Final results of a pivotal Phase 2 clinical trial of pralatrexate (PDX) for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) were reported by the study's principal investigator, Dr. Owen A. O'Connor of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital/Columbia. T-cell lymphoma (PTCL) is a biologically diverse group of blood cancers that account for as many as 15 percent of non-Hodgkin's lymphoma (NHL) cases in the United States.
Data from the PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial show that pralatrexate, a drug that partially works by mimicking the vitamin folic acid, has an estimated median duration of response of 287 days, or 9.4 months. As previously reported, 29 of 109 evaluable patients, or 27 percent, showed a complete or partial response.
"Until now, these patients could only expect to survive several weeks. This study shows that it may be possible to extend this to many months - a result that is nothing short of spectacular and may likely represent a breakthrough in the development of new drugs for T-cell lymphoma," said Dr. O'Connor, director of the Lymphoid Development and Malignancy Program and chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, and associate professor of medicine at Columbia University College of Physicians and Surgeons. "Based on these promising data, pralatrexate has the potential to play a clinically meaningful role in the treatment of patients with relapsed or refractory PTCL."
Pralatrexate, designed to look like the natural vitamin folic acid, disrupts DNA synthesis in tumor cells. The drug is designed to selectively accumulate in tumor cells, after which it then induces programmed cell death, or apoptosis, in the cancer cell.
There are currently no pharmaceutical agents approved for use in the treatment of either first-line or relapsed or refractory PTCL, and overall five-year survival is approximately 25 percent after first-line therapy. In addition to those PTCL patients who do not respond to first-line treatment, a significant number of first-line multi-agent chemotherapy responders relapse or become refractory after treatment.
The PROPEL trial is organized by Allos Therapeutics Inc., the maker of the drug. The company expects to submit a New Drug Application to the U.S. Food and Drug Administration for marketing approval of pralatrexate sometime in the first half of 2009. The results of the trial will be submitted for presentation at an upcoming scientific meeting and for publication in a peer-reviewed journal.
Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.
The critical PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial - an international, multicenter, open-label, single-arm study - enrolled a total of 115 patients with relapsed or refractory PTCL, 109 of whom are considered evaluable for response according to the trial protocol. It is believed that PROPEL is the largest prospectively designed single-agent trial conducted to date for this patient population.
To be eligible for the trial, patients' disease must have progressed after at least one prior treatment. Patients were considered evaluable if they received at least one dose of pralatrexate and their diagnosis of PTCL was confirmed by independent pathology review. Patients received 30 mg/m2 of pralatrexate intravenously once every week for six weeks followed by one week of rest per cycle of treatment. Patients also received vitamin B12 and folic acid supplementation. The primary endpoint of the trial is objective response rate, as assessed by central, independent oncology review using International Workshop Criteria (IWC). Duration of response is the key secondary endpoint.
Of the 29 patients who achieved a response according to central independent oncology review, 7 patients had a complete response (CR), 2 patients had a complete response unconfirmed (CRu) and 20 patients had a partial response (PR). According to the PROPEL investigators, 42 of 109 evaluable patients, or 39 percent, achieved a response. Of these, 15 patients had a CR, 4 patients had a CRu and 23 patients had a PR. PROPEL patients received a median of three prior systemic treatment regimens (range of 1 to 12), including 18 patients, or 16 percent, who had previously undergone an autologous stem cell transplant. In the trial, 66 percent of the patients who responded did so after cycle one of therapy. Patients will continue to be followed for long-term survival.
Peripheral T-Cell Lymphoma
According to the American Cancer Society, approximately 66,000 patients are expected to be diagnosed with non-Hodgkin's lymphoma in the United States in 2009. Annual prevalence is estimated to be approximately 9,500 patients. In addition to the 30 percent to 50 percent of PTCL patients that do not respond to first-line treatment, a significant number of first-line, multi-agent chemotherapy responders relapse or become refractory after treatment.
