Lung Cancer

Lung cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on lung cancer and immunotherapy clinical trials for lung cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to lung cancer patients.

Lung cancer is the most common cause of cancer mortality globally, representing 13% of all cancer diagnoses each year and nearly 1 in 5 cancer-related deaths. The majority of lung cancer patients present with advanced disease (stage IIIb/IV) and are, for the most part, not eligible for current curative treatments. For these patients, the overall 5-year survival rate is 12% to 15% and palliative treatment is the only option. Even for those who are eligible, current lung cancer treatments, including surgery, chemotherapy, and radiotherapy, can place a heavy burden on patients. Immunotherapy offers promising treatment alternatives that may help fight disease without significantly harming quality of life. New treatment options that can harness the immune system to fight lung cancer are the subject of ongoing research funded by the Cancer Research Institute.

 

Brief Statistics

• Lung cancer is the leading cause of cancer-related deaths in men and women worldwide. In the United States, lung cancer comprises 14% of cancer diagnoses and 30% of cancer deaths. There are more deaths due to lung cancer every year than breast, prostate, and colon cancers combined.

• Globally, 1.61 million lung cancer diagnoses were made in 2012 and 1.38 million deaths occurred. In the United States last year, 226,160 new cases of lung cancer were diagnosed and 160,340 people died.

• The two major forms of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC comprises approximately 80% of all lung cancers.

• Survival rates vary greatly with timing of detection and the type of lung cancer. For all stages combined, the five-year survival rate is 16%—17% for NSCLC and 6% for SCLC. If the cancer is discovered before it has spread (metastasized), the 5-year survival rate is more than 50%. However, only 15% of lung cancers are discovered at this stage.

 

Detection and Diagnosis

• Cigarette smoking remains the most significant risk factor for the disease. Tobacco use accounts for approximately 80% of all lung cancers in the United States and 71% globally. Pipe and cigar smoking have been associated with higher risk, as have exposure to asbestos, secondhand smoke, radiation, and air pollution, among other factors.
• It is difficult to detect lung cancer at an early stage. Studies have shown that yearly screenings with a chest X-ray are not effective in reducing mortalities. Newer tests—including low-dose spiral CT scans—show promise in identifying lung cancer early in individuals with a history of heavy smoking. More time is needed, however, for a full evaluation of the benefits and limitations of these tests—particularly with regard to lower-risk individuals.
• Symptoms may entail voice change, persistent cough, chest pain, recurring bronchitis or pneumonia, and/or blood-streaked sputum.

 

Promising Advances in Research and Treatment and CRI Impact

Several approaches to immunotherapy for lung cancer have shown promise in early clinical trials and have advanced to late-phase development. Although treatments for non-small cell lung cancer have advanced the farthest, a number of new immune-based treatments for small cell lung cancer, as well as for mesothelioma, are also in clinical development.

These include therapeutic vaccines that target shared or tumor-specific antigens, including the cancer/testis antigens MAGE-3, which is expressed in 42% of lung cancers, and NY-ESO-1, which is expressed in 30% of lung cancers, p53, which is mutated in approximately 50% of lung cancers, survivin, and MUC1.

A therapeutic vaccine targeting MAGE-A3, GSK1572932A, is currently being tested in a pivotal phase III trial that will determine whether or not the treatment successfully delays or prevents lung cancer recurrence among patients with stage Ib, II, or IIIa non-small cell lung cancer that has been completely removed by surgery. The first clinical results of vaccination with MAGE-A3 were reported in 2004 by investigators in the CRI/Ludwig Cancer Vaccine Collaborative [1]. This study provided critical data leading to the licensing of MAGE-A3 by GlaxoSmithKline in 2006 and the company’s launch in 2007 of its MAGE-A3 therapeutic vaccine phase III clinical trial for patients with lung cancer, the largest clinical trial ever conducted in the disease.

CVC clinical investigators have also shown promising results in lung cancer patients with vaccines targeting the NY-ESO-1 antigen. In a phase I clinical trial in Japan of a NY-ESO-1 vaccine completed in 2011, the treatment achieved integrated immune responses in nine of the ten patients treated, and two patients with lung cancer and one patient with esophageal cancer showed stable disease [2].

(Slide shows expression of NY-ESO-1 in lung cancer, highlighted by antibody staining. Benign stromal cells and tumor infiltrating lymphocytes in between the clusters of tumor cells do not express NY-ESO-1. Image courtesy of Yao-Tseng Chen.)

Other antigen-based immunotherapies in late-phase clinical trials for lung cancer include:

• Belagenpumatucel-L (Lucanix™) for patients with stage III and IV non-small cell lung cancer, a phase III trial of which will be completed shortly.
• GV1001, which targets the hTERT (human telomerase reverse transcriptase) subunit of telomerase, which is highly expressed in nearly all cancers but restricted in normal tissues, which will begin enrolling patients with inoperable stage III non-small cell lung cancer shortly.
• TG4010, which targets the MUC1 antigen and is currently recruiting patients with stage IV non-small cell lung cancer.
• INGN, a dendritic cell-based vaccine targeting p53 that is currently recruiting patients with extensive stage small cell lung cancer.
• A vaccine targeting the WT1 antigen, which is in a randomized phase II trial for patients with mesothelioma after completing surgery and chemotherapy and/or radiation.
• Trovax®, which targets the 5T4 protein widely found on mesothelioma cells, which will being enrolling patients in a phase II trial soon.

