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Chemotalk NewsletterChemotalk Newsletter, Vol. 53: September 1, 2012 Welcome to September. To start with... VACCINE FOR KIDNEY CANCER SHOWS ACTIVITY By Anna Azvolinsky, PhD The first RENAL CELL CARCINOMA (RCC) patients have been treated with an RCC-specific therapeutic vaccine in early-stage clinical trials. The results of the trials are published in Nature Medicine and demonstrate that RCC patients who have a measurable immune response to the vaccine, IMA901, have a prolonged overall survival. ³These studies show that patients achieve better clinical benefit if they are able to mount immune responses to multiple peptides in the IMA901 vaccine. This confirms the hypothesis that a broad attack of the immune system on multiple targets simultaneously is beneficial,² said Harpreet Singh-Jasuja, MD, in an email correspondence. Dr. Singh-Jasuja is one of the coauthors of the study and chief scientific officer at Immatics Biotechnologies in Germany. ³The results of the phase I study are certainly intriguing and support the general concept that vaccination against RCC may be feasible,² said Dr. Howard L. Kaufman, director of the Rush University Cancer Center and professor of surgery, immunology, and microbiology. A phase III pivotal trial is underway to test whether IMA901 can prolong overall survival among advanced RCC patients when added to a first-line treatment with sunitinib (Sutent), a widely used treatment for metastatic RCC. The international, randomized trial is slated to be completed by 2014. IMA901 was developed by Immatics Biotechnologies. The company, based in Tübingen, Germany, focuses on developing therapeutic vaccines against cancer. IMA901 is the most advanced vaccine in the company¹s pipeline, which includes vaccines for COLORECTAL CANCER, GLIOMA, GASTRIC CANCER, and NON-SMALL-CELL LUNG CANCER‹all of which are in earlier stages of clinical development. Results of a phase I/II trial of a vaccine that consisted of 13 antigens found in colorectal tumors were presented at this year¹s American Society of Clinical Oncology meeting in June and showed clinical benefit. IMA901, according to Immatics, is made up of 10 tumor-associated peptides present on the tumor cells of RCC patients. Each peptide was isolated using tissue samples from patients and validated as inducing a T cell response in clinical studies. All patients also express the human leukocyte antigen on their cancer cells. Clinical Trial Results The phase I trial included 28 patients, both treatment-naive and previously treated patients. Patients received consecutive IMA901 vaccinations in addition to the immunomodulator, granulocyte-macrophage colony-stimulation factor. One patient had a partial response at 3-month follow-up, and 11 patients had stable disease. T cell responses were associated with better disease control and lower levels of regulatory T cells, according to Singh-Jasuja. Those patients who had an immunogenic response to multiple tumor-associated peptides were more likely to have either a partial response or stable disease compared to patients who only responded to a single antigen in the vaccine. Regulatory T cells are thought to counteract the antitumor response of cancer vaccines. The phase II trial enrolled 68 patients, randomized one to one to either the vaccine plus cyclophosphamide, an immunostimulant or to the vaccine alone. Patients in the cyclophosphamide arm received a single injection of cyclophosphamide prior to the first vaccine injection. The vaccine was generally well tolerated with local skin reactions in both phase I and II trials. No serious safety issues were reported in the phase I trial. One complete response and two partial responses were seen in the phase II trial. The disease control rate was 31%. Similar to the phase I trial, the immune response for the phase II portion of the study was 64%. The researchers found survival time was prolonged among patients who responded to multiple tumor-associated peptides. Cyclophosphamide was found to prolong survival in those patients with a measurable immune response to the vaccine. The authors attribute this affect to the role of cyclophosphamide in reducing regulatory T cells. However, Kaufman noted that cyclophosphamide has been previously shown to decrease T regulatory cells and because this is not a controlled study, the direct antitumor effect of cyclophosphamide cannot be ruled out. ³The authors did report a strong correlation between immune response to the vaccine and survival, and this finding supports further development of the concept,² added Kaufman who added that the data should be interpreted with caution as the trial was conducted in late-stage RCC patients. From an analysis of over 300 potential biomarkers, the study also identified two potential outcomes serum biomarkers, apolipoprotein A-1 (APOA1) and chemokine ligand 17 (CCL17), that may predict which patients could achieve both immune and clinical responses, and thus an overall survival benefit, according to the authors. T he authors also suggest that myeloid-derived suppressor cells as well as T regulatory cells may play a role in RCC outcomes. This effect will be explored in the ongoing phase III trial with sunitinib‹a tyrosine kinase inhibitor that itself reduced T regulatory cells as well as myeloid-derived suppressor cells, as documented in patients. Vaccine Approach to Cancer Treatment ³In our view, one major issue in the field of cancer vaccine development is that previously antigens of insufficient number and possibly also insufficient quality have been used,² Singh-Jasuja explained. ³We believe that this is also the reason why so few studies have shown a conclusive association of the detected immune response to the vaccine and clinical benefit.² IMA901 combines 10 antigens in a single vaccine compared to other vaccines currently in late-stage development that consist of a single antigen. According to Singh-Jasuja, this allows for a broad immune system attack. Development of vaccines for RCC has been difficult as well-defined antigens have not been identified. Immunotherapy has recently been seen as one of the most promising approaches to cancer treatment as it has the potential to extend lifespan, without the chances of resistance development seen for targeted agents. Ipilimumab (Yervoy) was approved in 2011 for METASTATIC MELANOMA showing an overall survival benefit, sipuleucel-T (Provenge) for prostate cancer is now available to patients, and a next-generation immunotherapy, anti-PD1, is currently in phase II trials for a range of different cancers, including LUNG CANCER‹a cancer not typically thought of as immunogenic. ³Vaccines continue to be promising because they have a significant safety profile, better antigenic targets are being identified and improved adjuvants are now available that can help overcome local tumor escape and immunosuppressive mechanisms,² noted Kaufman, who believes the future of vaccine therapy will be combinations with other agents. Singh-Jasuja believes that while complex, immunotherapy will be successful if accompanied by predictive biomarker and pharmacodynamic biomarker isolation to both identify those patients who are most likely to respond and to track their progress. ³Most importantly for the patients, cancer immunotherapy has the prospect of significantly expanding the life span of patients and not just expanding progression-free survival,² said Singh-Jasuja. * * * NOVARTIS AND PENN UNITE ON NEW ANTICANCER PATH By Katie Thomas The drugmaker Novartis and the University of Pennsylvania announced a research and licensing agreement that aims to bring to market a new approach to fighting CANCER that has shown promising results in early trials. The alliance seeks to build on the recent results of an experimental treatment that trains a person's immune system to kill cancer cells Scientists at the university announced last year significant results in several patients with advanced CHRONIC LYMPHOCYTIC LEUKEMIA who were treated using the new technique, including two who went into complete remission. The treatment uses a disabled form of the HIV-l virus to carry cancer-fighting genes into the patients' T-cells, a type of white blood cell that fights viruses and tumors. Although the study involved patients with leukemia, researchers hope to apply the approach to treat patients with a variety of cancers. Other trials are under way for LYMPHOMA, MESOTHELIOMA, MYELOA and NEUROBLASTOMA. A spokeswoman for Penn declined to comment on the financial details of the arrangement, but included in the deal is a commitment by Novartis to contribute $20 million to build the Center for Advanced Cellular Therapies, which will be devoted to studying the new treatments, on the campus. Novartis and Penn say the deal will combine the intellectual resources of the university with the commercial wherewithal of the company, a major drugmaker. Penn is granting Novartis an exclusive worldwide license to the technologies, and Penn will receive royalty payments. "Penn's intellectual resources, combined with a pharmaceutical industry leader like Novartis, offer a powerful symbiotic relationship in our mutual goal of finding more effective treatments for cancer," J. Larry Jameson, dean of the Perelman School of medicine at the University of Pennsylvania and executive ice president for the Health System, said in a statement announcing the deal. The arrangement is being announced as major pharmaceutical companies are cutting back on their deals with biotech firms and collaborating increasingly with universities instead. Agreements between pharmaceutical companies and biotech companies totaled $189 billion in the first seven months of this year (2012), a decline from the $22.7 billion in deals that