Mesothelioma is a rare cancer that affects the tissue that lines many organs of the body. Approximately 30,000 cases are diagnosed every year worldwide, most of them in the pleura, or lining of the lungs. It occurs most often in people who have been exposed to asbestos.

"Mesothelioma is a difficult tumor to treat," said the study's lead author Joshua Reuss, MD, a thoracic medical oncologist with Georgetown's Lombardi Comprehensive Cancer Center. "Our study demonstrated the feasibility and safety of using immunotherapy before surgery for patients who have tumors that can potentially be removed surgically.

"Immunotherapy is making substantial contributions to extending the lives of patients with lung cancer and many other solid tumors. This is an important step in identifying mesothelioma patients who could benefit from immunotherapy in the perioperative period, meaning right before or after their surgery and in choosing patients who are actually candidates for that surgery," said Reuss, who is also an attending physician at MedStar Georgetown University Hospital.

Reuss designed the clinical trial during fellowship training at the Johns Hopkins Kimmel Cancer Center, the primary site where the study was conducted. He presented the results of the phase II study, Neoadjuvant Nivolumab or Nivolumab plus Ipililumab in Resectable Diffuse Pleural Mesothelioma, at the 2025 World Conference on Lung Cancer in Barcelona, Spain on September 8 and is lead author of the study published concurrently in the journal Nature Medicine (DOI 10.1038/s41591-025-03958-3).

Phase II clinical trials are designed to assess whether it is possible to deliver innovative treatments to specific patient populations, and whether the potential benefits of the therapy outweigh any adverse effects that patients experience.

"When looking at patient outcomes to date, the issue of whether any mesothelioma is truly resectable is controversial," said Reuss. "Several major studies have not shown improvement in survival when surgery is incorporated into systemic therapy for mesothelioma. This study incorporates immunotherapy into the treatment of patients who might benefit from surgery.

"Since they occur in the tissue that lines the lungs, mesotheliomas don't grow and spread like other cancers." Reuss said. "They don't typically form solid masses or nodules. These tumors are more fluid, or diffuse throughout the lining of the lung. That makes it more difficult to use our usual methods to determine how extensive a tumor is or to measure whether a treatment is effective by standard imaging assessments."

In this study, the clinical team worked closely with scientists in the laboratory to test a novel approach studying circulating tumor DNA (ctDNA) in their patient's blood. Tumors frequently shed cancer DNA into the blood stream. Oncologists can test the blood to detect the presence of this ctDNA, but their role in clinical decision-making is an evolving area of interest. This is particularly challenging in mesothelioma, a tumor type that has a low number of cancer mutations that can be detected by traditional ctDNA techniques.

"Imaging doesn't always capture what's happening with mesothelioma, especially during treatment," said the study's senior author, Valsamo Anagnostou, MD, PhD, the Alex Grass professor of oncology and co-director of the upper aerodigestive cancers program at Johns Hopkins. "By using an ultra-sensitive genome-wide ctDNA sequencing method, we were able to detect microscopic signs of cancer that imaging missed and predict which patients were most likely to benefit from treatment or experience relapse."

"This approach may give us a baseline to monitor the efficacy of that treatment," Reuss said. "If the ctDNA decreases or disappears, it is a good indication that the therapy is working, If not, it indicates a change in therapy may be warranted." Reuss added that further validation of this methodology is required before it can routinely be incorporated into clinical practice.

"These analyses contribute to our understanding of which patients with mesothelioma may be candidates for surgery," Reuss said. "Up until now, ctDNA assessments have not been part of the clinical landscape in the management of diffuse pleural mesothelioma, but our analyses suggest this may be nearing a change in the future."

Phase II clinical trials are not designed to measure the clinical efficacy of treatment options but both arms of this trial showed improvements in the time from treatment to when the tumors began to grow again and overall length of survival.

Reuss cautions against drawing conclusions about that data, but notes that the results do provide positive signals about the potential value of neoadjuvant immunotherapy for mesothelioma patients with tumors that can be surgically removed and point the way to future studies.

"This is a small study," he said, "and it does not tell us whether neoadjuvant immunotherapy will improve outcomes for these patients, but it does open windows of opportunity. We need to take what we learned and do further studies, dig deeper so that we can develop better therapies for patients with mesothelioma."

The study was conducted across multiple academic cancer centers. The trial was sponsored by Bristol Myers Squibb. The research was supported in part by the Department of Defense Congressionally Directed Medical Research Programs grant CA190755, the Johns Hopkins Kimmel Cancer Center NCI Support Grant NCI CCSG P30 CA006973, the US Food and Drug Administration grant U01FD005942-FDA, National Institutes of Health grant CA1211113, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center Grant UG1CA233259, the Robyn Adler Fellowship Award, the Commonwealth Foundation, the Mark Foundation for Cancer Research, and the Florence Lomax Eley Fund.

Reuss reports receives research funding through Georgetown University from Genentech/Roche, Verastem, Nuvalent, Arcus, Revolution Medicines, Regeneron, Amgen, DualityBio, and AstraZeneca, and serves in a consultant/advisory role for AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Seagen, Gilead, Janssen, Novocure, Regeneron, Summit Therapeutics, Pfizer, Lilly, Natera, Merck, EMD Serono, Roche Diagnostics, and OncoHost. Anagnostou reports receiving research funding from Astra Zeneca and Personal Genome Diagnostics, Bristol-Myers Squibb, and Delfi Diagnostics, is an advisor to Astra Zeneca and Neogenomics and receives honoraria from Foundation Medicine, Guardant Health, Roche and Personal Genome Diagnostics. Other author disclosures are included in the manuscript.

