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The rapid evolution of immuno-oncology research

Researchers are modifying human T cells (orange) to overcome immune suppression and respond aggressively to specific cancers (blue).Credit: Roger Harris/Science Photo Library/Getty Images

Between 2017 and 2019, the number of immuno-oncology (IO) drugs in development rose from 2,030 to 3,876, an increase of 91%1. Much more lies ahead.

After 34 years since the introduction of the first genuine IO therapy, interferon-alpha 2, the field is at an inflection point. New technologies, improved methods, and a few decades of accumulated knowledge, are driving research into a diverse portfolio of novel IO therapies and combinations2 that may have the potential to change the treatment landscape.

“Because it activates the immune system, immuno-oncology will address a larger patient population than other approaches to cancer treatment,” says Axel Hoos, head of oncology research and development at GSK, whose group is actively investigating multiple areas within IO.

As IO matures, therapeutic focus will shift from a reliance on a few important pathways to the management of many pathways, in concert. It is the difference between a graceful piano sonata and soaring symphony. What remains to be seen is which instruments will researchers and, ultimately, clinicians choose to include.

The power of combinations

Oncologists regularly treat cancers with combinations of therapies, such as surgery and radiation and more than one kind of chemotherapy. The next step could be to combine multi-modality targeting within a single immuno-oncology agent. As an example, Hoos says, “We’re trying to design two mechanisms of immuno-oncology in one drug.”

Obstacles exist. To attack more than one target, scientists must pinpoint patients who could benefit from these types of therapies. “It might take a number of biomarkers, maybe a multitude of them, like a signature,” says Michael Streit, who oversees GSK’s work in the dual-targeting space. It is unclear how long it might take.

In addition to blocking two targets with one treatment, researchers are also investigating combinations of a blocker and a stimulator.

“We’ve had great success with antagonistic drugs, like checkpoint inhibitors, but we’ve struggled for a long time to utilize agonists,” says Marc Ballas, who leads GSK’s work in this area. With antagonists and agonists each hitting different targets, we may have the ability to dial in and out the impact of each drug on the cancer,” he says.

That work is still relatively new, Ballas says. The first step is simply to better understand the mechanism of action for agonists, which, he says, “is part of a complex circuitry that we were not familiar with a few years ago.”

Adjusting for negative adaptations

Researchers have long known that tumours can introduce abnormalities into their local environments. “These abnormalities can fuel tumour growth, metastasis and immune suppression,” says Rakesh Jain a tumour biologist at Massachusetts General Hospital and Harvard Medical School. The tumour microenvironment (TME) can also confer resistance to all kinds of therapies, including radiation, chemotherapy, targeted therapy and immunotherapy.

To improve the efficacy of treatments, Jain is investigating methods to restore the TME. He showed that a decrease in blood flow correlates to an increase in an immuno-suppressive TME3. “By repairing blood flow,” Jain says, “any flavour of immunotherapy will work better.”

Jain has been researching vascular endothelial growth factor (VEGF), which promotes the growth of new blood vessels. Tumours tend to produce an unusual amount of VEGF, which leads to leaky blood vessels that reduce blood flow to the TME.

“The right dose of anti-VEGF improves the blood supply to a tumour, repairs the immune system in the TME and allows therapy to be delivered,” Jain explains. In the past 18 months, the U.S. Food and Drug Administration has approved five combinations of anti-VEGF drugs with checkpoint inhibitors.

Other researchers are investigating more pointed repairs to the TME. James Smothers, head of GSK’s immuno-oncology and combinations research, says he is particularly intrigued by macrophages. The white blood cells can differentiate into various forms that benefit healthy tissues in several ways, including wound healing and fighting cancer. “They are like Pac-Man — gobbling up dead or dying cells,” Smothers says.

Tumours can hijack the normal process of differentiation and create tumour-associated macrophages (TAMs). Rather than supporting an immune response, TAMs will actively suppress it by producing molecules that stifle cytotoxic T cells and natural killer cells.

To Smothers, the mechanism, though still not entirely understood, could present an opportunity. “Maybe we can plug into that circuit in some way to keep cancer from turning good macrophages into bad ones,” he says.

Leaning into computation

One of the forces driving the development of IO therapies is technological improvement. Tumour DNA, RNA, chromatin and proteomic profiling at bulk or single-cell resolution are becoming increasingly affordable and adopted.

“All of these techniques are being applied in immuno-oncology,” says X. Shirley Liu, a computational biologist at the Dana-Farber Cancer Institute and Harvard University. “It takes computational tools to generate knowledge from the data.”

While many computational tools have been developed, Liu says data access and integration approaches for IO cohorts are lacking. Her lab’s recent TIMER and TIDE web platforms are early attempts. Collaborations with other efforts from scientists or consortia will probably be synergistic and cost-effective.

“By collecting lots of data on such cells, we identify novel targets and prioritize the ones that would be the best to pursue,” Liu explains.

A broader reach for IO pathways

Despite the current range of patients who benefit from IO, Hoos envisions treating more people by stimulating specific pathways, such as one controlled by the signaling molecule called STING (stimulator of interferon genes).

“Turning on this pathway has been shown to activate the immune system very broadly,” Hoos says. STING triggers the production of type 1 interferon, which could activate a patient’s adaptive immune response to various cancers4.

Hoos adds that while some therapies need to be injected into a tumour, some research indicates that potential STING-focused ones could be administered systemically. “We could perhaps infuse a STING agonist and reach more cancers,” Hoos explains.

A lot of research on the STING pathway is underway, but as with the development of any IO therapy, one of the limitations is data. “Processing the data and drawing the right conclusions from it is key here,” says GSK’s Streit. “We need to be able to distinguish between background noise and a true signal.”

Sophisticated tools, such as artificial intelligence and machine learning, can offer help, but the greatest force multiplier, Streit says, is simple cooperation. “Closer collaboration between academic and industrial scientists and between companies would allow the combination of more data to develop richer databases to explore,” he says. On that foundation, new IO therapies will almost certainly emerge.

NP-GBL-ON-OGM-200003/ Aug2020

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