Another promising avenue of clinical research in lung cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash and/or enhance pre-existing anti-cancer immune responses.

• Ipilimumab (Yervoy™), which targets the CTLA-4 checkpoint molecule on activated immune cells, has been at the vanguard of this new immunotherapy approach. First tested by James P. Allison, Ph.D., the director of CRI’s Scientific Advisory Council, ipilimumab was the first treatment ever proven to extend survival in patients with metastatic melanoma, the most deadly form of skin cancer, and was approved for that indication in 2011. Based on promising results from a phase II trial, it is now being tested in phase III trials for non-small cell lung cancer and for small cell lung cancer.
• Nivolumab (BMS-936558) is an antibody targeting the PD-1 checkpoint molecule. Based on promising results from a phase I clinical trial completed in 2012 [3], the drug’s manufacturer, Bristol-Myers Squibb, has launched phase III trials of the agent in several cancers, including in non-squamous cell and squamous cell non-small cell lung cancers.
• Tremelimumab, another antibody targeting the CTLA-4 molecule, is undergoing testing in two phase II clinical trials for patients with mesothelioma (NCT01655888 and NCT01649024).

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for lung cancer that are currently enrolling patients. For more information about lung cancer immunotherapies in late-stage development see our page on the Cancer Immunotherapy Pipeline.

CRI and Lung Cancer Immunotherapy

CRI discoveries and ongoing work in lung cancer research and treatment also include:

• Through the CRI/Ludwig Cancer Antigen Discovery Collaborative, CRI investigators identified the antigen XAGE-1b as a promising target for lung cancer immunotherapy. XAGE-1b is a cancer/testis antigen expressed in 35 to 50 percent of lung cancers but not in adjacent healthy tissue. With a grant to Leiden University Medical Center, investigators Cornelis Melief, M.D., Ph.D., and Sjoerd van der Burg, Ph.D., are manufacturing XAGE-1b synthetic long peptides for therapeutic lung cancer vaccines to be conducted through the CRI/Ludwig Cancer Vaccine Collaborative.

• In related work, using designated grant funds from CRI, Eiichi Nakayama, M.D., a CVC investigator at Kawasaki University of Medical Welfare in Okayama, Japan, is analyzing spontaneous immune responses to XAGE-1b in non-small cell lung cancer patients. Dr. Nakayama’s studies will focus on characterizing the immune responses generated against XAGE-1b and ways to optimize it. Through these studies, Dr. Nakayama aims to identify fragments of the XAGE-1b that elicit the strongest immune responses, analysis of which will inform the best approaches to targeting XAGE-1b in therapeutic vaccines for lung cancer.

• Emily Conn Gantman, a CRI predoctoral student at The Rockefeller University, is studying the immune response in patients fighting lung cancer. Her research focuses on a unique population of small cell lung cancer patients that have a strong immune reaction to nervous system proteins that are being made in their lung tumors. Because these proteins are out of place in the cancerous tissue, the immune system is triggered to fight and kill the tumor cells. These patients display better outcomes with their lung cancer treatments than patients lacking this tumor immune response. Unfortunately, the link with the nervous system also results in an immune attack of neurons resulting in a devastating neurologic disease. Emily’s research aims to learn from these patients how to harness the power of the tumor immune response to improve available treatments, while fighting the dangerous autoimmune disorder.

• Erika Duan, a CRI predoctoral student at the Ludwig Institute for Cancer Research in Melbourne, Australia, is studying the conditions that regulate immune homeostasis in the lung. These conditions are tightly regulated to avoid either inadequate or excessive inflammation, with immune cells called macrophages playing a key role in maintaining this homeostasis. Through her CRI predoctoral award, Erika is studying how these lung macrophages regulate lung immune homeostasis, and how disruptions in their function promote epithelial cell hyperproliferation, an important initiating event of lung cancer. Through this work to understand lung immunity, Erika hopes to help pave the way to discovering better immunotherapy agents targeting this unique and complex microenvironment.

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A lung from a SHIP-1 knockout mouse shows increased infiltration of macrophages, a type of immune cell, into regions of lung epithelial hyperproliferation, the earliest cell change predisposing to lung cancer. Understanding these macrophages is important because they are thought to play a role in initiating and promoting hyperproliferation, as well as in suppressing the surrounding immune microenvironment, thereby preventing effective anti-lung cancer immunotherapy. (Photo courtesy of E. Duan)

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• The connective tissue, or stroma, in the tumor microenvironment plays a key role in suppressing the immune response to cancer. CRI postdoctoral fellow James N. Arnold, D.Phil., and others at the University of Cambridge showed that blocking cells expressing fibroblast activation protein alpha (FAP), a stromal cell type that was first identified in human cancers, facilitated immunologic control of tumors in models of lung and pancreatic cancer. Additional studies into the mechanisms of these responses suggest that strategies to interfere with the effects of FAP-expressing cells on T cells could complement current immunotherapies like anti-CTLA-4 antibodies to enhance the immune response against cancer.