There are four main types of mesothelioma immunotherapy in development. These include checkpoint inhibitors, monoclonal antibodies, therapeutic vaccines, and adoptive cell therapy.
Also known as biotherapy, immunotherapy is exactly what its name implies – treatment that uses parts of the immune system to fight diseases such as cancer. Recent advances in immunotherapy have proven useful in the treatment of a number of different cancers, though immunotherapy still plays a fairly minimal role in cancer treatment. For mesothelioma patients, it is only an option in clinical trials.
In the process of determining whether a cell is foreign or normal, immune cells need their specific molecules on their surface – known as “checkpoints” – to be activated or inactivated to trigger the immune response. One of these molecules is a protein called PD-1. When PD-1 on the immune cell interacts with PD-L1 a protein on the normal cell, PD-1 is inactivated and the immune cell knows not to attack the cell. Since some cancer cells can have many PD-L1 proteins on their surface, they can avoid being attacked by the immune system.
Checkpoint inhibitors can help increase the immune response to cancer cells by binding to PD-1 or PD-L1 to prevent them from binding to each other. As a result, immune cells will attack the cancer cells, because the checkpoint is blocked (inhibited). In 2015, the FDA approved PD-1 checkpoint inhibitor nivolumab (Opdivo) for treatment of non-small cell lung cancer. Other checkpoint inhibitors (Keytruda, Tecentriq) have been approved for other cancers, and Keytruda is currently being tested as a mesothelioma treatment.
Monoclonal antibodies are designed to target specific proteins or processes involved in tumor development, maintenance and/or progression. Two have been FDA approved to treat lung cancer. Bevacizumab (Avastin) blocks formation of new blood vessels that support the tumors and ramucirumab (Cyramza) blocks a protein that activates signaling pathways that support tumor vessel growth. Several others are currently being tested in clinical trials.
In recent studies, bevacizumab has also been shown to be useful in treating mesothelioma. In fact, the National Comprehensive Cancer Network – a network of 27 of the world’s leading cancer centers – recently updated their guidelines to include bevacizumab as part of a first-line treatment for nonresectable mesothelioma, in combination with chemotherapy.
Therapeutic vaccines invoke an immune response against tumor-specific antigens. For example, the most common targets for lung cancer are MAGE-3, a protein found in 42% of cases, NY-ESO-1 found in 30% and p53 which is mutated in 50% of cases. Survivin and MUC1 are also found in many lung cancer cases. Vaccines for lung cancer are in clinical trials. These include HyperAcute: a vaccine containing lung cancer cells with a mouse gene which stirs up an immune response. TG4010 targets MUC1 and was designed for patients with non-small lung cancers. DPV-001 was designed to target nine cancer antigens and includes an agent that activates toll-like receptors, proteins that contribute to the activation of the immune response.
Adoptive Cell Therapy
In adoptive cell therapy, specific immune cells called T cells are extracted from the patient, modified with chemicals or genetically and injected back into the patient. The modified cells are predicted to enhance the anticancer immune response. While this therapy is currently not FDA approved for lung cancer, several are in clinical trial. For example, one therapy involving the genetic alteration of T-cells so that they recognize NY-ESO-1 (a protein that is found in several lung cancer tumors) is currently in a phase II clinical trial (NCT01697527).