Radiofrequency ablation, currently used to treat liver cancer, may be effective in the removal of malignant lung tumors.
Researchers from the University of Pisa, Italy, have conducted a study into the plausibility of radiofrequency ablation (RFA) as a treatment for malignant lung tumors with participants from seven centers in Europe, USA and Australia.
The prospective, intention-to-treat, single-arm, multicenter clinical trial involved 106 patients with 183 lung tumors that were 3.5cm in diameter or smaller. This included 33 patients with non-small-cell lung cancer. A biopsy was carried out in all patients to verify the malignancy status of the tumors. All participants were considered unsuitable for surgery, radiotherapy or chemotherapy.
The use of RFA in lung cancer is still at an early, experimental stage, although its use in the treatment of liver cancer is more advanced. The minimally invasive procedure involves the insertion of a needle into a tumor and RFA was performed according to the standard rules for computed tomography-guided lung biopsy. End points were evaluated up to 2 years following the treatment. Primary end points were technical success (defined as the correct placement of the ablation device into all tumor targets with completion of the planned ablation protocol), safety (the incidence of treatment-related complications and alterations to pulmonary function) and confirmed complete response of tumors (according to a modified Response Evaluation Criteria in Solid Tumors). Secondary end points were overall survival, cancer-specific survival and quality of life.
The treatment was a technical success in all but one patient, attributed to the small size of the tumor, rendering the device unable to be inserted.
None of the patients died from the procedure. However, 27 patients suffered from pneumothorax and four suffered from pleural effusion, which required drainage. With regard to pulmonary function, this was not found to decline in any of the participants. Of the 85 assessable patients, a complete response of target tumors lasting at least 1 year was observed in 88%.
The authors concluded that, “Percutaneous RFA yields high proportions of sustained complete responses in properly selected patients with pulmonary malignancies, and is associated with acceptable morbidity. Randomised controlled trials comparing RFA with standard non-surgical treatment options are warranted.”
Source: Lencioni R, Crocetti L, Cioni R et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol. 9(7), 621–628 (2008).
Cervarix™ to form part of UK national immunization program against HPV
A national immunization program against Human Papillomavirus (HPV) will be implemented throughout the UK from September 2008 with the use of the cancer vaccine Cervarix™, manufactured by GlaxoSmithKline (GSK).
The national scheme aims to vaccinate all girls aged 12–13 years against the disease and a catch-up program for girls aged 14–18 years is due to follow in the next 2–3 years.
GSK’s vaccine provides immunity against strains HPV16 and 18, which account for over 70% of all cervical cancer cases. In the UK alone, approximately 3000 women are diagnosed with cervical cancer each year, with an average mortality rate of 1000 per year. Globally, the number of new cases each year is 500,000, with approximately 280,000 dying from the disease.
The Cervarix™ vaccine, perhaps controversially, was granted approval over Merck’s Gardasil cervical cancer vaccine, which provides additional protection against HPV types 6 and 11, which can cause genital warts.
Cervarix has been approved worldwide by 64 countries, including Europe, Australia, Singapore, the Philippines and Mexico; with licensing applications made in over 30 additional countries.
The UK immunization program will be one of the largest HPV vaccination programs of its kind in the world. Eddie Gray, President of Pharmaceuticals Europe for GSK, stated, “We are delighted to be working with the UK Department of Health to help reduce the burden of cervical cancer and believe the benefits of this program will be felt by women and their families for generations to come.”
Source: www.gsk.com/media/pressreleases/2008/2008_pressrelease_10071.htm
Novel tumor nanoparticles may act to trigger death of pancreatic cancer cells
Scientists have presented the first evidence that tumor-derived nanoparticles can trigger tumor cell death. The team has developed a new type of anticancer agent using nanoparticles made from pieces of tumor cells themselves. This new anticancer agent appears to halt tumor cell growth and proliferation.
