Vismodegib Approved by US FDA for the Treatment of Advanced Basal Cell Carcinoma
Vismodegib (Erivedge™) has become the first drug indicated for the treatment of basal cell carcinoma (BCC), the most common type of skin cancer in the EU, USA and Australia, to gain US FDA approval. It has first-in-class specificity as a ligand-specific inhibitor of the hedgehog pathway, which is abnormally activated in more than 90% of BCC cases. This signaling inhibition is achieved by vismodegib binding to and interfering with the transmembrane receptor smoothened, preventing abnormal signaling.
FDA approval came after a new drug application was submitted to the FDA in September 2011, based on Phase II data from the ERIVANCE BCC trial. The drug then underwent a subsequent priority review by the FDA, which led to its approval. Vismodegib is indicated for patients with BCC that has metastasized to other parts of the body, who relapsed after surgery or who cannot be treated with radiation or surgery.
The Phase II study was an international, single-arm, multicenter, two-cohort, open-label trial of 96 patients. The drug was assessed by independent review and was shown to achieve its primary end point of overall response rate. In patients with locally advanced BCC it was shown to shrink lesions in 27 out of 63 cases, and in patients with metastatic BCC, lesions were reduced in ten out of 33 cases, with the mean duration of response being 7.6 months. The drug has been shown to have a relatively low toxicity; however, adverse events, such as muscle spasms, hair and weight loss, diarrhea, fatigue, reduced appetite, constipation, vomiting and loss of taste in the tongue were observed, and approval for vismodegib comes with a boxed warning of potential risk of death or severe birth defects to unborn babies.
The drug is being marketed by Genentech (USA), a part of the Roche group, as a once-daily capsule that costs US$7500 per month, with the duration of treatment expected to be approximately 10 months. A marketing authorization application for vismodegib has been submitted by Roche in the EU in order to allow European to patients to gain access to the drug while a Phase II safety trial is also underway in order to potentially gain marketing authorization worldwide.
The drug is currently undergoing trials for other indications such as colorectal cancer, small cell lung cancer, advanced stomach cancer and pancreatic cancer.
– Written by Claire Attwood
Source: Genentech newsroom: www.gene.com/gene/news/press-releases/display.do?method=detail&id=13827
Novel Approach to Cancer Vaccine Development Has Clinical Potential
Many highly effective vaccines have been produced against infectious diseases that effectively stimulate the immune system, thus preventing infection. However, this is not the case for vaccines against cancer. Unlike infectious disease agents, cancer cells are not presented to the immune system as antigens, and so the generation of an effective immune response is fraught with difficulties. In fact, tumor cells have an immunosuppressive microenvironment, further decreasing the likelihood of clearance of the cancer cells by the immune system.
The first cancer vaccine for the treatment of prostate cancer unresponsive to hormone treatment, Sipileucel-T (Provenge™, Dendron Corp.), was licensed in 2011. However, the vaccine only improves patient survival for an average of 4.1 months.
A research group at Trinity College Dublin (Dublin, Ireland), led by Kingston Mills, professor of experimental immunology, have discovered a novel approach for the development of a cancer vaccine or immunotherapy. Their findings are published in Cancer Research, and the new approach has been patented, with plans in place for clinical development. Mills commented to our correspondent on the impact of his group’s novel approach, “Cancer vaccines are now a reality for treating human tumors and our approach has the capacity to significantly improve on existing technologies.”
It has been previously noted that Toll-like receptor ligands have the potential to treat tumors. However, their effect on inflammation in the tumor can be both positive and negative. Mills and his group demonstrated that, by using specific small-molecule inhibitors of PI3K, they could relieve immunosuppression in order to increase the inflammatory ability of the Toll-like receptor ligands, supporting antitumor immunity. In vitro data were confirmed in three different mouse models of cancer. Treated mice demonstrated delayed tumor growth and increased survival, with some animals showing complete tumor rejection and resistance to secondary challenge.
