We have recently reported that an immunotoxin targeting mesothelin produced durable major tumor regressions in patients with extensive treatment-refractory mesothelioma. These unprecedented tumor responses have prompted us to review how mesothelin was discovered and the advances that led to these tumor responses. This review is not comprehensive but focuses on major developments over the past 20 years since mesothelin was first identified in our laboratory. Mesothelin is a cell-surface glycoprotein whose expression in normal human tissues is restricted to mesothelial cells. Because it is highly expressed by many solid tumors, it is an attractive immunotherapy target. Antibody-based therapies currently in clinical trials include an immunotoxin, a chimeric monoclonal antibody, and an antibody drug conjugate. In addition, a mesothelin tumor vaccine and a mesothelin- chimeric antigen receptor are being evaluated in the clinic. SS1P, an anti-mesothelin immunotoxin, was the first mesothelin-directed therapy to enter the clinic, and its use showed that mesothelin-targeted therapy was safe in patients. More importantly, our recent work has shown that SS1P in combination with pentostatin and cyclophosphamide can result in durable tumor regression in patients with advanced mesothelioma and opens up the possibility that such an approach can benefit patients with many common cancers. Cancer Res; 74(11); 1–6. ©2014 AACR.

Biomarker studies have shown that expression of the T cell co-regulatory ligand PD-L1 on tumor cells correlates with clinical responsiveness to the PD-1 antibody nivolumab. Here we report the findings of a preclinical cancer vaccine study demonstrating a similiar correlate where PD-L1 is upregulated in the tumor microenvironment. We formulated an IFNγ-inducing cancer vaccine called TEGVAX that combined GM-CSF and multiple toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic anti-tumor immunity. Unexpectedly, TEGVAX also upregulated PD-L1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PD-L1 upregulation in this setting relied upon IFNγ-expressing tumor-infiltrating CD4+ and CD8+ T cells and administration of a PD-1 blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFNγ inducing cancer vaccines with immune checkpoint blockade.

Curtiland Deville, MD, is an Assistant Professor and Chief of the Genitourinary and Sarcoma Services in the Department of Radiation Oncology. He has a research interest in assessing and improving diversity in the cancer physician workforce as a means to addressing health disparities. In this article, he discusses National Minority Cancer Awareness Week.

On April 8, 1987, the U.S. House of Representatives’ Joint Resolution 119 designated the full third week in April as National Minority Cancer Awareness Week. As explained in the Congressional Record, Resolution 119 drew attention to “an unfortunate, but extremely important fact about cancer. While cancer affects men and women of every age, race, ethnic background and economic class, the disease has a disproportionately severe impact on minorities and the economically disadvantaged.”

Why Diversity and Disparities Matter

Each year in the United States more than 1.6 million* people are diagnosed with cancer. Of those, racial and ethnic minorities are disproportionately affected. Although complex social, economic, and cultural factors may play a role, ultimately when considering and controlling for all of the above, racial and ethnic differences in outcomes still exist across the majority of cancers.

Source: American Cancer Society:*

• Although white women are more likely to be diagnosed with breast cancer, black women are more likely to die from breast cancer.
• Blacks are less likely to be screened for colorectal cancer and more likely to die from it.
• Hispanic women are less likely to be screened for and more likely to be diagnosed with and die from cervical cancer.
• Blacks are less likely to be diagnosed with lung cancer, but more likely to die from it, if diagnosed.
• Black men are more likely to be diagnosed with prostate cancer and twice as likely to die from it compared to white men.

The Abramson Cancer Center’s Office of Diversity

The Abramson Cancer Center joined CityLights Network and American Cancer Society at the Ezekiel Baptist Church in southwest Philadelphia for a free community education program about prostate and breast cancer. Left: Carey Davis, director of CityLights Network, Tom Henry, Brenda Bryant, senior research / outreach coordinator for the ACC Office of Diversity, Curtiland Deville, Jr., MD radiation oncologist and Carmen Guerra, MD, Penn physician.

The Abramson Cancer Center Office of Diversity was established in 2013 by the Abramson Cancer Center director, Dr. Chi Van Dang. The Abramson Cancer Center Office of Diversity supports the Abramson Cancer Center’s mission, vision and values by promoting diversity and inclusion as an integral part of the Center’s goals to understand, prevent, treat and cure cancer.

The Abramson Cancer Center’s Office of Diversity supports initiatives like the Minority Cancer Health Awareness Week seeking to raise the awareness of cancer health disparities.

Be sure to subscribe to our blog to learn more about cancer disparities research happening at Penn.

For more resources and information:

• http://www.cancer.org/cancer/news/cancer-disparities-key-statistics
• http://www.cancer.org/acs/groups/content/@midwest/documents/document/acspc-029979.pdf
• http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-033638.pdf
• http://jco.ascopubs.org/content/early/2011/08/01/JCO.2011.35.8903.full.pdf
• http://minorityhealth.hhs.gov/NMHM14/
• http://www.oncolink.org/resources/article.cfm?id=969
• http://www.penncancer.org/

Join Penn Medicine’s Abramson Cancer Center and 6ABC for a special one-hour live web chat featuring physicians from the Penn Mesothelioma and Pleural Program this Thursday May 1st from 4-5 pm at 6abc.com/pennmedicine.

Mesothelioma – Did you know?

Mesothelioma is a rare, incurable disease, with approximately 2,000–3,000 new cases diagnosed a year in the United States. Exposure to asbestos accounts for up to 80% of all cases. Mesothelioma is more common in men mostly due to occupational exposure to asbestos.

Veterans, miners, factory workers, and those working in the manufacturing or construction business are at a greater risk of developing mesothelioma due to asbestos exposure.

Mesothelioma Can Be Treated

A popular misconception is that mesothelioma is a disease that can’t be treated. Due to the complexity of this incurable disease, a true multidisciplinary approach is needed to ensure the best care available.

The Penn Mesothelioma and Pleural Program team has expertise in all types of treatment, including Lung-Sparing Surgery and Photodynamic Therapy, Immunotherapy, Proton Therapy, Radiation Therapy and Chemotherapy.

It is hard to find a group with the subspecialized experience as the team at Penn Medicine.Patients benefit from Penn Medicine’s ongoing research and our passion to eradicate this disease while providing the highest possible quality of life for each patient and their families as well.

Our Experts Answering Your Questions

Want to know more about:

• Mesothelioma symptoms?
• Is Screening available?
• Penn Medicine’s multidisciplinary approach?
• Cutting edge treatment options?
• New breakthrough clinical trials?
• How to improve quality of life after diagnosis?

The Penn Medicine Mesothelioma and Pleural Program brings together internationally renowned experts. Representing the full spectrum of the Penn Mesothelioma and Pleural Program are director Joseph S. Friedberg, MD, Chief of the Division of Thoracic Surgery and co-director  Daniel Sterman, MD, Director of Interventional Pulmonary Services, Evan W. Alley, MD, PhD Interim Chief of the Division of Hematology and Medical Oncology Hematology-Oncology and Charles B. Simone, MD an Assistant Professor of Radiation Oncology at the Hospital of the University of Pennsylvania.

These Penn Medicine experts will be answering user-submitted questions in a live online chat next Thursday May 1st, from 4 – 5pm.