Exosomes, vesicles secreted by most hematopoietic cells on fusion of multi-vesicular endosomes with the plasma membrane, are thought to be released by tumor cells. They are also believed to have an antitumor role through immune cells. The authors therefore aimed to determine whether tumor exosomes have biological activities on tumor cells.
Exosomes were harvested and purified from pancreatic tumor cells in the study for use as pancreatic tumor nanoparticles to target tumor cells. Exosomes resemble lipid-based nanoparticles known as liposomes; however, an advantage over liposomes is that these nanoparticles are loaded with various tumor cell membrane proteins, making them specific for the tumor cells.
Once purified, the nanoparticles were administered to tumor cells, triggering cell death, which was proportional to the amount of nanoparticle added to the cells. When added to normal cells, there was no effect. The nanoparticles decreased tumor cell proliferation and increase Bax and decreased Bcl-2 expression. They also induced PTEN and glycogen synthase kinase-3 activation, decreased pyruvate dehydrogenase activity and triggered a down-regulation of cyclin D1 and poly(ADP-ribose) polymerase.
These effects result in the nanoparticles counteracting the constitutively activated phosphatidylinositol 3-kinase/Akt survival pathway, thus driving tumor cells towards apoptosis. The study thus determined that the nanoparticles were triggering apoptosis, although not by the common pathway triggered by most anticancer drugs. The exact mechanism by which they exert their cell-killing activity is not as yet known and will be the subject of further study.
This study provides the first evidence of an apoptotic function of tumor-derived nanoparticles on tumor cells. The authors propose that nanoparticles could have a role as signal carriers for cell interactions, which could have implications in many biomedical situations.
Source: Ristorcelli E, Beraud E, Verrando P et al. Human tumor nanoparticles induce apoptosis of pancreatic cancer cells. FASEB J. (2008) (Epub ahead of print).
Promising cancer immunotherapeutic agent unveiled
In an article published in the June issue of Clinical Cancer Research, a research team from Immutep SA (France) and Cell Genesys Inc. (CA, USA) has demonstrated the potential of a novel fusion protein, LAG-3Ig, to increase the potency of a cancer immunotherapy using GM-CSF-secreting tumor cells in a mouse model.
The LAG-3 (CD223) binds to MHC class II of antigen-presenting cells, such as dendritic cells and monocytes, and activates these cells. This, in turn, activates CD8 T cells, leading to antitumor and antiviral immune responses.
In this animal study, the tested LAG-3Ig is a murine homolog of ImmuFact® IMP321, a natural human T-cell immunostimulant. Animals receiving a combinational therapy (murine LAG-3Ig plus GM-CSF-secreting tumor cells) were shown to survive longer than those receiving either therapy alone and also exhibited a higher active CD8 T-cell count.
“Combination therapies are being evaluated with the goal of enhancing overall antitumor activity, which could allow treatment of patients with a large tumor burden,” explained Frédéric Triebel, Immutep’s scientific and medical director. “Elevated levels of TNFα were detected in the supernatant of splenocytes isolated from animals treated with the combination therapy compared to splenocytes from animals injected with the immunotherapy alone. This increased proinflammatory cytokine production that correlated with an overall enhancement of in vivo CD8 T-cell activation clearly indicates that LAG-3 further increases antitumor activity in conditions where GM-CSF is already used as an immunostimulant.”
The immunopotentiator IMP321 can be used alone as a monotherapy, in combination with chemotherapy, or as an adjuvant in therapeutic vaccines. The product is currently being tested in a number of clinical trials as therapeutics for different cancers, including renal cell carcinoma, breast cancer and melanoma.
Sources: Li B, VanRoey M, Triebel F, Jooss K. Lymphocyte activation gene-3 fusion protein increases the potency of a granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy. Clin. Cancer Res. 14(11), 3545–3554 (2008).
