Immunotherapy for 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 are diagnosed with advanced disease (stage IIIb/IV). For these patients, current treatment options including surgery, chemotherapy, and radiotherapy 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 EGF receptor blocker erlotinib (Tarceva®). As well, immunotherapies currently in development may offer significant benefit to lung cancer patients, including those for whom conventional treatments are ineffective. New treatments that 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. Globally, an estimated 1.8 million new lung cancer diagnoses are made each year and there are 1.6 million deaths. More deaths are caused by lung cancer every year than by breast, prostate, and colon cancers combined.
- Cigarette smoking remains the most significant risk factor for the disease. Tobacco use accounts for approximately 80%-90% of all lung cancers in the United States. Other significant risk factors include pipe and cigar smoking, as well as exposure to asbestos, secondhand smoke, radiation, and air pollution.
- 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 84% of all lung cancers.
- Symptoms of lung cancer may entail voice change, persistent cough, chest pain, recurring bronchitis or pneumonia, and/or blood-streaked sputum.
IMMUNOTHERAPY FOR LUNG CANCER
Once thought of as a type of cancer that was poorly immunogenic, lung cancer has recently emerged as an exciting new target of immune-based therapies [1]. 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 (NSCLC) have advanced the farthest, a number of new immune-based treatments for small cell lung cancer (SCLC), as well as for mesothelioma (another type of lung cancer), are also in clinical development. These treatments can be broken into four main categories: monoclonal antibodies, checkpoint inhibitors, therapeutic vaccines, and adoptive T cell transfer.
Monoclonal Antibodies
Monoclonal antibodies (mAbs) are molecules, generated in the lab, that target specific antigens on tumors. Many mAbs are currently used in cancer treatment, and some appear to generate an immune response. Bevacizumab (Avastin®), which targets vascular endothelial growth factor (VEGF), is FDA-approved for the treatment of non-squamous NSCLC. Several mAbs are currently being tested in clinical trials:
- 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).
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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).
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Cixutumumab, a mAb targeting the insulin-like growth factor-1 receptor (IGF-1R), is being tested in a phase II trial for patients with NSCLC (NCT01263782).
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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).
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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).
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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)
Checkpoint Inhibitors
A 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 or enhance pre-existing anti-cancer immune responses.
CTLA-4 antibodies
- Ipilimumab (Yervoy®), which targets the CTLA-4 checkpoint on activated immune cells, has been at the vanguard of this new immunotherapy approach. Developed by James P. Allison, Ph.D., director of CRI’s Scientific Advisory Council, ipilimumab was the first treatment ever shown 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 NSCLC (NCT01285609) and for SCLC (NCT01450761). Other open ipilimumab trials include:
A phase II trial of ipilimumab plus chemotherapy before surgery for patients with NSCLC (NCT01820754).
A phase I trial of ipilimumab plus targeted therapies (erlotinib or crizotinib) for patients with stage IV NSCLC who also have EGFR or ALK mutations (NCT01998126).
A phase I trial of ipilimumab plus Gleevec (imatinib mesylate), a c-Kit inhibitor, for patients with advanced cancer, including lung cancer (NCT01738139).
- Tremelimumab, another antibody targeting the CTLA-4 molecule, is being tested in a phase II clinical trial for patients with mesothelioma (NCT01655888).
PD-1 antibodies
- Nivolumab (Opdivo®) is an antibody targeting the PD-1 checkpoint molecule. Based on promising results from a phase I clinical trial completed in 2012 [2], the drug’s manufacturer, Bristol-Myers Squibb, launched phase III trials of the agent in several cancers, including in non-squamous cell and squamous cell NSCLC; the trials are active but no longer recruiting. Active nivolumab trials include:
A phase III trial of nivolumab for patients with advanced or metastatic NSCLC who have progressed during or after prior therapy (CheckMate 153; NCT02066636).
A phase II trial of nivolumab given after “epigenetic priming” with the drugs azacitidine and entinostat for patients with NSCLC (NCT01928576).
A phase I trial of nivolumab plus chemotherapy or targeted therapy, or nivolumab alone for patients with stage IIIB/IV NSCLC (CheckMate 012; NCT01454102).
A phase I/II trial of nivolumab with or without ipilimumab for patients with advanced or metastatic solid tumors, including SCLC (NCT01928394).
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Pembrolizumab (Keytruda®) is another antibody targeting the PD-1 checkpoint molecule, made by the drug company Merck. Pembrolizumab was approved by the FDA in September 2014 for the treatment of advanced melanoma and was granted a "Breakthrough Therapy" designation in October 2014 for the treatment of non-small cell lung cancer (NSCLC). The following pembrolizumab trials are open:
A phase III trial of pembrolizumab in patients with PD-L1-positive NSCLC (NCT01905657).