were done over the same period a year ago, according to a recent report by the venture capital firm of Burrill & Company. The downside, said G Steven Burrill, chief executive of Burrill, is that Novartis and other companies will be taking on more risk by getting involved in research at its earliest phases. "Now they're going to own all of the development, both the risk and the cost," he said. * * * STUDY SAYS CHEMOTHERAPY DURING PREGNANCY DOESN'T CAUSE COMPLICATIONS According to recent studies, chemotherapy treatment after the first trimester -- when most of the baby's critical growth occurs -- can be safe for baby and mother. There is growing evidence that pregnant women with cancer aren't putting their babies at risk by undergoing chemotherapy treatments. A new study that followed more than 400 pregnant women in Europe who were diagnosed with BREAST CANCER, found little to no evidence of negative health effects on infants whose mothers underwent chemotherapy -- good news for the one in a thousand women who are pregnant and also suffering from cancer. Infants whose mothers were treated with chemotherapy weighed less than those that weren't exposed to chemotherapy, but they were not at higher risk of birth defects, blood disorders or loss of hair. According to the German Breast Group, which led the study, premature birth not the chemotherapy treatment was responsible for babies being born at a low birth weight and other complications. "More complications were reported in the group of infants exposed to chemotherapy than in the group not exposed to chemotherapy," the study said. "However, most complications were reported in babies who were delivered prematurely, irrespective of exposure to chemotherapy." Incidences of pregnant women with cancer are growing and it may be because many women are delaying childbirth until later in their lives. "I would say it is an increasing problem because people are generally delaying pregnancy," said Dr. Stephanie Bernik, chief of surgical oncology at Lenox Hill Hospital in New York. "Women want to have careers before they start a family, so women are getting pregnant later." Additionally, pregnant women are often diagnosed with cancer at a more advanced stage because cancer symptoms can sometimes be mistaken for signs of pregnancy, making treatment more complex, Bernik said. Now, a small body of scientific research has increasingly brought hope to women who are pregnant with cancer or those who become pregnant after a cancer diagnosis. In the past, women have been told by their doctors that chemotherapy could harm their baby and were sometimes advised to terminate the pregnancy. However, recent studies have found that chemotherapy treatment after the first trimester -- when most of the baby's critical growth occurs -- can be safe for baby and mother. "Ideally, you would avoid chemotherapy in the first trimester of pregnancy," Dr. Bernik said. "The thought is that the fetus is really developing at that stage and the organs are being developed." It was also initially feared that the high hormone levels present during pregnancy could cause a specific kind of hormone-sensitive breast cancer to reoccur. But a recent, first-of-its-kind study found that it is safe for women to become pregnant after they were treated with this form of cancer -- which accounts for about 60 percent of all breast cancer cases. This growing evidence may play a critical role in giving doctors confidence to treat pregnant cancer patients, said Dr. Elyce Cardonick, a maternal fetal medicine physician at Cooper University Hospital in New Jersey. "The first time someone experiences a patient who is pregnant they may be very fearful to treat them," said Cardonick, who maintains a registry of pregnant cancer patients that tracks their progress during and after their pregnancy. "When that oncologist or a gynecologist has a second patient, you get a little more comfortable. Each physician might only see one or two patients like this in their careers; that's why it's important to maintain a registry." The study by the German Breast Group confirmed other research indicating that chemotherapy treatments carry fewer risks to an unborn child than was originally assumed. But more research needs to be done on the potential physical and mental effects of chemotherapy drugs on a child later in its life. "The role of chemotherapy is to save the patient to be a mom," Cardonick said. "It's a risk-to-benefit ratio. Nothing is 100 percent safe." * * * NEW RHEUMATOID ARTHRITIS STUDY (Reuters) - GlaxoSmithKline Plc and Johnson & Johnson's Janssen Biologics said on Thursday they have begun late-stage trial testing of a new treatment for moderately active to severely active rheumatoid arthritis. The trial is evaluating sirukumab, or CNTO 136, a human anti-interleukin (IL)-6 monoclonal antibody. The Phase III program comprises two studies. One, dubbed