NewYork-Presbyterian Hospital
NewYork-Presbyterian Hospital, based in New York City, is the nation's largest not-for-profit, non-sectarian hospital, with 2,242 beds. The Hospital has nearly 2 million inpatient and outpatient visits in a year, including more than 230,000 visits to its emergency departments - more than any other area hospital. NewYork-Presbyterian provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/The Allen Pavilion and NewYork-Presbyterian Hospital/Westchester Division. One of the largest and most comprehensive health care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. It ranks sixth in U.S.News & World Report's guide to "America's Best Hospitals," ranks first on New York magazine's "Best Hospitals" survey, has the greatest number of physicians listed in New York magazine's "Best Doctors" issue, and is included among Solucient's top 15 major teaching hospitals. The Hospital's mortality rates are among the lowest for heart attack and heart failure in the country, according to a 2007 U.S. Department of Health and Human Services (HHS) report card. The Hospital has academic affiliations with two of the nation's leading medical colleges: Weill Cornell Medical College and Columbia University College of Physicians and Surgeons. For more information, visit www.nyp.org.
Columbia University Medical Center
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The Medical Center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.
Source: NewYork-Presbyterian Hospital
Wednesday, 19 May 2010
Tuesday, 4 May 2010
A Century-Old Puzzle Comes Together, Scientists ID Potential Protein Trigger In Lung Disease Sarcoidosis
Lung researchers at Johns Hopkins have identified a possible protein trigger responsible for sarcoidosis, a potentially fatal inflammatory disease marked by tiny clumps of inflammatory cells that each year leave deep, grainy scars on the lungs, lymph nodes, skin and almost all major organs in hundreds of thousands of Americans.
The disorder, whose cause has been a persistent mystery for nearly a century, strikes mostly young adults and disproportionately affects African Americans.
The link between sarcoidosis and overproduction of the suspected protein trigger, called serum amyloid A, was revealed after a six-year investigation encompassing more than two dozen laboratory experiments, including some on diseased lung tissue samples from 86 patients in the Baltimore area.
"The increase in production of serum amyloid A explains for the first time how inflammation can persist in the lungs without being triggered by an active infection," says study senior investigator and pulmonologist David Moller, M.D., a professor at the Johns Hopkins University School of Medicine. Moller is also director of the sarcoidosis clinic at The Johns Hopkins Hospital.
Study lead investigator Edward Chen, M.D., says the new findings also clear the path for developing drug treatments or vaccines that can block serum amyloid A from binding to cell receptors and kicking off inflammation.
In the short term, however, Moller says his team has plans to use the study results to create diagnostic tests that could better predict which people with the disease are likely to heal on their own or are more likely to suffer persistent inflammation, which can lead to scarring, difficulty breathing, and heart failure that can only be fixed by lung transplantation.
In a report published in February in the American Journal of Respiratory and Critical Care Medicine, the Johns Hopkins scientists described their research on what was behind the microscopic clusters of inflamed tissue and white blood cells, or granulomas, which are a defining feature of sarcoidosis.
Such lung lesions are not unique to sarcoidosis and can be triggered by infections, such as in tuberculosis, which is often confused with sarcoidosis. But unlike tuberculosis, sarcoidosis is not an infectious disease, does not yield to antibiotics, and is not limited to any particular organ, occurring as well in the eyes, skin, brain, heart and liver.
Of particular interest to researchers was the role played by so-called amyloids, a set of proteins known to cause other persistent inflammatory conditions, such as amyloidosis. Indeed, a different kind of amyloid has been tied to plaques in the brain tissue of people with Alzheimer's disease.
Key among the researchers' findings in sarcoidosis patients was that serum amyloid A stood out because it was heavily concentrated within the granulomas in diseased and scarred lung tissue. Researchers found the protein a hundred to a thousand times more widespread in sarcoidosis tissue samples than in samples from people with tuberculosis, another granuloma-forming lung disease. Similarly elevated amyloid levels were seen in comparison tests with tissue samples from people with lung cancer and Crohn's disease.
Further tests in patients' lung cell cultures showed that adding serum amyloid A spiked production of at least a half-dozen key inflammatory chemicals known to be involved in damaging tissue.
In another series of experiments in mice, the team discovered that granuloma formation in the lungs sped up when the mice were given injections of synthetic serum amyloid A. Mice had previously been injected with specially coated plastic beads designed to trigger sarcoidosis-like lesions. Adding the synthetic protein led to the same biochemical reactions in the mice as observed in humans, suggesting to the researchers that serum amyloid A played a key role in triggering sarcoidosis.
