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Radioimmunotherapy and Gemcitabine Combination Shows Early Promise for Metastatic Pancreatic Ductal Cancer

May 19, 2014
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NEW ORLEANS — A combination of several small doses of an investigational radioimmunotherapy and the chemotherapy gemcitabine had superior outcomes compared with radioimmunotherapy alone in patients with metastatic pancreatic ductal cancer, according to phase Ib clinical trial data presented at the AACR special conference on Pancreatic Cancer: Innovations in Research and Treatment, held May 18-21.

Vincent J. Picozzi Jr., M.D.

Vincent J. Picozzi Jr., M.D.

“Radiation therapy is an effective therapy against most cancers, including pancreatic cancer,” said Vincent J. Picozzi Jr., M.D., director of the Pancreas Center of Excellence at the Virginia Mason Medical Center’s Digestive Disease Institute. “However, an antibody that can recognize a target found only on most pancreatic cancer cells and that can carry a radioactive source with it has the potential to kill cancer cells throughout the body, as opposed to conventional radiation therapy, which is delivered as a ‘beam’ to a specific area of the body.”

One such radioimmunotherapy, 90Y-clivatuzumab tetraxetan, was used in this trial: PAM4 is the antibody and yttrium-90 (90Y) is the source of radiotherapy, and they are held together by a linker.
 
“The antibody binds to a protein called MUC5ac, which is a protein found on the surface of most pancreatic cancer cells, but not normal cells,” explained Picozzi. “90Y, a radioactive form of yttrium that emits radiation over a distance of about a quarter of an inch, is attached to this antibody.

“We found that 90Y-clivatuzumab tetraxetan, when used with low-dose gemcitabine, is a safe, low-side-effect therapy that can prolong survival for at least some patients with metastatic pancreatic cancer, even when no chemotherapy options exist,” he added. “Our studies imply that radiolabelled antibodies are safe to use in advanced pancreatic cancer, and that it may be possible to attach other anticancer agents besides 90Y to clivatuzumab tetraxetan to fight pancreatic cancer.”

In this trial, 58 patients, median age 63.5 years, including 33 males, who received at least two prior therapies, were randomly assigned to either arm A (29 patients) or arm B (29 patients). Patients from both arms received 6.5 mCi/m2 90Y-clivatuzumab tetraxetan for three weeks, divided into multiple smaller doses per cycle. Patients from arm A also received low-dose gemcitabine for one week and then in combination with the radioimmunotherapy for three weeks in each cycle. Patients received treatment for up to nine cycles, with four-week delays in between. The goal was to determine the safety and efficacy of this approach in this advanced population and evaluate the contribution of low-radiosensitizing doses of gemcitabine to the regimen.

Twenty-seven and 26 patients from arms A and B, respectively, completed at least one cycle of treatment. Patients terminated treatment due to disease progression or clinical deterioration, but 12 and 11 patients from arms A and B, respectively, completed two or more cycles of treatment.

The investigators found that the patients from arm A were 45 percent more likely to live longer, compared with patients from arm B. For patients who received only one treatment cycle, there was little survival difference between arm A and arm B. However, the overall survival was 7.9 months and 3.4 months, respectively, for patients from arm A and arm B who received multiple cycles of treatment.

In arm A, two patients had partial responses, and three patients are still alive 13 and 15 months after the start of their treatment.

Side effects were minimal, and the only clinically significant side effect that occurred with any frequency was reduction in blood counts, said Picozzi.

A larger, randomized phase III trial is underway to confirm these results.

“Patients are experiencing gradually increasing success in treating pancreatic cancer, even in advanced disease,” said Picozzi. “There are a variety of new approaches being developed for the treatment of pancreatic cancer, among the most promising of which is using the immune system in various ways to fight it.”

This study was funded by Immunomedics Inc. Picozzi declares no conflicts of interest.

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#AACRPanCa14

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Potential New Therapeutic Approach Identified for Two Types of Pancreatic Cancer

May 19, 2014
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NEW ORLEANS — Blocking the protein CD47, which was found at elevated levels on both pancreatic neuroendocrine tumor cells and pancreatic ductal adenocarcinoma cells, caused tumor regression in preclinical models of both these types of pancreatic cancer, according to results presented here at the AACR special conference on Pancreatic Cancer: Innovations in Research and Treatment, held May 18–21.