SIRROUND-T, includes patients whose disease is active despite anti-tumor necrosis factor therapy. The second, dubbed SIRROUND-D, includes patients with active rheumatoid arthritis despite anti-rheumatic drug therapy. The studies are multi-center, randomized trials that compare the drug - administered under the skin - with a placebo. Both are double-blinded, meaning neither the patients nor the researchers will know which patients will get the real drug and which the dummy pill. Sirukumab is an investigational drug that is not approved to treat any disease anywhere in the world. * * * TESTING WHAT WE THINK WE KNOW By H. Gilbert Welch By 1990, many doctors were recommending hormone replacement therapy to healthy middle-aged women and P.S.A. screening for PROSTATE CANCER to older men. Both interventions had become standard medical practice. But in 2002, a randomized trial showed that prevention hormone replacement caused more problems (more heart disease and BREAST CANCER) than it solved (fewer hip fractures and colon cancer). Then, in 2009, trials showed that P.S.A. screening led to many unnecessary surgeries and had a dubious effect on prostate cancer deaths. How would you have felt -- after over a decade of following your doctor's advice -- to learn that high-quality randomized trials of these standard practices had only just been completed? And that they showed that both did more harm than good? Justifiably furious, I'd say. Because these practices affected millions of Americans, they are locked in a tight competition for the greatest medical error on record. The problem goes far beyond these two. The truth is that for a large part of medical practice, we don't know what works. But we pay for it anyway. Our annual per capita health care expenditure is now over $8,000. Many countries pay half that -- and enjoy similar, often better, outcomes. Isn't it time to learn which practices, in fact, improve our health, and which ones don't? To find out, we need more medical research. But not just any kind of medical research. Medical research is dominated by research on the new: new tests, new treatments, new disorders and new fads. But above all, it's about new markets. We don't need to find more things to spend money on, we need to figure out what's being done now that is not working. That's why we have to start directing more money toward evaluating standard practices -- all the tests and treatments that doctors are already providing. There are many places to start. Mammograms are increasingly finding a microscopic abnormality called D.C.I.S., or ductal carcinoma in situ. Currently we treat it as if it were invasive breast cancer, with surgery, radiation and chemotherapy. Some doctors think this is necessary, others don't. The question is relevant to more than 60,000 women each year. Don't you think we should know the answer?* Or how about this one: How should we screen for COLON CANCER? The standard approach, fecal occult blood testing, is simple and cheap. But more and more Americans are opting for colonoscopy -- over four million per year in Medicare alone. It's neither simple or cheap. In terms of the technology and personnel involved, it's more like going to the operating room. (I know, I've had one.) Which is better? We don't know. Let me be clear, answering questions like these is not easy. The Veterans Affairs Cooperation Studies Program is in fact preparing to take on the colonoscopy versus fecal occult blood testing question. The trial, which will involve up to 50,000 patients, will last a decade and surely cost millions of dollars. Research like this takes more than grant money. For starters, it takes a research infrastructure that monitors what standard practice is -- data on what's actually happening across the country. Because of Medicare, we have a clear view for patients age 65 and older, but it's a lot cloudier for those under 65. Basic questions like how common annual physical exams are and what testing is part of them are unanswerable. It also takes a research culture that promotes a healthy skepticism toward standard medical practice. That requires physician researchers who know what standard practice is, have the imagination to question it and the skills to study it. These doctors need training that's not yet part of any medical school curriculum; they need mentoring of senior researchers; and they need some assurance that investigating accepted treatments can be a viable option, instead of career suicide. We have to move quickly. The administrative demands of clinical care on one side, and the competition for research funding on the other make it increasingly difficult for researchers to see patients. They become isolated from standard practice, and their ability to study it diminishes. Clinicians who are well positioned to study these issues are increasingly directed toward enhancing productivity -- questions about how can