On Target is a recurring feature from STAT that dives deep into the most promising drug targets in oncology. This column is adapted from a new STAT report, “Targeting cancer: the new frontier of immunotherapy and precision oncology.”
Scientists working to produce immunotherapies for solid tumor cancers have spent decades searching for biological targets that can help them distinguish between healthy cells and cancerous ones. Finding such biomarkers is critical to developing treatments that can kill the cancer without also killing the patient.
But so far, researchers have only identified a few proteins that meet that requirement. One of the most promising is mesothelin or MSLN, a protein found in certain cancers, including ovarian and pancreatic cancers and some mesotheliomas. Mesothelin is also found in some healthy membrane tissues, like the mesothelium of the pleura and peritoneum, meaning that therapies that target mesothelin would attack those tissues, as well.
But patients can survive without these membranes, and scientists believe any damage they might suffer from the therapy isn’t critical as long as the therapy also destroys or beats back the cancer.
The abundance of mesothelin on various solid tumor cancers leads some researchers to believe that the protein might be key to getting cell therapies and bispecific antibodies — which can bind to two different antigens— to work. And, as STAT’s latest report, “Targeting cancer: the new frontier of immunotherapy and precision oncology,” explains, there are now several cancer immunotherapies and precision therapies that use mesothelin to target cancer being developed by companies like Atara Biotherapeutics and Lonza.
“Every investigator has their favorite antigen they’re going after,” said Kristin Anderson, a cell therapy researcher at the Fred Hutchinson Cancer Center. “I’m excited about [mesothelin] because it’s overexpressed in 75% to 80% of high-grade ovarian cancer patients. It’s a high-priority antigen for me and my team to work on.”
Ira Pastan, a cell biologist and immunologist at the National Institutes of Health, and his colleagues discovered mesothelin in the 1990s. Their original goal was to find out what gave a cancer cell its molecular identity. Pathologists peering down their microscopes can tell from the shape and organization of tissues not only whether they’re malignant but whether the cells are breast, lung, pancreatic or another type of cancer.
Researchers, including Pastan, believed there must be something in a cancer cell, like an embedded protein, that set it apart from other cells. “Something that says, ‘I’m a breast cancer cell. Look at me,’” Pastan said. And if there were, he added, then you should be able to create drugs and therapies that would target that protein and use it to mark cancer cells for death.
So Pastan started looking for therapeutic targets in cancers that arose in organs that are sometimes removed as part of surgical treatment. If they did hit upon some proteins that were potential targets, the toxicity might be limited to organs that are not necessary to sustain life, like the prostate or ovaries.
To look for antigens, Pastan injected a tumor into mice, then looked for antibodies on the surface of the cancer cells that reacted. “We looked in ovary, breast, prostate, and found candidates in all three, but the only one that panned out was immunizing mice with ovarian cancer. That target turned out to be mesothelin,” Pastan said.
Pastan and his colleagues then found that mesothelin was a cell surface protein and that it was only present on certain membranes in the body. “It’s not in the liver, the brain, the stomach. It had a pretty limited distribution on normal tissue,” he said. “That’s how we discovered it. Then we showed it was present in many other cancers: almost all pancreatic cancers, most ovarian cancers, and mesothelioma.”
It’s not yet clear what mesothelin’s role is either in normal biology or in cancer. Pastan and his colleagues created mesothelin “knockout” mice, mice without the gene allowing them to create mesothelin. Breaking a gene in an animal model is a classic experiment in biology, since it might cause physical defects in the mice that offers clues to the gene’s function. For instance, knocking out a gene important to eye formation might lead to blind mice. But in this case, the knockout mice seemed totally normal.
“They breed fine. They lived to a normal age. Their immune system is OK,” Pastan said. “We could never find any major defects.” He said he found the result both exciting and disappointing. On the one hand, it made it much more difficult to elucidate mesothelin’s role in biology, but on the other hand it meant that targeting the protein might not lead to any untoward side effects. Since then, researchers have found that mesothelin tends to be most highly expressed in the aggressively growing edges of a tumor. That study, and other experiments, suggest that mesothelin might be important in cancer growth and metastasis.
In one experiment, Christine Alewine at the NIH wanted to see what would happen to a certain type of pancreatic cancer cell that could not express mesothelin. She found that cancers that could not create mesothelin seemed to metastasize and grow more slowly than the cancers that could make the protein. Alewine also studied a specific pancreatic cancer cell line created in lab experiments that was more aggressive, and found that it had increased expression of mesothelin.
Critically, Alewine and her colleagues also saw that mesothelin only seemed to help the cancer grow and metastasize early in the course of disease. In her experiments, mesothelin expression seemed to be related to the formation of new blood vessels that can help shuttle in nutrients that the cancer needs to grow or metastasize. But once the tumor or metastasis was established, mesothelin seemed to provide no further benefit to the cancer.
“Our data show that MSLN confers this growth advantage to pancreatic tumor cells within the first 7 days of metastatic colonization by increasing microvasculature, proliferation, and invasion,” she wrote in May 2021 in the journal Molecular Cancer Research. But after that, the growth advantage is not seen. So blocking MSLN would be unlikely to shrink or cure established metastases.
As a result, companies that are targeting mesothelin are for the most part not seeking to block the action of the protein. Instead, they are seeking to use mesothelin as a way to mark cells for death. One way is by using engineered immune cells like CAR-T cells that are designed to kill any cell in the body carrying mesothelin. That’s an approach that scientists at Atara Biotherapeutics and Memorial Sloan Kettering are taking.
“We’ve been working on mesothelin for 12 years now,” said Prasad Adusumilli, a cell biologist at Sloan Kettering and the lead researcher on the study.
In the past, CAR-T therapies targeting mesothelin had been shown to be safe but with limited efficacy. CAR-T therapies in general have been disappointing as treatments for solid tumors, for many reasons. These reasons include the fact that solid tumors create a microenvironment that’s hostile to immune cells, and possibly physiological barriers that prevent efficient migration of CAR-T cells and other immune cells to the tumor.
But Adusumilli is combining the CAR-T therapy with another immunotherapy called checkpoint blockade, which works by releasing a natural brake on the immune system, causing it to become more active. By following a mesothelin-targeted CAR-T therapy with one of these drugs in clinical trials, Adusumilli is hoping that might provide just the extra boost the immune system may need to more effectively fight the cancer.
It’s still too early to draw any conclusions from the results, Adusumilli said, but so far the data have been encouraging. “As a researcher, it’s a great privilege to care for the patients. When you see the response, we go through waves of emotion. Is it a fluke? Is it transient?” he said. “But the best thing in the clinical trials has been the patient’s weight. They gain weight for hundreds of days.”
Previous On Target columns explored claudin-6, TGF-beta, and immune checkpoint inhibitors.