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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 patients with this form of cancer.
Lung cancer is the most common cause of cancer mortality globally, responsible for nearly 1 in 5 cancer-related deaths, or an estimated 1.6 million people. In the U.S., lung cancer is by far the leading cause of cancer-related death among both men and women; more deaths are caused by lung cancer every year than by breast, prostate, and colon cancer combined.
Cigarette smoking remains the most significant risk factor for the disease, accounting for approximately 80% of all lung cancers.
The two major forms of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), so named because of how the tumor cells look under a microscope. NSCLC comprises approximately 85% of all lung cancers. Of these, the great majority are the non-squamous type of NSCLC, while a smaller fraction are the squamous type.
The majority of lung cancer patients are diagnosed with advanced disease (stage IIIb/IV). For these patients, conventional treatment options including surgery, chemotherapy, and radiation are unlikely to result in cure, although they may significantly improve survival and provide symptom relief. Patients with specific genetic mutations may benefit from targeted therapies such as the epidermal growth factor receptor (EGFR) blockers erlotinib (Tarceva®), afatinib (Gilotrif®), and gefitinib (Iressa®). These drugs block the signal from EGFR that tells cells to grow. They can be used to treat patients with certain mutations in the EGFR gene, which are more common in women and people who have not smoked.
Immunotherapies may offer significant benefit to lung cancer patients, including those for whom other treatments are ineffective. Bevacizumab (Avastin®) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), a protein that helps new blood vessels grow. By preventing tumors from growing new blood vessels, a process called angiogenesis, Avastin starves the tumor of nutrients. Ramucirumab (Cyramza®) is another angiogenesis inhibitor that can be used to treat NSCLC.
In 2015, two new immunotherapy drugs, nivolumab (Opdivo®) and pembrolizumab (Keytruda®) were approved by the FDA for the treatment of lung cancer. These two approvals were landmark events for the treatment of lung cancer in 2015.
Immunotherapy for lung cancer
Once thought of as a type of cancer that was poorly recognized by the immune system, lung cancer has recently emerged as an exciting new target of immune-based therapies . Some patients with advanced lung cancer have benefited greatly from immunotherapies, experiencing durable remissions and prolonged survival. Current immunotherapies for lung cancer can be broken into four main categories: checkpoint inhibitors, monoclonal antibodies, therapeutic vaccines, and adoptive cell therapy.
A very promising immunotherapy approach to the treatment of lung cancer is the use of immune checkpoint inhibitors. These treatments work by “taking the brakes off” the immune system, allowing it to mount a stronger and more effective attack against cancer. Several different types of checkpoint inhibitors, targeting different checkpoints or "brakes" on immune cells, are currently in use:
PD-1/PD-L1 checkpoint inhibitors
One important braking molecule targeted by checkpoint inhibitors is called PD-1, found on certain immune cells. In March 2015, the FDA approved the PD-1 checkpoint inhibitor nivolumab (Opdivo®), made by Bristol-Myers Squibb (BMS), for the treatment of advanced squamous NSCLC that has stopped responding to chemotherapy. This approval was based on results of a phase III trial in which patients receiving nivolumab lived, on average, 3.2 months longer than patients receiving standard chemotherapy. This translates into a 40% reduced risk of death compared to standard chemotherapy. In October 2015, the FDA expanded its approval of nivolumab to include non-squamous NSCLC. This approval was based on the results of a phase III trial that showed that patients who received nivolumab lived an average of 12.2 months compared to 9.4 months for those receiving standard chemotherapy.
In addition, pembrolizumab (Keytruda®), a PD-1 checkpoint inhibitor made by Merck, was approved in October 2015 for patients with NSCLC (both squamous and non-squamous). (PD-L1 is a protein that binds to the PD-1 checkpoint on immune cells; cancers often make PD-L1 as a way to ward off an immune attack.) In a phase I clinical trial, about 22% of NSCLC tumors tested had PD-L1 expression at a level of at least 50%. This subset of NSCLC had a response rate of 41%.