we do this better faster or more consistently -- instead of questions about whether the practices are warranted in the first place. Here's a simple idea to turn this around: devote 1% of health care expenditures to evaluating what the other 99% is buying. Distribute the research dollars to match the clinical dollars. Figure out what works and what doesn't. The Patient-Centered Outcomes Research Institute (created as part of the Affordable Care Act to study the comparative effectiveness of different treatments) is supposed to tackle questions of direct relevance to patients and could take on this role, but its budget -- less than -0.03% of total spending -- is far from sufficient. A call for more medical research might sound like pablum. Worse, coming from a medical researcher, it might sound like self-interest (cut me some slack, that's another one of our standard practices). But I don't need the money. The system does. Or if you prefer, we can continue to argue about who pays for what -- without knowing what's worth paying for.
EDITOR'S NOTE: While I agree with many of this writer's points, until a test exists that tells us if there are any single cancer cells floating around in our bodies, cells that haven't aggregated into something that can be seen on a scan or in a blood test, it's up to patients and their doctors to evaluate each individual patient and then make treatment decisions based on something like an educated guess. There are no certainties, when it comes to cancer. * * * GENE TESTS IN YEAST AID WORK ON CANCER By Carl Zimmer People have been searching for new medicines for thousands of years, and yet we have barely explored the universe of possibilities. Recently chemists at the University of Bern in Switzerland tried to estimate how many promising molecules have yet to be tested. In June the published their best guess: over a million billion billion billion billion billion billion. Blindly testing those molecules one at a time is not practical, and most of them will turn out to be useless anyway. So many scientists are looking or strategies they can use to zero in ore quickly on promising candidates. At the University of Texas at Austin, a team of biologists is spending the search by exploring our evolutionary history. They are finding surprising links between the biology of humans and that of our most distant relatives -- links that point the way to new drugs. In the journal PLoS Biology, the researchers describe the first fruit of this approach: a drug that shows a promising ability to shrink tumors. It's CANCER-fighting ability has been hiding in plain sight since the 1960s, when it was approved to treat fungal infections. Until the new research, no one had thought to test the drug against cancer. One reason that drug hunting is so vexing is that scientists still don't know much about the functions of many genes inn humans. It's much easier to study the genes in other species. Scientists have systematically mutated more than 6,000 genes in yeast, for example, observing the changes those mutations activate in the organism. Humans and yeast share a common ancestor that lived some 12 billion years ago. That single-celled creature had already evolved clusters of genes that worked together to do particular jobs, like dividing cells or resisting stress The lineage that led to humans and the lineage that lad to yeast both inherited the same clusters of genes. Over the next 1.2 billion years, the clusters took on different jobs. But many of the genes in the original cluster remained, working together on the new tasks. Dr. Edward Marcotte, a molecular biologist at the University of Texas, reasoned that he might be able to uncover human gene clusters by looking at their counterparts in other species. In yeast, for example, he and his colleagues identified 68 genes that work together to build cell walls Dr. Marcotte and his colleagues then looked at the scientific literature about the human versions of those genes. Five of them, they found, are involved in building blood vessels. It is next to impossible, statistically speaking, that this overlap was the result of chance. It's far more likely that the cell-wall cluster in yeast and the blood-vessel cluster in humans evolved from an ancestral cluster of genes. Aside from the five genes that were known to be involved in blood vessel formation. Dr. Marcotte and his colleagues found other human genes matching those in the yeast cluster. But no one knew the function of those genes. Dr. Marcotte hypothesized that they also helped build blood vessels. To find out, he and his colleagues did experiments on frog embryos. The researchers found eight additional genes that also helped build blood vessels, bringing the total to 13 so far. This strategy has allowed Dr. Marcotte and his colleagues to make discoveries about hundreds of other genes. Plants have a network of genes for sensing