Novel and Emerging Strategies
One of the most exciting frontiers in cancer medicine is the emerging field of cancer vaccines and immunotherapies (Emens 2008). This cutting-edge approach involves reprogramming a cancer patient’s immune system to more aggressively target his or her cancer (Bodey 2000; Butterfield 2014). The basic idea behind therapeutic cancer vaccines is more or less similar to that of vaccination against infectious diseases. However, instead of aiming to prevent disease, cancer vaccines are designed to initiate an immune response against a disease already present in a patient (Palucka 2013).
New technology and improved understanding of lung cancer and its interactions with the immune system have led to new opportunities in immunotherapy, with several vaccines in late-stage clinical trials (Brahmer 2013). Specifically, researchers have identified scores of proteins selectively expressed or modified by tumor cells but not by normal, noncancerous cells. These proteins, which are referred to as tumor-associated antigens (TAAs), can be exploited with cancer vaccines to act as “flags” for the immune system to recognize cancers and eliminate them as if they were virally-infected cells (Buonaguro 2011; Brahmer 2013; Palucka 2013).
Two types of vaccines are under investigation: tumor cell vaccines (composed of actual cancer cells, sometimes the patient’s own) and antigen-based vaccines (target specific proteins expressed by the tumor cells) (Brahmer 2013).
Vaccines in late-stage clinical trials include belagenpumatucel-L (Lucanix), made with four irradiated NSCLC cell lines that, in a phase II clinical trial with 75 patients, elicited a 15% response rate and significantly improved the median overall survival in those who received a high dose as compared to those who received a lower dose (Brahmer 2013). A phase III trial comparing belagenpumatucel-L to placebo following front-line chemotherapy in NSCLC patients is ongoing as of the time of this writing (Fakhrai 2012). Antigen-specific vaccines include melanoma-associated antigen-A3 (MAGE-A3), which targets a tumor-specific antigen expressed only on some tumors, including about a third of NSCLCs; the BLP-25 liposome vaccine and TG4010 vaccine, both of which target an abnormal protein expressed on epithelial cells; and CimaVax EGF, which induces antibodies against EGF to block the binding between EGF and its receptor EGFR (Brahmer 2013; Fernandez Lorente 2013; Mancebo 2012).
Personalizing Cancer Care with Circulating Tumor Cell Testing
The one word that cancer patients dread most is “metastasis.” Metastasis is the spread of cancer cells from the primary tumor into distant organs or tissues. In most cases of cancer-related death, it is not the primary tumor but rather the emergence of distant metastasis that claims the lives of cancer victims (Liberko 2013).
In order for cancer to metastasize, cells of the primary tumor must break away and infiltrate the circulatory system to be transported to another part of the body. These cancer cells flowing through the bloodstream are called circulating tumor cells (CTCs) (Wang, Liu 2011). In recent years, technological advances have given clinicians the ability to collect and evaluate CTCs from a cancer patient’s blood sample. These innovations have been paving the way for new diagnostic and therapeutic strategies based upon quantitative and qualitative analysis of CTCs in several types of cancer (Liberko 2013).
Quantitative CTC analysis allows for the enumeration of CTCs in a patient’s peripheral blood and provides some prognostic insight in several types of cancer. Generally, greater numbers of CTCs in peripheral blood correlate with worse prognosis. An analytical methodology called CellSearch has been approved by the US FDA to enumerate CTCs in breast, colon, and prostate cancer patients (Janssen Diagnostics 2014). CellSearch CTC quantitation counts the number of CTCs in the patients’ peripheral blood and contextualizes the result within evidence-based reference ranges.
Unfortunately, not enough studies have been completed on lung cancer patients to allow meaningful prognostic reference ranges and CTC count thresholds to be established as of the time of this writing, but additional research is underway and lung cancer patients may soon be able to benefit from CTC analysis using CellSearch or other methodologies (Hashimoto 2014). For example, one study published in 2014 showed that NSCLC patients with higher numbers of CTCs at baseline, as determined using the CellSearch methodology, demonstrated worse overall and progression-free survival than patients with lower CTC counts. This study also revealed that patients with lower CTC counts during chemotherapy had better overall and progression-free survival than those with higher counts (Muinelo-Romay 2014). Similarly, a study on 21 limited-stage and 38 extensive-stage SCLC patients employed the CellSearch methodology to detect CTCs before, after one cycle, and at the end of chemotherapy. CTC count after one cycle of chemotherapy was found to be a strong predictor of response to chemotherapy and survival. Moreover, patients with low baseline CTC counts survived longer than those whose CTC counts were higher (Hiltermann 2012). Another study, this time using a different CTC detection methodology called TelomeScan, revealed that SCLC patients with fewer than 2 CTCs per 7.5 mL of blood prior to the initiation of treatment survived significantly longer (14.8 months) than patients with 2 or more CTCs per 7.5 mL of blood (3.9 months). The researchers who conducted the study concluded “…CTC count prior to treatment appears to be a strong prognostic factor” (Igawa 2014).
