非小细胞肺癌(NSCLC)[编辑]
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| 组织学类型 | 分布频率 (%) |
|---|---|
| 非小细胞肺癌 | 80.4 |
| 小细胞肺癌 | 16.8 |
| 类癌[45] | 0.8 |
| 肉瘤[46] | 0.1 |
| 无特定类型 | 1.9 |
由于预后方案相似，几种非小细胞肺癌归为一类。主要有三类：鳞状细胞癌、肺腺癌和大细胞肺癌。
| 组织学小类 | 非小细胞肺癌频率 (%) | ||
|---|---|---|---|
| 吸烟者 | 从不吸烟者 | ||
| 鳞状细胞癌 | 42 | 33 | |
| 肺腺癌 | 肺腺癌 (无特指) | 39 | 35 |
| 细支气管肺泡癌 | 4 | 10 | |
| 类癌 | 7 | 16 | |
| 其他 | 8 | 6 | |
鳞状细胞癌占肺癌的25%[48] ,通常起始于气管。在肿瘤中常发现有空腔和细胞凋亡。充分分化的鳞状细胞癌经常比其他类型的癌生长的慢。[3]
肺腺癌占肺癌的40%。[48]通常起始于外围肺组织。大多数肺腺癌和吸烟有关；但在从不吸烟者中，肺腺癌是最常见的肺癌类型。[49] 肺腺癌的一类，细支气管肺泡癌，在女性从不吸烟者中很普遍，会对治疗有不同的反应。[50]
小细胞肺癌(SCLC)[编辑]
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小细胞肺癌，也叫“燕麦细胞癌”[51] ，不太常见。 这个癌常在大的呼吸道（主要或分支气管）里并发展迅速，很快就长的很大。[52]小细胞里有神经分泌细胞颗粒球 (内含内分泌荷尔蒙的囊泡）, 因此会和内分泌-副癌综合症有关。[53] 虽然起初会对化疗比较敏感，但最终预后效果不佳且通常远端转移。小细胞肺癌分局限期和广泛期。这类肺癌很大程度上和吸烟有关。[54]
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. The 5-year survival rate for lung cancer ranges from <5% to about 50% depending on stage.
Patients with specific genetic mutations may bendefit 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 1.61 million new lung cancer diagnoses are made each year and there are 1.38 million deaths. More deaths are caused by lung cancer every year than by breast, prostate, and colon cancers combined.
- In the United States, lung cancer comprises 14% of cancer diagnoses and 27% of cancer deaths. In 2013, an estimated 228,190 new cases of lung cancer will be diagnosed and 159,480 people will die.
- The two major forms of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC comprises approximately 84% 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%—18% for NSCLC and 6% for SCLC. If the cancer is discovered before it has spread (metastasized), the 5-year survival rate is 52%. 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%-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.
- 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.
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 have advanced the farthest, a number of new immune-based treatments for small cell lung cancer, 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, immune 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. 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 patients with late-stage non-squamous non-small cell lung cancer (SUNRISE; NCT01999673).
- Rilotumumab, a mAb targeting hepatocyte growth factor (HGF), is being tested in a phase II/III trial as second line therapy for squamous cell lung cancer (NCT02154490).
Immune 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 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 (NCT01285609) and for small cell lung cancer (NCT01450761).
- Tremelimumab, another antibody targeting the CTLA-4 molecule, is being tested in two phase II clinical trials for patients with mesothelioma (NCT01655888 and NCT01649024).
PD-1 antibodies
- 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 [2], the drug’s manufacturer, Bristol-Myers Squibb, has launched phase III trials of the agent in several cancers, including in non-squamous cell (NCT01673867) and squamous cell (NCT01642004) non-small cell lung cancers.
- MK-3475 is another antibody targeting the PD-1 checkpoint molecule also in phase III development in PD-L1-positive non-small cell lung cancer (NCT01905657).
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, has launched a phase II trial (NCT01846416) in patients with PD-L1-positive locally advanced or metastatic non-small cell lung cancer. The trial is currently recruiting patients.
- MEDI4736, another PD-L1 antibody, is being tested in a phase I trial with an expansion cohort in non-small cell lung cancer (NCT01693562), and in a phase II/III trial as second-line therapy for patients with recurrent stage IIIB-IV non-small cell lung cancer (NCT02154490).