Several other PD-1/PD-L1 checkpoint inhibitors are also in late-stage clinical testing. For reference, the PD-1 and PD-L1 inhibitors and the relevant pivotal phase III trials are listed below:
Atezolizumab (MPDL3280A), made by Genentech/Roche, is an antibody targeting PD-L1. Current research suggests that blocking PD-L1’s ability to bind PD-1 is an effective way to block the PD-1 checkpoint pathway. Atezolizumab received a “Breakthrough Therapy” designation by the FDA in February 2015 for PD-L1-positive NSCLC that has progressed after chemotherapy. Open phase III trials include:
A phase III study of MPDL3280A in combination chemotherapy for patients with chemotherapy-naïve stage IV non-squamous NSCLC (NCT02367781)
A phase III study of MPDL3280A in combination with chemotherapy and bevacizumab (Avastin) in patients with chemotherapy-naïve stage IV non-squamous NSCLC (NCT02366143)
A phase III study of MPDL3280A versus chemotherapy for patients with PD-L1-positive chemotherapy-naive stage IV non-squamous NSCLC (NCT02409342)
A phase III study of MPDL3208A in combination with chemotherapy in patients with chemotherapy-naïve stage IV squamous NSCLC (NCT02367794)
A phase III study of MPDL3280A versus chemotherapy in patients with PD-L1-positive chemotherapy-naive stage IV squamous NSCLC (NCT02409355)
Durvalumab (MEDI4736), a PD-L1 antibody, made by AstraZeneca/MedImmune, is being tested in a variety of trials for patients with lung cancer. Open phase III trials include:
A phase III study of MEDI4736 given alone or with tremelimumab versus standard of care therapy in patients with locally advanced or metastatic NSCLC (stage IIIB-IV) who have received prior therapy and do not have known EGFR or ALK mutations (ARCTIC; NCT02352948)
A phase III study of MEDI4736 for patients with completely resected NSCLC (NCT02273375)
A phase III study of MEDI4736 in patients with locally advanced, unresectable (stage III) NSCLC who have not progressed following chemoradiation therapy (PACIFIC; NCT02125461)
Avelumab, made by Merck KGaA, is a PD-L1 antibody that is being tested in a phase III trial versus chemotherapy in patients with NSCLC that has progressed after chemotherapy (NCT02395172)
CTLA-4 checkpoint inhibitors
Ipilimumab (Yervoy®), made by BMS, is a checkpoint inhibitor that targets the CTLA-4 checkpoint on immune cells. Developed by James P. Allison, Ph.D., director of CRI’s Scientific Advisory Council, and manufactured by BMS, ipilimumab was the first treatment ever shown to extend survival in patients with metastatic melanoma, and was approved for that indication in 2011. It is now being tested in clinical trials for lung cancer. Tremelimumab, made by AstraZeneca/MedImmune, is another CTLA-4-targeting antibody in development. Although there is limited clinical development of CLTA4-targeting drugs in NSCLC as single agents, combination approaches with PD-1 and PD-L1 antibodies have demonstrated encouraging data (discussed below).