Cloning killer T cells may aid remission in advanced melanoma patients
In a novel immunotherapeutic approach, a 52-year old male metastatic melanoma patient was infused with billions of clones of his own CD4+ tumor-killing T cells and had a complete remission, leading experts to hypothesise that we are a step closer to being able to control cancer.
Researchers, led by Cassian Yee of the Fred Hutchinson Cancer Research Center (DC, USA) cultured five billion T cells outside of the patient’s body, programming them to attack a specific type of melanoma cancer cell; after 2 years, the patient’s symptoms had vanished.
This method offers the advantage of no associated toxic side effects, as is common with standard chemotherapy or radiation therapy, and provides a breakthrough for scientists that have long been attempting to clone immune cells for such treatment.
The patient was enrolled in a clinical research trial following previous failures to respond to standard treatments. The melanoma was in an advanced metastatic state when the patient was infused with his own immune cells and it had already spread to the lymph node in his groin and one of his lungs. However, after 60 days of treatment the patient’s symptoms had vanished and, furthermore, after 2 years of treatment, PET and CT scans showed that no tumors were present despite having received no additional therapies.
Yee and his colleagues advise that these findings, while encouraging, need to be confirmed in a larger study before this can be considered a valid effective treatment.
Source: Hunder NN, Wallen H, Cao J et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358(25), 2698–2703 (2008).
Sorafenib in primary hepatocarcinoma patients
Spanish researchers have demonstrated a survival benefit of oral sorafenib in patients with primary hepatocarcinoma, the most prevalent tumor observed in the liver. Results indicated that patients treated with sorafenib lived, on average, up to 40% longer than patients who did not receive the drug. Sorafenib has already been approved by the US FDA and EMEA for the treatment of individuals with advanced renal cell cancer, and trials evaluating the efficacy of the agent in patients with metastatic melanoma are ongoing. Sorafenib is a mulitkinase inhibitor that targets two classes of kinases, including Raf kinases and VEGF receptor, both of which are known to have roles in the growth and progression of tumors.
According to experts from the Barcelona Clínic Liver Cancer Group, trials in the treatment of hepatocellular carcinoma have previously been difficult due to the common coexistence of liver disease in this subset of patients. Additional liver conditions, such as hepatic cirrhosis, can cloud the evaluation of the source of any clinical benefit experienced by trial participants. Traditionally, prognosis for sufferers of this disease has been poor, but over the last 5 years significant advancements have been made in the development of tumor-targeting biologicals, which aim to slow the progression of tumors and may offer patients a chance to extend their life-spans significantly.
Source: Llovet JM, Di Bisceglie AM, Bruix J et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl Cancer Inst. 100(10), 698–711 (2008).
Avastin®: effective in colorectal cancer patients with K-Ras mutations?
A Phase III trial has shown that Roche’s Avastin® (bevacizumab), a monoclonal antibody that targets VEGF, is effective in colorectal cancer patients even if they possess a mutation in the K-Ras gene. This promising data gives real hope for colorectal cancer sufferers, especially those with the defect in K-Ras, which is thought to affect approximately 50% of patients, and has been shown to hinder the response of some individuals to various anticancer agents. The results were presented at the 10th World Congress on Gastrointestinal Cancer held in Barcelona, Spain this June.
“These data demonstrate that the addition of Avastin to standard chemotherapy is active for patients with metastatic colorectal cancer with both K-Ras wild-type and mutant tumors,” explained the principal investigator Herbert Hurwitz from Duke University (NC, USA). “The high response rate, progression-free survival, and overall survival in the K-Ras wild-type group are impressive and confirm that Avastin should be part of the first-line management of patients, irrespective of K-Ras status.”
Avastin has already received regulatory approval for therapy in patients with advanced colorectal, breast, lung, and kidney cancer, and Roche plan to continue to expand their investigation of the compound in over 20 tumor types and a variety of clinical settings.
Sources: Saltz LB, Clarke S, Díaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized Phase III study. J. Clin. Oncol. 26(12), 2013–2019 (2008).