Tag: breast cancer

Company News: Three Peer-Reviewed Papers by ISA Pharmaceuticals Introduce Strategies to Improve Immunotherapy Against Cancer

–  Local Delivery of Checkpoint Control Antibodies Greatly Improve Efficacy and Safety

–  Promising Potential for Combinatorial Strategies

ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced the publication of three peer-reviewed papers that demonstrate the benefit of local delivery of a checkpoint control antibody targeting CTLA-4 (cytotoxic T lymphocyte antigen-4) for the successful eradication of cancer and the reduction of side effects. The papers include a review that underlines the importance of strategies for combinatorial treatments to improve further the immunotherapy of cancer. ISA Pharmaceuticals is developing cancer immunotherapies along those lines, in particular its Synthetic Long Peptide (SLP®) vaccine ISA101 for the treatment of HPV-induced diseases, such as cervical cancer and head and neck cancer, and ISA203 for the treatment of various tumors including lung cancer, head and neck cancer, breast cancer and melanoma.

In a paper just published in Clinical Cancer Research [1], a team of scientists from Leiden University Medical Center (LUMC) and ISA Pharmaceuticals report that in preclinical mouse models of cancer, the injection of a CTLA-4 blocking antibody in a slow-release formulation close to the tumor is very effective in activating a systemic anti-tumor (CD8+) T cell response. CTLA-4 is a crucial immune checkpoint protein that down-regulates the body’s immune response. The low-dose local treatment (50μg subcutaneously in a slow-release vehicle) eradicates tumors, including distant tumors, as effectively as a high-dose systemic treatment (2×200μg intraperitoneally). The method also leads to a 1000-fold decrease of antibody levels in the serum, thereby reducing adverse events and the risk of autoimmunity.

These findings are supported by an increasing number of studies demonstrating that local targets, mainly present in the microenvironment of tumors and draining lymph nodes, are key players in tumor progression. As published in a second paper by researchers from LUMC and ISA, a review in the International Journal of Cancer [2], local immunotherapies have clear advantages over systemic treatments, both in their ability to shift tumor-promoting mechanisms towards effective tumor-eradicating immunity and in terms of reducing the risks of systemic administration.

In the third publication in Seminars in Immunology [3], current cancer immunotherapy approaches are reviewed, concluding that most standalone immunotherapeutic strategies either fail to affect progressive diseases and survival significantly – or only do so in a minority of patients. The authors support combinations of synthetic vaccines that stimulate tumor-specific T cell responses and adjuvants, immune-modulating antibodies, cytokines, or chemotherapy.


[1] Fransen MF et al. (2103), Clin Cancer Res, Published Online First June 20, 2013; doi: 10.1158/1078-0432.CCR-12-0781

[2] Fransen MF et al. (2013), Int. J. Cancer, 132: 1971–1976; doi: 10.1002/ijc.27755

[3] Arens R et al., (2013), Sem Immunol, Published Online First May 21, 2013;
doi: 10.1016/j.bbr.2011.03.031

Food for Thought: It’s becoming a habit – IQWiG takes approval studies apart

Germany’s Institute for Quality and Efficiency in Health Care (IQWiG) this year put out several negative assessments of newly introduced drugs, stating the data did not prove “additional benefit” over existing treatments. In all cases, IQWiG came to the conclusion after deviating from the study design the companies had discussed with the regulators. Instead, IQWiG’s experts divided the patient population into subgroups, saying those subgroups needed different comparator treatments. As a result, these data were either not available or the subgroups were too small to demonstrate statistical significance.

One example is Pfizer’s Xiapex injectable collagenase, approved in early 2011 to treat Dupuytren’s contracture. IQWiG stated that Xiapex does not provide an additional benefit to patients because “it was not possible to derive such additional benefit from the dossier and because the manufacturer did not provide additional or suitable data” to substantiate the claim.

While the manufacturer had compared the Xiapex injection to a surgical treatment, partial fasciectomy (PF), IQWiG for its assessment established six subgroups of patients according to the severity of the disease and chose three different treatment options as comparator: no therapy, percutaneous needle fasciectomy (PNF) and partial fasciectomy (PF). As a result, IQWiG was able to state that Pfizer did not provide evaluable data because the company’s selected comparators differed from IQWiG’s comparators for all but one patient subgroup.