To better understand how serum amyloid A might be driving granuloma formation, the team used special antibodies to block various cell surface receptor sites where the protein would bind to the white blood cells and spur inflammation. Tests in human lung cells showed that blocking one particular receptor, toll-like receptor-2 (TLR2), inhibited the sustained inflammatory reaction typically associated with sarcoidosis. But when left to bind on its own, without an antibody blocking TLR2, the open receptor could attach to serum amyloid A, and raised production of inflammatory chemicals would ensue.
"Not only have we shown that serum amyloid A is a key protein trigger in sarcoidosis, but we also have evidence that the resulting inflammation is dependent on binding the protein at toll-like receptor-2, which opens up a host of possibilities that drugs blocking this binding site could prove an effective treatment for this disease," says Chen, an assistant professor at Johns Hopkins.
Funding support for the report and research was provided by the National Institutes of Health, the American Thoracic Society, the Foundation for Sarcoidosis Research, the Life and Breath Foundation, and the Hospital for the Consumptives of Maryland (Eudowood.)
Source: Johns Hopkins Medicine
The disorder, whose cause has been a persistent mystery for nearly a century, strikes mostly young adults and disproportionately affects African Americans.
The link between sarcoidosis and overproduction of the suspected protein trigger, called serum amyloid A, was revealed after a six-year investigation encompassing more than two dozen laboratory experiments, including some on diseased lung tissue samples from 86 patients in the Baltimore area.
"The increase in production of serum amyloid A explains for the first time how inflammation can persist in the lungs without being triggered by an active infection," says study senior investigator and pulmonologist David Moller, M.D., a professor at the Johns Hopkins University School of Medicine. Moller is also director of the sarcoidosis clinic at The Johns Hopkins Hospital.
Study lead investigator Edward Chen, M.D., says the new findings also clear the path for developing drug treatments or vaccines that can block serum amyloid A from binding to cell receptors and kicking off inflammation.
In the short term, however, Moller says his team has plans to use the study results to create diagnostic tests that could better predict which people with the disease are likely to heal on their own or are more likely to suffer persistent inflammation, which can lead to scarring, difficulty breathing, and heart failure that can only be fixed by lung transplantation.
In a report published in February in the American Journal of Respiratory and Critical Care Medicine, the Johns Hopkins scientists described their research on what was behind the microscopic clusters of inflamed tissue and white blood cells, or granulomas, which are a defining feature of sarcoidosis.
Such lung lesions are not unique to sarcoidosis and can be triggered by infections, such as in tuberculosis, which is often confused with sarcoidosis. But unlike tuberculosis, sarcoidosis is not an infectious disease, does not yield to antibiotics, and is not limited to any particular organ, occurring as well in the eyes, skin, brain, heart and liver.
Of particular interest to researchers was the role played by so-called amyloids, a set of proteins known to cause other persistent inflammatory conditions, such as amyloidosis. Indeed, a different kind of amyloid has been tied to plaques in the brain tissue of people with Alzheimer's disease.
Key among the researchers' findings in sarcoidosis patients was that serum amyloid A stood out because it was heavily concentrated within the granulomas in diseased and scarred lung tissue. Researchers found the protein a hundred to a thousand times more widespread in sarcoidosis tissue samples than in samples from people with tuberculosis, another granuloma-forming lung disease. Similarly elevated amyloid levels were seen in comparison tests with tissue samples from people with lung cancer and Crohn's disease.
Further tests in patients' lung cell cultures showed that adding serum amyloid A spiked production of at least a half-dozen key inflammatory chemicals known to be involved in damaging tissue.
In another series of experiments in mice, the team discovered that granuloma formation in the lungs sped up when the mice were given injections of synthetic serum amyloid A. Mice had previously been injected with specially coated plastic beads designed to trigger sarcoidosis-like lesions. Adding the synthetic protein led to the same biochemical reactions in the mice as observed in humans, suggesting to the researchers that serum amyloid A played a key role in triggering sarcoidosis.