Geoffrey W. Krampitz, M.D.

Geoffrey W. Krampitz, M.D.

“Our analysis of tumor samples from patients with pancreatic neuroendocrine tumors and those with pancreatic ductal adenocarcinoma has shown that for both these types of pancreatic cancer, CD47 is expressed at elevated levels on the cells that make up the bulk of the tumors and on the tumor-initiating cells, which are the cells that propagate disease and cause metastasis,” said Geoffrey W. Krampitz, M.D., a doctoral candidate in the laboratory of Irving L. Weissman, M.D., director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine and the Ludwig Center for Cancer Stem Cell Research at Stanford in California. “We also found that using a monoclonal antibody that blocks CD47 eradicates tumors in various preclinical models of both pancreatic neuroendocrine tumors and pancreatic ductal adenocarcinoma.

“We are optimistic that targeting CD47 in this way could provide a new approach for treating patients with pancreatic cancer who have a desperate need for improved treatment options,” added Krampitz, who is also a general surgery resident in the Department of Surgery at Stanford Hospital and Clinics.

Krampitz and Jeffrey A. Norton, M.D., chief of the Divisions of General Surgery and Surgical Oncology at Stanford University School of Medicine, obtained tumor samples from 39 patients with pancreatic neuroendocrine tumors who were undergoing surgery to remove their cancers. Analysis of 19 of these samples showed that some cells in the tumors had characteristics of tumor-initiating cells and that these cells, as well as the bulk tumor cells, had elevated levels of CD47.

The researchers also obtained tumor samples from 39 patients with pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, who were undergoing surgical resection. As with the pancreatic neuroendocrine tumors, all the pancreatic ductal adenocarcinoma cells in the samples examined had elevated levels of CD47.

They then tested the effects of blocking CD47 function in a number of different preclinical models of pancreatic neuroendocrine tumors and pancreatic ductal adenocarcinoma. Antitumor activity was observed in each model. In one model, in which mice were transplanted with tumors from either patients with pancreatic neuroendocrine tumors or those with pancreatic ductal adenocarcinoma, treatment with a monoclonal antibody that recognizes and attaches to CD47 and blocks its function caused dramatic tumor regression.

“CD47 is a ‘don’t-eat-me’ signal,” explained Krampitz. “Most cells have this protein on their surface and it stops them from being removed by immune cells called macrophages. As cells age or become damaged, they lose expression of CD47, which leads to their elimination by macrophages through a process called programmed cell removal. Pancreatic neuroendocrine tumors and pancreatic ductal adenocarcinomas have co-opted CD47 to help them avoid removal by the immune system. We have preliminary evidence that suggests that by blocking the don’t-eat-me signal, our monoclonal antibody promotes the clearance of cancer cells by programmed cell removal.

“We need to do more preclinical studies but are hopeful that our participation in the recently announced Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team will allow us to test our approach in the clinic in the not-too-distant future,” he added.

This study was supported by funds from the Virginia and D.K. Ludwig Foundation for Cancer Research, the National Cancer Institute, the A. P. Giannini Foundation, the Siebel Stem Cell Institute and the Thomas and Stacey Siebel Foundation, an Anonymous Donors Fund, and the American College of Surgeons. Krampitz declares no conflicts of interest.

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#AACRPanCa14

New Blood-based Biomarker Panel May Enable Pancreatic Cancer Diagnosis at an Early Stage

May 19, 2014
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NEW ORLEANS — A panel of four blood biomarkers, comprised of the known pancreatic cancer biomarker CA 19-9 and three new biomarkers, successfully distinguished individuals with pancreatic cancer from individuals who were healthy, had chronic pancreatitis, or had pancreatic cysts approximately 90 percent of the time, according to results presented here at the AACR special conference on Pancreatic Cancer: Innovations in Research and Treatment, held May 18–21.

Ayumu Taguchi, Ph.D., M.D.

Ayumu Taguchi, Ph.D., M.D.

The four blood biomarkers together correctly identified 92 percent, 85 percent, and 92 percent of samples as having come from patients with pancreatic cancer when compared with samples from healthy individuals, patients with chronic pancreatitis, and patients with pancreatic cysts, respectively. The panel also correctly identified as negative for pancreatic cancer, 94 percent, 90 percent, and 91 percent of samples from healthy individuals, patients with chronic pancreatitis, and patients with pancreatic cysts, respectively.

