In 2017, the U.S. Food and Drug Administration approved the first chimeric antigen receptor T (CAR-T) cell therapy for a form of acute lymphoblastic lymphoma, a blood cancer. The FDA’s then Commissioner Scott Gottlieb said, “We’re now entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.”

Five CAR-T cell therapies have now been approved by the FDA, while many more are in trials and development. Researchers are also developing potential therapies that rely on engineered T cell receptors (TCRs), which employ an approach similar to CAR-T cells to open up a host of new targets.

Yet for the enthusiasm that surrounds engineered T-cell therapies, they have a grave limitation: Most remain stubbornly resistant in solid tumors, which comprise the vast majority of all cancers. In 2020 alone, lung, colorectal, liver, stomach and female breast cancers—all of which are solid tumors—claimed nearly 5 million lives globally.

There are two reasons. Blood-cancer cells often provide unique targets for therapies, while solid cancers do not. They also float freely in the vascular system, making them relatively accessible to treatment. Solid tumors are more difficult to access, and are often contained in a microenvironment that dampens the body’s immune response.

Despite these challenges, Aiman Shalabi, vice president R&D, cell and gene therapies at GlaxoSmithKline, says cell therapy for solid tumors is on the way.

Shalabi has nearly 25 years experience in developing drugs for cancer. While he is bullish on T-cell therapies for solid cancers, he also acknowledges that it could take another three to five years to reach an inflection point. To build on the initial progress he says, scientists must identify adequate targets and ensure that T cells remain active when engaging with a tumor. Both obstacles remain difficult, but new research hints at a path forward. 

Finding the tumor

The success of any cell therapy largely depends on its affinity for a specific molecular target expressed by a cancer. One class of tumor targets is called tumor-associated antigens, or TAAs. Both CAR-T cells and TCR-T cells can be engineered to hunt and eliminate cells with specific TAAs, though they do so in slightly different ways. CAR-T cells most frequently recognize TAAs naturally expressed on the cell surface, which are accessible targets. TCR-T cells recognize targets from inside the cells presented by a cell’s human leukocyte antigen (HLA) system. That system displays TAA peptides from inside the cell on its surface, like a lifeguard waving a flag.

While TAAs are often expressed at high levels in solid tumors, researchers have found that they are frequently expressed at low levels in non-cancerous cells, too. That has left researchers to track down targets that are only specific to tumors, not healthy cells. One target gaining favor is NY-ESO-1, which stands for New York esophageal squamous cell carcinoma 1. NY-ESO-1 is expressed in a number of different solid cancers, but according to Neeta Somaiah, a medical expert in sarcomas at The University of Texas MD Anderson Cancer Center, it is rarely expressed in healthy cells.

Though NY-ESO-1 has been considered a unique cancer target for more than 20 years—and many studies have been conducted to validate that view—Shalabi says the challenge has been that no one could develop an agent that could access this target and show a biological impact. 

That’s now changed, and scientists understand why. According to Somaiah, who recently worked on a GSK-sponsored study for treating advanced synovial sarcoma, no one had fully considered the role of the human leukocyte antigen (HLA). Typically, for a TCR to recognize a target it must recognize the combination of tumor antigen and HLA. But there are many possible antigen fragments and a variety of HLA subtypes, making for many combinations.

Until recently, researchers had only investigated one combination, as relates to NY-ESO-1. Scientists, including Somaiah, are now working to isolate T cells with TCRs that recognize different configurations of NY-ESO-1 and the HLA system. Researchers have also engineered TCR-T cells that can access NY-ESO-1. Either line of inquiry—or both—could one day lead to TCR-T cell therapeutics for solid cancers.

Surviving in the tumor

Finding a unique target in a solid tumor is only half of the battle. Once T cells reach a tumor, whether CAR-T or TCR-T cells, they have a tendency to simply stop working, a condition called T-cell exhaustion.

The reasons for T cell exhaustion remain unclear, but scientists keep learning more about the process. For instance, one team of scientists recently revealed a long list of molecules on the cell’s surface that correlate with exhaustion. That seems to indicate the phenomenon is more complex than previously imagined.

“We’re now realizing that exhaustion isn’t a single state,” says Rick Klausner, founder and board chair of Lyell Immunopharma in San Francisco.

Also, T cells appear to have multiple routes that lead to exhaustion. Scientists at the University of Pennsylvania’s Perelman School of Medicine found four stages of exhaustion, with only one of them being terminally inactivated. The scientists also found that a higher number of inhibitory receptors on the surface of these cells correlated with lower function. Klausner and others are exploring ways to block those receptors to keep T cells active.

That’s not the only approach that might keep T cells active when engaging with solid tumors. Regulatory T cells (Tregs) could provide another target. Those cells inhibit the activity of other T cells. During T cell-based treatments, some molecular pathways attract Tregs to tumors, which could play a part in T-cell exhaustion. A team of scientists from several biotechnology companies, including Lyell, blocked part of that pathway, decreasing the number of Tregs near the tumor. That could increase the impact of T cell-based treatment.

While the impact of this more foundational science could take time to translate from the bench to the bedside, Shalabi says the ultimate goal is clear, and is coming: “We want more soldiers trained to kill foreign objects, like cancer. We want them living longer. And we want them to kill cancer for a very long time.”