To better understand how serum amyloid A might be driving granuloma formation, the team used special antibodies to block various cell surface receptor sites where the protein would bind to the white blood cells and spur inflammation. Tests in human lung cells showed that blocking one particular receptor, toll-like receptor-2 (TLR2), inhibited the sustained inflammatory reaction typically associated with sarcoidosis. But when left to bind on its own, without an antibody blocking TLR2, the open receptor could attach to serum amyloid A, and raised production of inflammatory chemicals would ensue.
"Not only have we shown that serum amyloid A is a key protein trigger in sarcoidosis, but we also have evidence that the resulting inflammation is dependent on binding the protein at toll-like receptor-2, which opens up a host of possibilities that drugs blocking this binding site could prove an effective treatment for this disease," says Chen, an assistant professor at Johns Hopkins.
Funding support for the report and research was provided by the National Institutes of Health, the American Thoracic Society, the Foundation for Sarcoidosis Research, the Life and Breath Foundation, and the Hospital for the Consumptives of Maryland (Eudowood.)
Source: Johns Hopkins Medicine
Monday, 3 May 2010
Tumors Hide Out From The Immune System By Mimicking Lymph Nodes
A new mechanism explaining how tumors escape the body's natural immune surveillance has recently been discovered at EPFL (Ecole Polytechnique Fédérale de Lausanne) in Switzerland. The study shows how tumors can create a tolerant microenviroment and avoid attack by the immune system by mimicking key features of lymph nodes. The discovery, published in Science and in Science Express, online March 25, 2010, underscores the role of the lymphatic system in cancer and may open up new possibilities for cancer treatment.
"The tumor tricks the body into thinking it is healthy tissue," says lead author Melody Swartz, head of the Laboratory of Lymphatic and Cancer Bioengineering (LLCB) and EPFL professor. Swartz and her team set out to understand how immune tolerance is induced by tumors, allowing them to progress and spread. The researchers from EPFL concentrated their efforts on a certain protein that is normally present in healthy lymph nodes to attract T cells and program them to perform vital immune functions. They found that some tumors can secrete this protein to transform the outer layer of the tumor into lymphoid-like tissue. This outer layer then attracts and effectively re-programs the T cells to recognize the tumor as friend not foe, resulting in a tumor that goes undetected by the immune system.
Since most tumors progress only if they have escaped the immune system, this new understanding of one mechanism by which the tumor can bypasses or hides from immune defenses is an important step towards future cancer therapies. "The finding that tumors can attract naïve and regulatory T cells and educate them has important implications for tumor immunotherapy," says Jacqui Shields, from LLCB. The study also opens up potential novel areas of research focusing on the relationship between lymphatic systems and cancer research. According to Shields, the concept that tumors mimic lymphoid tissue to alter the host's immune response represents a new understanding of tumors' interactions with the lymphatic system.
The laboratory is affiliated with the EPFL's Institute of Bioengineering and the Swiss Institute for Experimental Cancer Research.
Source: Ecole Polytechnique Federale de Lausanne (EPFL)
"The tumor tricks the body into thinking it is healthy tissue," says lead author Melody Swartz, head of the Laboratory of Lymphatic and Cancer Bioengineering (LLCB) and EPFL professor. Swartz and her team set out to understand how immune tolerance is induced by tumors, allowing them to progress and spread. The researchers from EPFL concentrated their efforts on a certain protein that is normally present in healthy lymph nodes to attract T cells and program them to perform vital immune functions. They found that some tumors can secrete this protein to transform the outer layer of the tumor into lymphoid-like tissue. This outer layer then attracts and effectively re-programs the T cells to recognize the tumor as friend not foe, resulting in a tumor that goes undetected by the immune system.
Since most tumors progress only if they have escaped the immune system, this new understanding of one mechanism by which the tumor can bypasses or hides from immune defenses is an important step towards future cancer therapies. "The finding that tumors can attract naïve and regulatory T cells and educate them has important implications for tumor immunotherapy," says Jacqui Shields, from LLCB. The study also opens up potential novel areas of research focusing on the relationship between lymphatic systems and cancer research. According to Shields, the concept that tumors mimic lymphoid tissue to alter the host's immune response represents a new understanding of tumors' interactions with the lymphatic system.
The laboratory is affiliated with the EPFL's Institute of Bioengineering and the Swiss Institute for Experimental Cancer Research.
Source: Ecole Polytechnique Federale de Lausanne (EPFL)
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