Combination checkpoint inhibitor approaches
For patients with other types of cancer (i.e., melanoma), clinical trials have shown the superiority of approaches that combine two different immune checkpoint inhibitors. Combination immunotherapy approaches are also now being explored for patients with lung cancer. Two separate combinations (nivolumab + ipilimumab and durvalumab + tremelimumab) are being tested in phase III trials versus standard-of-care chemotherapy as first-line treatment for both PD-L1-positive and PD-L1-negative NSCLC:
A phase III trial of nivolumab versus nivolumab plus ipilimumab versus chemotherapy in patients with stage IV NSCLC (CheckMate 227, NCT02477826)
A phase III trial of durvalumab (MEDI4736) with or without tremelimumab versus standard-of-care chemotherapy in patients with NSCLC (MYSTIC, NCT02453282)
A phase III trial of durvalumab (MEDI4736) plus tremelimumab versus standard-of-care chemotherapy for patients with NSCLC (NEPTUNE, NCT02542293; not yet open)
Monoclonal antibodies (mAbs) are molecules, generated in the lab, that target specific markers, called antigens, found on tumors. Many mAbs are currently used in cancer treatment, and some appear to generate an immune response. Several mAbs are FDA approved to treat lung cancer, including bevacizumab (Avastin®) and Ramucirumab (Cyramza®). Other mAbs are currently being tested in clinical trials for patients with lung cancer, including:
Bavituximab, a mAb that targets an immune-suppressing molecule in tumors, is being tested with docetaxel versus docetaxel alone in a phase III trial in patients with late-stage non-squamous NSCLC (SUNRISE; NCT01999673)
Patritumab, a human epidermal growth factor receptor-3 (HER3)-targeted mAb, given in combination with erlotinib (Tarceva), is being tested in a phase III trial for patients with locally advanced or metastatic NSCLC (NCT02134015)
Rilotumumab, a mAb targeting hepatocyte growth factor (HGF), is being tested in a phase II/III trial as second line therapy for squamous cell NSCLC (NCT02154490), and in a phase I/II study along with erlotinib (Tarceva) for patients with recurrent or progressive NSCLC that has been treated with prior chemotherapy (NCT01233687)
Cetuximab (Erbitux), a mAb targeting the epidermal growth factor receptor (EGFR), is being tested in a phase II trial for patients with stage IIIB NSCLC that can be removed by surgery (NCT01059188)
IMMU-132, an antibody-drug conjugate (ADC), is being tested in a phase I/II study for patients with epithelial cancers, including NSCLC and SCLC (NCT01631552)
Demcizumab, a mAb targeting Delta-like ligand 4 (DLL4), an activator of the Notch signaling pathway (which is known to be important in cancer stem cells and cancer), is being tested in combination with chemotherapy in a phase I/II trial for patients with untreated extensive stage SCLC (NCT01859741)
Therapeutic cancer vaccines are immunotherapies designed to elicit an immune response against shared or tumor-specific antigens. These antigens include MAGE-3, which is found in 42% of lung cancers; NY-ESO-1, found in 30% of lung cancers; p53, which is mutated in approximately 50% of lung cancers; survivin and MUC1.
CRI/Ludwig investigators have 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 .
The slide at left 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.)
Therapeutic cancer vaccines in clinical trials for lung cancer include:
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, is being tested in a phase III study (NCT01579188) for patients with inoperable stage III NSCLC
Tergenpumatucel-L (HyperAcute®) for patients with stage III or IV NSCLC, currently being tested in a phase II/III trial (NCT01774578). Tergenpumatucel-L is a therapeutic vaccine consisting of human lung cancer cells genetically modified to include a mouse gene to which the immune system responds strongly
TG4010, which targets the MUC1 antigen, is being tested in a phase II/III study (NCT01383148) for patients with stage IV NSCLC
DRibbles (DPV-001), a vaccine made from nine cancer antigens plus TLR adjuvants, is being tested in a phase II trial for patients with stage III NSCLC (NCT01909752)
Adoptive Cell Therapy
A fourth major avenue of immunotherapy for lung cancer is adoptive cell therapy. In this approach, immune cells called T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Several clinical trials of adoptive cell therapy techniques are currently under way:
A phase II trial of T cells genetically engineered to recognize NY-ESO-1, given along with dendritic cells pulsed with NY-ESO-1 antigen as a vaccine, for patients with advanced or refractory malignancies, including lung cancer (NCT01697527)
A phase II trial of tumor-infiltrating lymphocytes (TIL) in people with NSCLC following chemotherapy (NCT02133196)
A phase II trial of T cells engineered to target NY-ESO-1 antigen in patients with cancers that express NY-ESO-1, including lung cancer (NCT01967823)
A phase I/II trial of T cells engineered to target VEGFR2 in patients with aggressive cancer that has not responded to standard therapy, including lung cancer (NCT01218867)
A phase I/II trial of T cells engineered to target MAGE-A3 in patients with metastatic cancer that expresses MAGE-A3, including lung cancer (NCT02111850)
A phase I/II trial of T cells genetically engineered to recognize mesothelin, for patients with mesothelin-expressing metastatic cancer or mesothelioma (NCT01583686)
A phase I study of T cells genetically engineered to target NY-ESO-1 in combination with the checkpoint inhibitor ipilimumab (NCT02070406)
A phase I trial of T cells genetically engineered to target mesothelin for patients with malignant pleural disease (NCT02414269)
A phase I/II study genetically engineered T cells in patients with WT1-expressing NSCLC and mesothelioma (NCT02408016)
Go to our Clinical Trial Finder to find clinical trials of immunotherapies for lung cancer that are currently enrolling patients.