Mills summarized the data, “Our study has demonstrated that the induction of effector T cells and consequently the efficacy of cancer vaccines and immunotherapeutics in animal models can be considerably enhanced by removing the immunosuppressive arm of the immune response mediated by Tregs.” It is hoped that, with this new approach, cancer vaccines can become a major component in the arsenal of treatments against cancer.
– Written by Caroline Purslow
Source: Marshall NA, Galvin KC, Corcoran AM et al. Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res. 72, 581–591 (2012).
Researchers Elucidate Mechanism Behind Vemurafenib-Induced Secondary Melanomas
Approximately one quarter of patients treated with vemurafenib develop secondary skin squamous cell carcinomas and keratoacanthomas. Researchers have now elucidated the mechanism behind these secondary melanomas.
Vemurafenib (Zelboraf®, Genentech, CA, USA) is the first FDA-approved treatment for BRAF V600E mutation-positive metastatic melanoma. Approximately 50% of patients with metastatic melanoma carry the BRAF V600E mutation. Of these patients, treated with vemurafenib, approximately one quarter will develop secondary melanomas as a result of their treatment.
Researchers at the University of California Los Angeles’s Jonsson Comprehensive Cancer Center (CA, USA), working with investigators from the Institute of Cancer Research (London, UK), Roche (CA, USA) and Plexxikon (CA, USA), have now uncovered the mechanism of action of vemurafenib and the reason for the development of secondary melanomas during treatment.
Dr Antoni Ribas (Division of Hematology/Oncology, University of California, CA, USA), senior co-author of the paper, spoke to our correspondent on the importance of vemurafenib, “Regarding vemurafenib, I consider it the most significant advance in the treatment of patients with metastatic melanoma in the past 30 years. It provides an unprecedented high and reproducible response rate in patients with BRAF-mutant melanoma. Since we understand the molecular mechanisms of how it works, we are now generating the data to fully understand how melanoma becomes resistant to it, and are already testing in the clinic means to prevent and treat acquired resistance.”
Researchers performed molecular analyses on tumor samples from patients treated with vemurafenib that developed secondary melanomas, in order to elucidate the mechanism of action by identifying the oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A and TP53). An analysis was also carried out on an independent validation set. It was found that 60% of samples had RAS mutations, in particular HRAS Q61L.
HRAS Q61L mutant cell lines treated with vemurafenib demonstrated an association with MAPK pathway signaling and the activation of ERK-mediated transcription. This interaction was confirmed in a mouse model of HRAS Q61L-mediated skin carcinogenesis, where a vemurafenib analogue accelerated growth of HRAS-positive lesions. This growth was blocked by concomitant treatment with a MEK inhibitor, which blocks the ERK1/2 signaling pathway.
One of the authors, Professor Richard Marais from the Institute of Cancer Research, who developed the animal model for the study, commented on the significance of the findings, “By understanding the mechanism by which these squamous cell cancers develop, we have been able to devise a strategy to prevent the second tumors without blocking the beneficial effects of the BRAF drugs,” Marais said. “This may allow many more patients to benefit from these important drugs.”
– Written by Caroline Purslow
Source: Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).
Exciting New Drug-Delivery Candidate Could Exploit Low pH of Tumors
Researchers at the University of California Davis (CA, USA) have synthesized a novel nanoparticle that releases its contents when exposed to a low pH. The study presents an exciting new drug-delivery system, which the authors say has potential to significantly improve cancer therapy.
One of the main issues in anticancer drug-delivery systems is enabling their toxic load to only target the tumor, and to not be released at off-target sites. Conversely, the system must release the drug once it reaches its target. The UC Davis research team’s nanoparticle has the benefit of remaining stable during delivery, but is able to release its payload under two stimuli: low pH and Mannitol (a US FDA-approved sugar alcohol), offering much more control over the delivery of the drug. As co-author of this research, Juntao Luo (SUNY Upstate Cancer Research Institute, NY, USA) further explains this issue to Future Medicine “Many nanoparticle drug-delivery systems suffer from their low structural stability and release drugs prematurely in the blood circulation before reaching the tumor target.”