In the case of Eisai’s breast cancer drug Halaven eribulin, IQWiG’s verdict ruled that it could not find evidence for eribulin resulting in a prolonged life expectancy. IQWiG added that Halaven might provide an overall survival benefit for patients for whom taxanes or anthracyclines are no longer an option, but it was unclear whether the benefit was significant. Again, the assessment was made by subdividing the patient group. IQWig defined two subpopulations – one for which an additional anthracycline or taxane treatment was thought to be an option and one for which this was not.

Eisai, in contrast, had compared Halaven to a “Treatment of Physician’s Choice” (TPC) as there are no established national or international treatment guidelines for a standard therapy of women with metastatic or locally advanced breast cancer after failure of two standard chemotherapies including an anthracycline or taxane. This design of Eisai’s EMBRACE was established in discussions with the European Medicine’s Agency (EMA). Being a European study, the participating physicians sometimes opted for therapies not approved in Germany – a reason for IQWiG to not include these data in its assessment. As a result, only 69% of the EMBRACE study patients were regarded as suitable for an assessment.

The same approach was taken in the assessment of Novartis’ Gilenya fingolimod, the first oral treatment for Multiple Sclerosis (MS) approved in 2011. IQWiG once again performed separate assessments of the drug in three groups of patients, choosing three different comparators. Following this operation, IQWiG was able to find data only for one of these subgroups in the study, not enough to establish an additional benefit with sufficient statistical significance. However, one of the comparisons chosen by IQWiG – fingolimod against glatiramer acetate in patients with relapsing/remitting MS – would have been impossible as fingolimod is approved as second-line therapy in this indication while there are no studies of glatiramer acetate differentiating between first-line and second-line treatments.

In all cases, manufacturers may respond to the assessment, after which the Federal Joint Committee (G-BA) will review IQWiG’s recommendation before making a final decision.  If G-BA deviates from IQWiG’s negative assessment, the manufacturers have to negotiate the price with the Statutory Health Insurance Funds Association (GKV-Spitzenverband) under the AMNOG pricing scheme. If G-BA agrees with the IQWiG assessment that a drug has no clinical benefit beyond available treatments, the drug will be added to the reference pricing system, which gives the same base price to all comparable drugs in the respective therapeutic group.

Food for Thought: Trade Media Update

MedNous this week opens up with an article on FDA’s revoking the breast cancer indication for Avastin, saying that the decision did not come as a surprise after the FDA’s Oncologic Drugs Advisory Committee (ODAC) in June voted unanimously to have the indication removed. Avastin had been subject to FDA’s accelerated approval process in this indication.

In contrast, BioCentury Extra reports that FDA encouraged Genentech Inc to continue to study the drug in this indication to identify patients who may benefit and also details Genentech’s plans for Avastin in this indication. It also writes that in the previous months, the National Comprehensive Cancer Network (NCCN) continued to recommend Avastin as an option in breast cancer despite the negative ODAC vote.

The In Vivo Blog comments on the Avastin decision by saying that it introduced some predictability into the accelerated approval regulatory pathway. Companies should continue to use progression-free survival as a surrogate endpoint but not forget to that FDA has some expectations, e.g. for quality of life benefits, and that sponsors should design trials with supportive measures that can themselves turn into additional claims.

BioCentury this week in its cover story reports on the next-generation, interferon-free treatment regimes for HCV which have been in the focus of the recent Liver Meeting of the American Association for the Study of Liver Diseases (AASLD), stating that the new standard of care introduced only this year  following the approval of two HCV protease inhibitors, may be supplanted quickly by new regimes that are tailored to virus subtypes and patient populations.

SciBx is focusing on novel small molecule inhibitors of Monoacylglycerol lipase (MAGL), which regulates the levels of several compounds that signal through the endocannabinoid pathway. However, now that researchers have shown that it MAGL inhibitors reduce neuroinflammation, there is increased interest in the industry in these inhibitors. MAGL also is explored as a cancer target as reported by Derek Lowe in its “In the Pipeline” blog.