Another aspect of CTC testing – qualitative CTC analysis – can be used to help guide cancer treatment decisions. Recent technological advances have allowed CTC testing to evolve from simply counting numbers to characterizing intricate molecular properties of CTCs (Dong 2012; Rahbari 2012; Boshuizen 2012).
A major hurdle in the treatment of metastatic cancer is that tumor cells that break away from the primary site may develop different metabolic properties than the original tumor from which they emerged. This presents several problems because physicians often rely upon molecular analysis of a tissue sample from a primary tumor to guide treatment. For example, once a patient is diagnosed with cancer and a tumor is identified, a tissue sample (biopsy) is often taken from the tumor and sent to a pathologist for molecular analysis. This elucidates the properties of the tumor cells and allows oncologists to select interventions with a higher likelihood of success based upon the molecular characteristics of the cancer cells. However, in several cancer types, molecular differences have been observed between primary and metastatic tumors, even within the same patient (Cavalli 2003; Smiraglia 2003). Interventions based upon molecular analysis of the primary tumor may, therefore, not be effective against metastatic tumors (Biofocus 2011).
Qualitative CTC analysis is a step toward overcoming this barrier. Characterization of the molecular and genetic properties of CTCs allows oncologists to select a drug regimen that may be more effective against metastatic tumors. Using a process known as “chemosensitivity testing,” pathologists can analyze the properties of CTCs and determine which chemotherapeutic drugs are likely to kill the cells based upon their specific genetic makeup. Oncologists can then develop a treatment regimen consisting of drugs to which the patient’s CTCs are susceptible (Biofocus 2011; Rüdiger 2013).
Although qualitative CTC analysis stands at the cutting edge of cancer care currently available, such services are accessible for cancer patients through organizations such as the International Strategic Cancer Alliance (http://is-canceralliance.com/) and Biofocus® (http://www.biofocus.de/de/onkologie/ueberblick/ueberblick/). Services such as these allow cancer patients to submit a blood sample to highly specialized labs to undergo qualitative CTC analysis, the results of which are reported back to the patient who can then share them with his or her oncologist (Biofocus 2011).
Individuals interested in more information on CTC testing can contact the International Strategic Cancer Alliance using the contact info below.
International Strategic Cancer Alliance
873 E. Baltimore Pike #333
Kennett Square, PA 19348
Prescribed to over 100 million people with type 2 diabetes worldwide, metformin (Glucophage) lowers serum levels of glucose by making cells more sensitive to insulin and reducing the production of glucose by the liver (Viollet 2012).
Metformin has also been shown to potently activate a cellular protein called adenosine monophosphate-activated protein kinase (AMPK) (Hardie 2012). This inhibits a protein called mammalian target of rapamycin (mTOR), which drives cellular metabolism and promotes cellular growth (Gwinn 2008). AMPK activation was also shown to selectively inhibit cancer cells that are deficient in the tumor suppressor gene p53 (Buzzai 2007).
Epidemiological studies have found that people with type 2 diabetes who use metformin have a significantly lower risk of developing lung cancer (Mazzone 2012; Noto 2012). In addition, studies on lung cancer cells have found that metformin promotes the anti-cancer properties of the chemotherapeutic agent cisplatin and radiation therapy regimens (Storozhuk 2013; Lin 2013).
Preliminary results from a small study of 16 patients with diabetes and stage III NSCLC found that adding metformin to chemo-radiotherapy dramatically reduced local recurrence, with just 2 recurrences during a median follow-up of 10.4 months (Penn Medicine 2013; Csiki 2013). Another study that evaluated data on 99 patients with NSCLC and type 2 diabetes found that those who received chemotherapy and metformin had significantly longer progression-free survival compared to subjects receiving insulin and chemotherapy (Tan 2011).
Non-steroidal Anti-inflammatory Drugs and Aspirin
Cyclooxygenase-2 (COX-2) is an enzyme that converts an omega-6 fatty acid called arachidonic acid into prostaglandin H2 (PGH2), a messenger molecule involved in inflammation and pain; COX-2 enzyme activity is generally increased in cancer cells (Khan 2011; Mazhar 2005). A reason non-steroidal anti-inflammatory drugs (NSAIDs) possess significant anti-inflammatory and analgesic properties is because they inhibit COX-2 (Mao 2011; Menter 2010; Dionne 2001; Ishiguro 2014). Aspirin in particular has been associated with a reduced risk of lung cancer (Xu 2012). Several epidemiological studies have also found that use of the selective COX-2 inhibitor celecoxib (Celebrex) was associated with as much as a 72% reduced risk of developing lung cancer (Harris 2007).
Additionally, several studies have found that COX-2 expression increases during lung cancer progression and high levels of COX-2 are associated with a poorer prognosis (Takahashi 2002; Jiang 2013; Mao 2011). Specifically, these studies found that high levels of COX-2 were significantly associated with the development of squamous cell carcinoma, early-stage NSCLC, and the adenocarcinoma subtype of NSCLC (Jiang 2013). A COX-2 inhibitor, apricoxib (Capoxigem), has completed a phase II study in patients who failed a platinum-containing regimen for advanced disease. The study found that combination therapy with apricoxib and erlotinib in 120 patients with advanced lung cancer who showed a reduction in the urinary biomarker for PGEM, an indication of high COX-2 activity, demonstrated a 71% improvement in disease control rate; 93% improvement in median progression-free survival; and 205% improvement in median overall survival (Gitlitz 2011).
