treatment with checkpoint inhibitors.
A similar human study from Gajewski’s group that transplanted stool samples in patients was “quite compelling,” Gajewski told UChicago Medicine’s publication Medicine on the Midway last fall. Gajewski worked with the University’s Polsky Center for Entrepreneurship and Innovation to file patent applications and the University licensed the technology to Evelo Biosciences, a biotech company in Cambridge, Massachusetts.
The next step, Gajewski said in Medicine on the Midway, are microbes “that could boost antitumor immunity in patients.” In October 2018 Luke started a clinical trial to assess the effects of the capsule form of an Evelo microbial drug in patients with melanoma. The drug is also being tested in other cancer types.
The patent-to-pill path of that bacteria strain is an example of “translational” science, taking research and turning it into drug therapies eventually bound for clinical trials, with FDA approval as the endgame. Gajewski is an inventor on 46 patents and has contributed inventive discoveries to at least four immunotherapies. Three of his patent portfolios are licensed to companies developing immunotherapies, and he’s been at work with the University on a start-up company, launching in 2019, that will build immunotherapies based on new discoveries in his lab.
In addition, Gajewski worked with scientists at Aduro Biotech to understand how STING agonists—the name stands for “stimulator of interferon genes,” a protein complex that helps detect tumor cells and promotes an aggressive antitumor response—can be used to stimulate an immune response. The therapy is now in phase 1 trials.
His work to determine that immune-boosting compounds that block an enzyme called indoleamine 2,3-dioxygenase (IDO) can work in combination with checkpoint inhibitors was key to the development of a class of drugs known as IDO inhibitors. But, like any road to discovery, this one is fraught with obstacles: Gajewski’s IDO collaborator, the biotech company Incyte, was among three companies to cancel major multinational phase 3 clinical trials of IDO inhibitors this past year. In a May 2018 article, Science magazine called the cancellations a “surprising failure” that “quickly reverberated across the pharmaceutical industry.”
That setback explains why Luke is careful about using the c-word. Just when it looks like a cure might be at hand, the prospect can just as likely slip away. Best of times, worst of times.
“That was supposed to be the next big thing in melanoma, and it was just an absolute bust,” said Luke. “That really set the field to take a step back, and that was probably a good thing.”
Another take on the trial result comes from Thelma Tennant, PhD’03, the oncology innovations and ventures lead at Polsky. “Cancer drug development is high risk, high reward,” said Tennant, who has worked with Gajewski for more than 10 years to translate his research into patents, licenses and partnerships that bring drugs to trial. The risk, she said, must be offset by sound planning, from the inception of the idea to the design and implementation of the clinical trial.
“Jason and Tom are among many clinician-researchers doing a lot of deep thinking on what happened with Epacadostat” she said, referring to Incyte’s canceled IDO inhibitor trial. “One problem was that they didn’t have a clear biomarker.”
The next crucial work is to trace the line from the trial failure back to the lab, where Gajewski and Luke are now pursuing biomarkers. Even the setbacks in cancer immunotherapy furnish precious information that will be critical to making the next leap.
“We have a collection of clinical researchers who excel at both clinical research and bench research,” Tennant said. “They see what’s happening in patients and take it back to the lab and make new discoveries that can rationalize what’s happening in the clinic or, better yet, revolutionize the field.”
Partnering with clinical researchers like Gajewski and Luke are molecular engineers, who look for leaks and systemic problems and set to work on fabricating solutions. They peer into the tumor microenvironment, which may be hot—or, more likely, cold, lacking T cells—and has all kinds of other characteristics.
In 2014 the husband-wife team of Jeffrey Hubbell, the inaugural Eugene Bell Professor in Tissue Engineering, and Melody Swartz, the William B. Ogden Professor in Molecular Engineering, came from the Institute of Bioengineering in Lausanne, Switzerland, to lead the immunoengineering and cancer effort at the Institute for Molecular Engineering. Their labs are in the bright and airy William Eckhardt Research Center on Ellis Avenue.