Additional authors include Paul K. Lee, Reza J. Mehran, Chen Hu, Suqi Ke, Amna Jamali, Mimi Najjar, Noushin Niknafs, Jaime Wehr, Ezgi Oner, Qiong Meng, Gavin Pereira, Samira Hosseini-Nami, Mark Sausen, Marianna Zahurak, Richard J. Battafarano, Russell K. Hales, Joseph Friedberg, Boris Sepesi, Julie S. Deutsch, Tricia Cottrell, Janis Taube, Peter B. Illei, Kellie N. Smith, Drew M. Pardoll, Anne S. Tsao, Julie R. Brahmer, and Patrick M. Forde.

Published online August 19 in JACC-CardioOncology, the study showed that peripheral ischemia-restricted blood flow in the arteries in the legs-caused breast tumors in mice to grow at double the rate seen in mice without restricted flow. These findings build on a 2020 study from the same team that found ischemia during a heart attack to have the same effect.

Ischemia occurs when fatty deposits, such as cholesterol, accumulate in artery walls, leading to inflammation and clotting that restrict the flow of oxygen-rich blood. When this happens in the legs, it causes peripheral artery disease, which affects millions of Americans, and can increase the risk of heart attack or stroke.

"Our study shows that impaired blood flow drives cancer growth regardless of where it happens in the body," says corresponding author Kathryn J. Moore, PhD, the Jean and David Blechman Professor of Cardiology in the Department of Medicine, Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine. "This link between peripheral artery disease and breast cancer growth underscores the critical importance of addressing metabolic and vascular risk factors as part of a comprehensive cancer treatment strategy."

Importantly, the research team found that restricted blood flow triggers a shift toward immune cell populations that cannot efficiently fight infections and cancer, mirroring changes seen with aging.

Systemic Skewing

To examine the mechanisms behind the link between cardiovascular disease and cancer growth, the study authors developed a mouse model with breast tumors and induced temporary ischemia in one hind limb. The team then compared cancer growth in mice with and without impaired blood flow.

Their findings build on the nature of the immune system, which evolved to attack invading bacteria and viruses, and under normal conditions, to detect and eliminate cancer cells. These protective functions rely on stem cell reserves in the bone marrow, which can be activated as needed to produce key white blood cell populations throughout life.

Normally, the immune system responds to injury or infection by ramping up inflammation to eliminate threats, then scaling back to avoid harm to healthy tissue. This balance is maintained by a mix of immune cells that either activate or suppress inflammation. The researchers found that reduced blood flow disrupts this equilibrium. It reprograms stem cells in the bone marrow to favor the production of "myeloid" immune cells (monocytes, macrophages, neutrophils) that dampen immune responses, while reducing output of lymphocytes like T cells that help to mount strong anti-tumor responses.

The local environment within tumors showed a similar shift, accumulating more immune-suppressive cells- including Ly6Chi monocytes, M2-like F4/80+ MHCIIlo macrophages, and regulatory T cells - that shield cancer from immune attack.

Further experiments showed that these immune changes were long-lasting. Ischemia not only altered the expression of hundreds of genes, shifting immune cells into a more cancer-tolerant state, but also reorganized the structure of chromatin-the protein scaffolding that controls access to DNA-making it harder for immune cells to activate genes involved in fighting cancer.

"Our results reveal a direct mechanism by which ischemia drives cancer growth, reprogramming stem cells in ways that resemble aging and promote immune tolerance," says first author Alexandra Newman, PhD, a postdoctoral scholar in Dr. Moore's lab. "These findings open the door to new strategies in cancer prevention and treatment, like earlier cancer screening for patients with peripheral artery disease and using inflammation-modulating therapies to counter these effects."

Moving forward, the research team hopes to help design clinical studies that evaluate whether existing inflammation-targeted therapies can counter post-ischemic changes driving tumor growth.

Along with Drs. Newman and Moore, study authors from the Cardiovascular Research Center and the Leon H. Charney Division of Cardiology, both within the Department of Medicine at the NYU Grossman School of Medicine, were Jose Gabriel Barcia Duran, Richard Von Itter, Jessie Dalman, Brian Lim, Morgane Gourvest, Tarik Zahr, Kristin Wang, Tracy Zhang, Noah Albarracin, Whitney Rubin, Fazli K. Bozal, Chiara Giannarelli, Michael Gildea, and Coen van Solingen. Also an author was Kory Lavine of the Department of Pathology and Immunology at Washington University School of Medicine, Saint Louis.

The study was supported by American Heart Association grants 915560, 25CDA1437452, 23POST1029885, 25PRE1373174, and 23SCEFIA1153739; as well as by National Institutes of Health grants T32GM136542, F30HL167568, T32HL098129; R01 HL151078, R01 HL161185, R35 HL161185, R01HL153712, R01HL172335, R01HL172365, and P01HL131481. The work was also supported by the Sarnoff Cardiovascular Research Foundation, the LeDucq Foundation Network, and Laura and Isaac Perlmutter Cancer Center support grant P30CA016087.