A phase II study of pembrolizumab for patients with NSCLC who have brain metastases (NCT02085070).
A phase II study of pembrolizumab for patients with microsatellite unstable (MSI) tumors, including lung cancer (NCT01876511).
A phase I/II trial of pembrolizumab in combination with chemotherapy or targeted therapy for patients with NSCLC (KEYNOTE-021; NCT02039674)
A phase I/II trial of pembrolizumab in combination with an IDO inhibitor for patients with advanced NSCLC (KEYNOTE-037; NCT02178722).
A phase I trial of pembrolizumab for patients with advanced, biomarker-positive solid tumors, including lung cancer (KEYNOTE-28; NCT02054806).
PD-L1 antibodies
- MPDL3280A is an antibody targeting PD-L1 (the binding partner of checkpoint molecule PD-1). Based on promising results from an ongoing phase I trial in patients with advanced solid tumors, the drug’s developer, Genentech, launched a phase II trial (NCT01846416) in patients with PD-L1-positive locally advanced or metastatic non-small cell lung cancer. The trial is active, but not longer recruiting patients. Active MDPL3280A trials include:
A phase II trial of MPDL3280A for patients with PD-L1-positive, locally advanced or metastatic NSCLC (NCT02031458).
A phase I trial of MPDL3280A for patients with locally advanced or metastatic solid tumors, including lung cancer (NCT01375842).
A phase I trial of MPDL3280A in combination with bevacizumab (Avastin), or with bevacizumab and chemotherapy, for patients with advanced NSCLC (NCT01633970).
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MEDI4736, another PD-L1 antibody, made by MedImmune, is being tested in a variety of trials for patients with lung cancer. The following MEDI4736 trials are currently open:
A phase II/III trial of MEDI4736 as second-line therapy for patients with recurrent stage IIIB-IV NSCLC (NCT02154490).
A phase II trial of MEDI4736 for patients with locally advanced or metastatic NSCLC (NCT02087423).
A phase I trial of MEDI4736 for patients with NSCLC (NCT01693562).
A phase I trial of MEDI4736 combined with gefitinib (an EGFR inhibitor) in subjects with NSCLC (NCT02088112).
Combination immune checkpoint approaches
- Combination immune checkpoint inhibition may represent an opportunity to improve efficacy as has recently been shown in melanoma [3]. The following combination trials are currently recruiting patients:
A phase I trial of MEDI4736 plus tremelimumab for patients with advanced solid tumors, including NSCLC (NCT01975831). This trial is being conducted by investigators in the CRI/Ludwig Clinical Trials Network.
A phase I study (NCT01454102) of nivolumab with ipilimumab therapy in patients with advanced NSCLC is currently being conducted.
A phase Ib trial of MEDI4736 in combination with tremelimumab for patients with advanced NSCLC (NCT02000947).
A phase I study of lirilumab (an anti-KIR antibody) in combination with nivolumab in patients with advanced solid tumors, including lung cancer (NCT01714739).
A phase I trial of BMS-986016 (an anti-LAG-3 antibody) with or without nivolumab for patients with solid tumors, including lung cancer (NCT01968109).
A phase I trial of BMS-986015 (anti-KIR) in combination with ipilimumab for patients with selected advanced tumors, including lung cancer (NCT01750580).
Therapeutic Vaccines
Therapeutic vaccines target shared or tumor-specific antigens, including MAGE-3, which is expressed in 42% of lung cancers, NY-ESO-1, which is expressed 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 [5].
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).
- MUC1 peptide-based vaccine for patients with any stage of NSCLC is currently being tested in a phase I/II trial (NCT01720836).
- CV9202 RNActive®-derived cancer vaccine, which consists of six different cancer antigens, is currently being tested in a phase I trial (NCT01915524) for patients with stage IV NSCLC.
- INGN, a dendritic cell-based vaccine targeting p53, is being tested in a phase II/III trial (NCT01383148) for patients with extensive stage SCLC.
- WT1 antigen vaccine is being tested in a phase II trial (NCT01265433) for patients with mesothelioma after completing surgery and chemotherapy and/or radiation.
- TroVax®, which targets the 5T4 protein widely found on mesothelioma cells, is being tested in a phase II trial for patients with mesothelioma (NCT01569919).
Adoptive T Cell Transfer
A third major avenue of immunotherapy for lung cancer is adoptive T cell transfer. In this approach, 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 T cell transfer 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 NSCL 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).
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:
- 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)
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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.
- 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.
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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 2014; American Lung Association; NCI Surveillance Epidemiology and End Results (SEER); GLOBOCAN 2012; ClinicalTrials.gov; CRI grantee progress reports and other documents
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Last updated October 2014
- See more at: http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/lung-cancer#sthash.KDWwjs3S.dpuf
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