However, COX-2 inhibitors are not without their own risks. In fact, drugs that specifically inhibit COX-2 such as celecoxib and rofecoxib (Vioxx), which has been withdrawn from the US market, are associated with an increased risk of cardiovascular events like heart attack. To this effect, in 2004 and 2005, the US FDA and other public health authorities advised physicians and patients that selective COX-2 inhibitors should be used with caution in persons at risk for cardiovascular events (Bennett 2005; Antman 2007).
Aspirin, which nonselectively inhibits COX-1 and COX-2, also appears to confer protection against lung cancer (Harrington 2008). Evidence from an animal model showed that aspirin reduces lung cancer metastasis to regional lymph nodes. This same experiment also found that aspirin treatment significantly lowered the mortality rate of lung cancer among mice (Ogawa 2014).
Epidemiological evidence indicates that regular aspirin use may reduce lung cancer risk. In one study, 398 Chinese women with lung cancer were compared to healthy control subjects. Women who regularly used aspirin were 50% less likely to have lung cancer. The researchers concluded “Our results suggest that aspirin consumption may reduce lung cancer risk in Asian women and are consistent with current understanding of the role of cyclooxygenase in lung carcinogenesis” (Lim 2012). Aspirin has also been shown to improve post-surgical prognosis for lung cancer patients. Researchers analyzed data from a thoracic surgery database and found that individuals using aspirin before undergoing potentially curative lung cancer surgery had a significantly increased survival rate compared to those not using aspirin. This finding was especially meaningful considering that aspirin users tended to have a higher cardiovascular risk profile, which generally increases mortality risk (Fontaine 2010).
Enhancing Immune Function with GM-CSF and IL-2
The evasion of the immune system by malignant cells is thought to be an important aspect of tumor development (Arens 2012). The immune system kills the majority of malignant cells that emerge within the body; only those capable of neutralizing immune cells or avoiding detection give rise to a progeny of tumor cells (Hanahan 2011). Indeed, studies on genetically modified mice have shown that deficiencies in NK cells, CD8+ cytotoxic lymphocytes, or CD4+ helper T cells all increase susceptibility to carcinogen-induced cancer (Teng 2008; Hanahan 2011). This is troubling for cancer patients because numerous studies document that cancer surgery results in substantial reduction in NK cell number and/or activity (Da Costa 1998; Shakhar 2003; McCulloch 1993; Rosenne 2007). In one investigation, NK cell activity in women having surgery for breast cancer was reduced by over 50% on the first day after surgery (McCulloch 1993). A group of researchers stated that “we therefore believe that shortly after surgery, even transitory immune dysfunction might permit neoplasms [cancer] to enter the next stage of development and eventually form sizable metastases” (Shakhar 2003). In another study, colorectal cancer patients with reduced NK cell activity before surgery had a 350% increased risk of metastasis during the following 31 months (Koda 1997).
Interleukin-2 (IL-2), an endogenous cytokine that can also be administered as a drug, helps promote the expansion of a subpopulation of NK cells in the body (Caligiuri 1990; Fehniger 2000; Choi 2008; Cheever 1986), while granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances the ability of the immune system to attack cancer cells (Rowe 1995; Buchsel 2006; Arellano 2008; Freeman 2007). A clinical trial on 26 patients with advanced non-small cell lung cancer whom had previously received treatment tested gemcitabine plus docetaxel with or without IL-2 and GM-CSF. Recipients of IL-2 and GM-CSF demonstrated a greater objective response and increased numbers of several immune cells (eosinophils, basophils, and activated mononuclear blood cells). The researchers concluded that “Addition of immune-adjuvant cytokines'[IL-2 and GM-CSF] may enhance the activity of [gemcitabine plus docetaxel]” (Correale 2009). Animal model experimentation has shown that GM-CSF and IL-2, when administered together, confer robust immunological benefits. In one study on immunocompromised mice deficient in NK cells, the combination of IL-2 and GM-CSF prevented Epstein-Barr virus-induced lymphoproliferative disease, which is a cancer-like condition (Baiocchi 2001).
Novel Biomarkers for the Early Detection of Lung Cancer
Research is underway to identify biomarkers for lung cancer in patients’ exhaled breath, which may lead to techniques for earlier diagnosis. This strategy is possible due to metabolic changes that occur in or around cancer cells that may generate products (volatile organic compounds) that can be detected in exhaled breath (Amann 2011). In 2009, investigators developed a sensor, based on gold nanoparticles, which can distinguish the exhaled breath of people with lung cancer from the breath of healthy individuals. Several volatile organic compounds, which are present in 1-20 parts per billion in normal human breath, are elevated to 10-100 parts per billion in the breath of lung cancer patients, and these fine sensors can detect this difference (Peng 2009). This type of test is reported to be inexpensive, non-invasive, and portable, representing a promising screening strategy for the future (Peng 2009; Mazzone 2009).