CRI contributions and impact
CRI discoveries and ongoing work in lung cancer research and treatment include:
In 2015, a team led by Naiyer Rizvi, M.D., of Columbia University Medical Center, showed that those lung cancer patients who responded best to the anti-PD-1 checkpoint inhibitor pembrolizumab had higher levels of genetic mutations in their tumors. The team used an approach called whole-exome sequencing to identify these mutations. In two independent cohorts, higher mutational burden in tumors was associated with improved objective response and durable clinical benefit. These results suggest that the genomic landscape of lung cancers—in particular, a tumor’s ‘mutational load’—shapes response to anti-PD-1 therapy. The paper was published in Science.
A team led by Michel Sadelain, M.D., Ph.D., and colleagues at MSKCC are taking a new approach to chimeric antigen receptor (CAR) T cell therapy in the lungs. CAR T cells are genetically engineered immune cells with enhanced capability to recognize and destroy cancer cells. Unlike ongoing CAR T cell therapy trials, Sadelain constructed a CAR treatment where the primary route of administration is via the intrapleural membranes around the lungs, as opposed to the customary intravenous infusion. They have shown in a preclinical study that intrapleurally administered mesothelin-targeted CAR T cells were able to effectively eradicate mesothelioma and lung cancer with 30-fold greater efficacy than intravenously administered CAR T cells. A clinical trial testing the approach in humans is now under way. If proven to be successful, this approach can be extended to other mesothelin-expressing cancers, such as pancreatic, bile duct, gastric, colorectal, and ovarian.
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 Clinical Trials Network.
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 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.
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)
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.
CRI Scientific Advisory Council associate director Ellen Puré, Ph.D., has been awarded a CLIP grant to study the ability of genetically engineered T cells, referred to as FAP-CAR-T cells, to specifically kill the cancer-supporting stromal cells surrounding tumors while sparing normal cells. Their initial results in animal models showed that administration of these FAP-CAR-T cells can inhibit the growth of established primary lung cancer tumors. Their project will demonstrate whether this type of immunotherapy can be effectively combined with conventional therapies or cancer vaccines to enhance therapeutic impact and will also determine whether the approach is effective against metastatic disease.
Maureen Cox, Ph.D., a CRI postdoctoral fellow at the University of Toronto, is investigating the role of chronic asbestos-induced inflammation as a cause of mesothelioma. Mesothelioma is a rare form cancer that affects the protective lining of the lungs and other internal organs. It does not develop until years after asbestos exposure, and asbestos itself does not cause DNA mutations. Therefore, it is presumed that a process induced by asbestos exposure, such as persistent inflammation, is responsible for malignant mesothelioma development. Persistent inflammation is linked to the development of several cancers, including colon cancer and gastric cancer. Exposure to asbestos fibers results in death of mesothelial cells and release of the danger signal HMGB-1, which can trigger inflammation. Cox hypothesizes that HMGB1-driven inflammation is necessary for the development of malignant mesothelioma following asbestos exposure, and she is testing this hypothesis by generating mice that lack the hmgb1 gene.
Sources: National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2015; American Lung Association; NCI Surveillance Epidemiology and End Results (SEER); GLOBOCAN 2012; ClinicalTrials.gov; CRI grantee progress reports and other documents
Last reviewed and updated October 2015
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