Combination immune checkpoint approaches
- Combination immune checkpoint inhibition may represent an opportunity to improve efficacy as has recently been shown in melanoma [3]. MEDI4736, a PD-L1 antibody, is being tested in combination with a CTLA-4 antibody, tremelimumab, for patients with advanced solid tumors in a phase I trial (NCT01975831) by investigators in the CRI/Ludwig Clinical Trials Network.
- A phase I study (NCT01454102) of nivolumab with ipilimumab therapy in patients with advanced non-small cell lung cancer is currently being conducted.
Therapeutic Vaccines
Therapeutic vaccines 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.
The first clinical results of vaccination with MAGE-A3 were reported in 2004 by investigators in the CRI/Ludwig CVC Trials Network [4]. 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. Due to disappointing results, this trial was stopped in April 2014; the company is continuing to explore ways to identify subsets of patients who may benefit from the treatment.
CVC clinical 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 above 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 or IV non-small cell lung cancer, a phase III trial (NCT00676507) of which will be completed shortly. Belagenpumatucel-L is a therapeutic vaccine using genetically modified lung cancer cells. (This trial is ongoing but no longer recruiting patients.)
- Tergenpumatucel-L (HyperAcute®) for patients with stage III or IV non-small cell lung cancer, 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.
- 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. A phase III study (NCT01579188) is scheduled to begin enrolling patients with inoperable stage III non-small cell lung cancer shortly.
- TG4010, which targets the MUC1 antigen, is being tested in a phase II/III study (NCT01383148) for patients with stage IV non-small cell lung cancer.
- MUC1 peptide-based vaccine for patients with any stage of non-small cell lung cancer is currently being tested in a phase I/II trial (NCT01720836).
- INGN, a dendritic cell-based vaccine targeting p53 that is being tested in phase II/III trial (NCT01383148) for patients with extensive stage small cell lung cancer.
- A vaccine targeting the WT1 antigen, which is in a randomized 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 enrolling patients in a phase II trial (NCT01569919).
- 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 non-small cell lung cancer.
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 phase II trials of adoptive T cell transfer techniques are currently under way.
- T cells genetically engineered to target CEA (carcinoembryonic antigen) are being tested in a phase II trial (NCT01723306) for patients with confirmed CEA-expressing adenocarcinomas. CEA is expressed in approximately 30% of lung cancer tumors.
- T cells genetically engineered to target the NY-ESO-1 tumor-specific antigen are being tested in a phase II trial (NCT00670748) for patients with metastatic cancers expressing NY-ESO-1.
- White blood cells genetically engineered to recognize NY-ESO-1, given along with dendritic cells pulsed with NY-ESO-1 antigen as a vaccine, are being tested in a phase II trial (NCT01697527) for patients with stage IV, advanced, or refractory malignancies.
- White blood cells genetically engineered to recognize a protein called mesothelin, found on certain cancers, are being tested in a phase I/II (NCT01583686) trial for patients with mesothelin-expressing metastatic cancer or mesothelioma.
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 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.
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 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 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 new 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 2013; American Lung Association; NCI Surveillance Epidemiology and End Results (SEER); GLOBOCAN 2008; ClinicalTrials.gov; CRI grantee progress reports and other documents
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[3] Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013 Jul 11;369(2):122-33. PMID: 23724867
[4] Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E, Santiago D, Ferrara CA, Matsuo M, Selvakumar A, Dupont B, Chen YT, Hoffman EW, Ritter G, Old LJ, Gnjatic S. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol 2004 Mar 1;172(5):3289-96. PMID: 14978137
[5] Kakimi K, Isobe M, Uenaka A, Wada H, Sato E, Doki Y, Nakajima J, Seto Y, Yamatsuji T, Naomoto Y, Shiraishi K, Takigawa N, Kiura K, Tsuji K, Iwatsuki K, Oka M, Pan L, Hoffman EW, Old LJ, Nakayama E. A phase I study of vaccination with NY-ESO-1f peptide mixed with Picibanil OK-432 and Montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen. Int J Cancer 2011 Dec 15;129(12):2836-46. PMID: 21448901
Last updated November 2013
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