Luo and Kit Lam (UC Davis) describe their nanoparticle in the journal Angewandte Chemie International Edition. The boronate-crosslinked micelles that the researchers synthesized consist of a hydrophilic polyethylene glycol outer layer linked to a cholic acid core by reversible boronate crosslinks. When exposed to the triggering stimuli, the boronate crosslinks break and the entire nanoparticle ‘bursts’, releasing its contents. This nanoparticle is novel in that the boronate-crosslinked micelles are dual-responsive, and will burst under both an acidic tumor microenvironment, or from the exogenous administration of Mannitol. The team has optimized the stability of the boronate-crosslinked micelles, so that they are more stable off-target and, conversely, much more sensitive when subjected to these stimuli.
Commenting on the novelty of the work, Luo states: “This new class of nanoparticles holds promise for greater accuracy and effectiveness in delivering chemotherapeutics to tumors.” He went on to explain that the team has also published another disulfide crosslinked micelle system, and, together with these findings they hope that this new technology, “can be readily translated into novel and effective therapeutic agents for human cancer treatment”. Their future plan is to optimize the loading of agents to their nanoparticle and then study its effect in vivo.
The group plans to perform Phase I studies in dogs and, if successful, continue to Phase I studies in humans. Additionally, they aim to further increase the efficacy of their nanoparticle by ‘decorating’ the nanocarriers with cancer-targeting ligands. Luo states that their initial research has potential: “We expect that patients with deadly metastatic cancers will benefit from such novel nanotherapies. It holds great promise for a significant improvement in cancer therapy.”
– Written by Alice O’Hare
Source: Li Y, Xiao W, Xiao K et al. Well-defined, reversible boronate crosslinked nanocarriers for targeted drug delivery in response to pH value and cis-diols. Angew. Chem. Int. Ed. doi:10.1002/anie.201109103 (2012) (Epub ahead of print).
Immune Function May Persist Following Alemtuzumab Therapy for Cutaneous T-Cell Lymphoma
A study published recently in Science Translational Medicine has provided an encouraging indication that functional immunity may be spared after the treatment of leukemic cutaneous T-cell lymphoma patients with the monoclonal antibody alemtuzumab.
Alemtuzumab targets the cell surface marker CD52, a protein that is present on mature lymphocytes. It is currently used in the treatment of a range of lymphocytic malignancies, including chronic lymphocytic leukemia and cutaneous T-cell lymphoma. However, since the antibody targets both healthy and malignant blood cells, a significant concern following therapy is the enhanced risk of opportunistic infections.
While the new study confirmed that alemtuzumab treatment led to the depletion of circulating T cells in patients with leukemic cutaneous T-cell lymphoma, the persistence of effector memory T cells in the skin was observed after therapy. In addition, the researchers observed a notable lack of infections in these patients following alemtuzumab therapy.
“We noticed that our patients were not getting infections, and we looked in the skin. We saw healthy T cells remaining there, despite the fact that there were no T cells in the blood,” highlighted Rachel Clark, an author of the study.
“We used to believe that most T cells responsible for protecting against infection were in the bloodstream,” added Clark. “But we now realize that highly protective T cells also inhabit tissues such as the skin, lungs and GI tract. It is these tissue resident T cells that are critical in protecting us from infection on a day-to-day basis.”
– Written by Edward Parker
Sources: Clark RA, Watanabe R, Taegue JE et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl. Med. 4(117), 117ra7 (2012); Brigham and Women’s Hospital: www.brighamandwomens.org/about_bwh/publicaffairs/news/pressreleases/PressRelease.aspx?sub=0&PageID=1056