gravity, for example Dr. Marcotte and his colleagues have discovered a human version of the network, which helps build the nervous system. Mutations to this nerve network can cause deafness. Dr. Marcotte and his colleagues then used this strategy to search for new drugs. The scientific literature is packed with studies on how potential drugs affect other species Dr. Marcotte's research hinted that there were connections to human health hidden in the results. Genes that guide the formation of blood vessels ay offer targets for cancer drugs, for example. Tumors grow so quickly that they need extra blood vessels to supply them with oxygen and nutrients. They release signals that spur nearby blood vessels to sprout new branches. Dr. Marcotte suspected that a drug that attacks the yeast cell-wall cluster would also attack blood vessels in cancer cells. "We could make a blind prediction," he said. Hye Ji Cha, a graduate student on Dr Marcotte's team, programmed a computer to search through millions of test results of different drugs on yeast. She found a handful of molecules that targeted the cluster of genes that builds cell walls. The drug that exited the scientists most was a compound known as thiabendazole. It was thrilling in its familiarity: Thiabendazole was approved by the Food and Drug Administration for fighting fungal infections back in 1967. One of the biggest worries in the search for drugs is that a promising compound will turn out to have toxic side effects. Thiabendazole's long track record made it unlikely that Dr. Marcotte and his colleagues would get such an unpleasant surprise. "We were particularly interested in it because it was human-approved," Dr. Marcotte said. To see if thiabendazole would attack blood vessels as they predicted, the scientists began by rearing frog tadpoles. Ordinarily, the tadpoles start to develop blood vessels three days after hatching. But when Dr Marcotte and his colleagues gave thiabendazole to the tadpoles, their blood vessels disintegrated into free-floating cells. "The cells actually let go of each other," Dr. Marcotte said. The effects of thiabendazole were precise and limited. As soon as the scientists washed the drug out of the tadpoles, they immediately started rebuilding their blood vessels. Dr. Marcotte and his colleagues then tried out thiabendazole on human blood vessel cells. Normally, the cells organize themselves into tubes. But when exposed to the drug, they fell apart. These experiments gave Dr. Marcotte and his colleagues the confidence to try out thiabendazole on tumors. They transplanted human tumors into mice. Left untreated, the tumors grow rapidly, fueling their growth by coaxing the mice to build blood vessels. In mice treated with thiabendazole, on the other hand, the tumors grew much more slowly. After 27 days, the drug-treated tumors were only about a quarter of the size of the untreated ones. "I'm really excited about this coming out," Dr. Morris Groves, the director of the Texas Oncology - Austin Brain Tumor Center, said of the new research. Despite his excitement, he warned that thiabedazole might not prove effective on cancers in people. "Ninety-five percent of drugs are probably going to fail," he said. "You just build your world around it." Even if thiabendazole doesn't reach the clinic, Dr. Groves thinks that Dr. Marcotte's strategy for systematically exploring evolution will accelerate the discovery of drugs. "You can mechanize that and make it a lot faster," Dr. Groves said. "That's a great step forward." * * * Finally ... LIMITING THE FALLOUT OF CANCER TREATMENT By Jane E. Brody Radiation therapy to treat CANCER depends on much higher doses than are used in imaging, and these treatments have long been known to increase a patient's risk of later developing another cancer. Doctors consider this risk of radiation therapy reasonable when the goal is to prevent death from the original cancer.* Last year in a report in The Lancet Oncology researchers from the National Cancer Institute and M. D. Anderson Cancer Center in Houston reported that among 647,672 adult cancer patients treated five or more years earlier, about 8% developed a second cancer years later related to radiation treatment of the first cancer More than half of the second cancers occurred in survivors of BREAST and PROSTATE CANCERS. As expected, the risk of developing a second cancer was highest among those originally treated at younger ages and most often involved organs exposed to the highest doses of radiation. In recent years, radiologists have taken great pains to limit radiation exposure to nontarget organs -- for example, by using a cone beam when treating breast cancer -- which should reduce the risk of radiation-induced second cancers. * * * Here's to a rainy fall! See you next month. * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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