Immunotherapy Potential Option in Mesothelioma Treatment

Steven A. Rosenberg, MD, PhD

In malignancies with limited response rates to existing radiation and/or chemotherapy, immunotherapy is being investigated as a potential adjunct, with promising results, particularly in the treatment of malignant mesothelioma.

Malignant mesothelioma is a malignancy of mesothelial cells that line the lungs, heart, peritoneum, and other surfaces. According to the American Cancer Society, approximately 3000 new cases are diagnosed each year.¹The most common site for this tumor is the pleural surface lining the lungs, which has historically been associated with asbestos exposure. This form of malignant mesothelioma is an aggressive and often fatal disease because of its advanced stage at diagnosis. Even with treatment, most patients do not survive beyond 2 years from diagnosis.

The approved treatments available for malignant mesothelioma include surgery for early-stage disease, chemotherapy, and radiation. Despite these treatments, the prognosis remains poor. However, with the advent of gene therapy against solid tumors, a different route of attacking the malignant cells is being investigated.

Steven A. Rosenberg, MD, PhD, of the National Institutes of Health, is one of the pioneers and lead researchers in the use of gene and immunotherapy against solid tumors. “The sporadic mutations that occur within the cancer, if we can attack immunologically those mutations, we can have a highly specific and highly sensitive approach to cancer treatment,” Rosenberg said.

One of the therapies Rosenberg researches is adoptive cell transfer (ACT), a specific form of immunotherapy that involves isolating tumor infiltrating T lymphocytes and manipulating them in cell culture. These cells are altered to target the malignant cells and are infused into the patient at high concentrations. Early results in solid cancers such as melanoma and lymphoma are promising. The limitation of ACT using tumor infiltrating T lymphocytes, however, is that not all solid tumors have sufficient quantities of the cells.

A form of ACT using chimeric antigen receptors on T cells is being examined in phase I studies in the treatment of mesothelioma and other solid tumors at the Abramson Cancer Center of the University of Pennsylvania, Philadelphia. Chimeric antigen receptors are designed to recognize an altered form of a protein called mesothelin found on malignant mesothelioma cells. After introduction into the patient’s immune system, these genetically engineered T cells can then identify and destroy malignant cells by targeting mesothelin, eventually initiating programmed cell death.

Another form of immunotherapy manipulates key checkpoint inhibitors of the immune system. The immune system has negative and positive regulatory pathways to ensure the proper balance of immune surveillance. T cells play a crucial role in maintaining this balance, with disease states occurring when they are both overactive and underactive.

Further explaining the role of T cells in immune surveillance, Prasad S. Adusumilli, MD, of Memorial Sloan Kettering Cancer Center in New York City, stated in an interview with theLos Angeles Times, “The moment T cells go there, they see the enemy—the cancer cell—they activate themselves and they activate other T cells, and they proliferate.”

Building on this premise, researchers are investigating therapies directed against a specific protein found on the surface of T cells, called cytotoxic T-lymphocyte antigen-4 (CTLA-4). One mechanism by which cancer cells escape immune surveillance is by upregulating CTLA-4. This ultimately results in negative regulatory signals to the immune system, allowing the cancer cells to proliferate undetected. Therapies designed to block CTLA-4 would interfere with this process and enable the cytotoxic T cells to remain activated and therefore able to destroy the malignant cells.

Clinical Pearls

• Immunotherapy uses the body’s immune system to recognize and destroy cancer cells, particularly in malignancies such as malignant mesothelioma, which has limited response rates to existing radiation or chemotherapy treatments.
• Adoptive cell transfer (ACT) is a specific form of immunotherapy that involves isolating tumor infiltrating T lymphocytes and manipulating them in cell culture to target the malignant cells; they are then infused into the patient at high concentrations.
• A form of ACT using chimeric antigen receptors on T cells is being examined in phase I studies.
• Tremelimumab, a monoclonal antibody directed against CTLA-4 (a T-cell surface protein), is the focus of phase II clinical trials for malignant mesothelioma.
• Although immunotherapy provides a novel targeted approach in the treatment of malignant mesothelioma, long-term studies will address questions about its ability to affect the prognosis in an already aggressively fatal disease.

One such therapy is a monoclonal antibody, tremelimumab, now the focus of phase II clinical trials. In early studies, tremelimumab has already been shown to affect a radiologic response in some patients with advanced-stage mesothelioma.²Investigation of this drug continues in patients with unresectable disease.

Although immunotherapy provides a novel targeted approach in the treatment of malignant mesothelioma, questions remain about its ability to affect the prognosis in an already aggressively fatal disease. While long-term studies will likely provide the answers to these questions, there is no doubt that the use of genetically altered immune cells in cancer therapy is an exciting direction for future studies.

“[W]e’re no longer dependent on the body’s natural ability to raise an immune cell, we can create that cell outside the body,”³Rosenberg summarized.

References

1. Malignant mesothelioma. American Cancer Society.http://www.cancer.org/cancer/malignantmesothelioma/detailedguide/malignant-mesothelioma-key-statistics. Revised December 19, 2013. Accessed November 18, 2014.
2. Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.Lancet Oncol. 2013;14(11):1104-1111.
3. Steven Rosenberg, MD, PhD. YourCancerToday.com. https://www.youtube.com/watch?v=6_VFTP0yyuY. Accessed November 21, 2014.