SCRIP this week deals with plans of the French health ministry to collect more than €290 million for the pharmaceutical industry in 2012 to reduce health care spending. In addition, it reports on plans to widening the tax on pharmaceutical industry promotion.In its editorial, SCRIP focuses on German media trying to scandalize the deaths attributed to Boehringer Ingelheim’s Pradaxa drug (see the akampioneer).

Food for Thought: Weekly Wrap-Up

Solar cells can become cheap bulk ware, even for developing countries, writes Manfred Lindinger in Frankfurter Allgemeine Zeitung (FAZ). He introduces a technology for printing a sheet of zinc oxide, a polymer containing fullerenes and an electrode made from polymers on paper. The technology developed at Technical University Chemnitz can use ordinary printing machines and paper, and the resulting solar paper can be bended and folded. However, the efficiency is still very poor (1.3% at 5 V compared to 10 or more with conventional ones). Life span will amount to a few months. For other approaches to make cheaper solar cells, see this post.

Martina Lenzen-Schulte, also in FAZ, explains how measle viruses leave cells to enter the airway. Today it is known that they do not proliferate in the outer epithelium cells but in lymph nodes. The way back is facilitated by the membrane protein nectin-4, which acts as a transporter carrying the virus through epithelial cells. Lenzen-Schulte also reports that the effect may explain why cancer cells, which often overexpress nectin-4, are vulnerable to measle and other viruses. This might pave a way to develop new oncolytic viruses.

Ernst-Ludwig Winnacker, the nestor of the German biotechnology industry, makes the case for green biotechnology in the weekly Die Zeit. Winnacker criticizes the concept of coexistence that tries to avoid a blending of genetically modified and conventionally bred plants by defining a minimum distance between cultivated areas. In Germany, a farmer cultivating GMOs is liable for every case of cross-breeding, a provision that effectively prohibits GMO cultivation as there is a zero threshold for “contamination”. Winnacker also criticizes the strategy of patenting genetically modified plants instead of protecting them with the traditional plant variety rights that allow for exemptions for the further use of GMOs by breeders and farmers. Green biotechnology, he writes, has – at least in Europe – become the scapegoat for everything that is wrong with modern agriculture, from monoculture to declining biodiversity to the death of bees, although Europe is almost free from GM plants. As 25 years of research into the risk of green biotechnology have not been able to reveal any real danger, Winnacker proposes to amend the German law on genetic engineering and to simply omit the measures restricting the cultivation of GMOs.

Diabetics may soon be able to measure blood sugar without pricking, reports Der Spiegel. A new technology developed by researchers of John’s Hopkins University enables measuring of blood sugar in tear fluid.

In Wirtschaftswoche, Matthias Hohensee introduces US-based 23andme company which offers genetic testing at a rate of $99 plus a flat fee of $9 per month for access to the data. The company, which was criticized for exaggerating the benefits of personal genetic testing, also changed its business model and is now offering its records comprising the data of 125,000 people for research purposes, e.g. to find out why certain hereditary diseases display incomplete penetrance in different carriers of the respective genes.

Theres Lüthi in Neue Zürcher Zeitung (NZZ) reports on clinical studies by Roche and Novartis in people suffering from Down’s or fragile X syndrome in an attempt to improve cognitive abilities.

Alyson Krueger in Forbes reports on a talk on synthetic biology given by Andrew Hessel of Singularity University during the Technonomy 2011 conference. Hessel describes synthetic biology as computer-assisted genetic design that goes from an idea to printing DNA to ultimately booting DNA and forecasts it will render the task of engineering life as straightforward as programming software, or creating a vaccine as simple as Tweeting.

Alex Knapp, also in Forbes, describes a “cyborg yeast” designed by researchers from the University of California at San Francisco and ETH Zurich, Switzerland. In the yeast, the expression of a certain gene can be switched on and off by different shades of red light. The technique may lead to advances in the production of proteins by yeast cultures.

The Economist reports on the first computational pathologist which can can distinguish between grades of breast-cancer cells to provide a more accurate prognosis than a human pathologist can manage.

And finally, scientists found a single gene which can make you appear kinder, reports Catherine de Lange in New Scientist. In experiments conducted at the University of Toronto, people with the so-called GG version of the oxytocin receptor gene were judged to be kinder than those with GA or AA versions. Those with GG variations used significantly more non-verbal empathetic gestures in their storytelling such as smiling and nodding which made them appear kinder.


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