“Our biomarker panel was much better at distinguishing patients with pancreatic cancer from those who were healthy, had chronic pancreatitis, or had pancreatic cysts compared with CA 19-9 alone,” said Ayumu Taguchi, Ph.D., M.D., assistant professor at The University of Texas MD Anderson Cancer Center in Houston. “This means that our panel has the potential to substantially reduce the number of patients who would have to undergo extremely invasive screening procedures.”

According to Taguchi, only about 10 percent of patients with pancreatic cancer are diagnosed when the disease is localized, a situation that improves outcomes. Moreover, current imaging techniques for pancreatic cancer detection are not amenable to widespread screening programs and the CA 19-9 blood-based biomarker is not sufficiently reliable to be used broadly, he added.

Taguchi and colleagues analyzed levels of CA 19-9 and 20 other potential biomarkers in blood samples from 98 patients with pancreatic cancer, 50 healthy individuals, and 29 patients with chronic pancreatitis. This initial analysis allowed them to determine the best combination of potential biomarkers for further study.

The four-biomarker panel was validated using blood samples from two independent cohorts: One consisted of 42 patients with early-stage pancreatic cancer, 50 healthy individuals, and 50 patients with chronic pancreatitis and the other consisted of 22 patients with early-stage pancreatic cancer and 14 patients with benign pancreatic cysts. In these analyses, CA 19-9 alone correctly identified as negative for pancreatic cancer blood samples from 78 percent, 78 percent, and 76 percent of healthy individuals, patients with chronic pancreatitis, and patients with pancreatic cysts, compared with 94 percent, 90 percent, and 91 percent for the four-biomarker panel, respectively.

“We need to further validate our panel using larger numbers of samples collected before diagnosis of early-stage pancreatic cancers,” said Taguchi. “However, we are hopeful that we can develop a panel that will have clinical application.”

This study was supported by funds from the National Cancer Institute Early Detection Network and The Lustgarten Foundation. Taguchi declares no conflicts of interest.

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#AACRPanCa14

Water Pipe Smoking Causes Significant Exposure to Nicotine and Cancer-causing Agents

May 16, 2014
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PHILADELPHIA — Young adults who smoked water pipes in hookah bars had elevated levels of nicotine, cotinine, tobacco-related cancer-causing agents, and volatile organic compounds (VOC) in their urine, and this may increase their risk for cancer and other chronic diseases, according to a study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Gideon St.Helen, Ph.D.

Gideon St.Helen, Ph.D.

“This study reports systemic intake of tobacco-specific nitrosamines and VOCs after a typical water pipe-smoking session in a hookah bar setting, thus making the findings generalizable to most water pipe users in the United States,” said Gideon St.Helen, Ph.D., postdoctoral fellow in the Division of Clinical Pharmacology and the Center for Tobacco Control Research and Education at the University of California, San Francisco.

After a single evening of water pipe smoking in a hookah bar, young men and women had in their urine a 73-fold increase in nicotine; fourfold increase in cotinine; twofold increase in NNAL, a breakdown product of a tobacco-specific nitrosamine, NNK, which can cause lung and pancreatic cancers; and 14 to 91 percent increase in the breakdown products of VOC such as benzene and acrolein that are known to cause cancer and cardiovascular and respiratory diseases.

“There was also a substantial increase in nicotine levels, which raises concerns about the potential addictiveness of water pipe smoking and possible effects on the developing brains of children and youths who use water pipes,” added St.Helen. “Water pipe smoking is generally perceived to be a safe alternative to cigarette smoking, even for children and youths. Our study shows that water pipe use, particularly chronic use, is not risk-free.”

St.Helen and colleagues recruited 55 healthy, experienced water pipe smokers, ages 18 to 48 years, to the study. Participants were instructed to refrain from any type of smoking for a week.

At the end of this period they provided a “before” urine sample and smoked water pipes at a hookah bar of their choice in the San Francisco Bay area. Soon after the visit, they provided the “after” urine sample, and filled a form to provide detailed information on their smoking session including total time spent smoking, number of bowls smoked, and number of shared users. They also provided a first-voided urine sample the next morning, which helped researchers estimate the clearance of the tobacco-related chemicals of interest.

The study participants spent on average 74 minutes smoking water pipes and smoked an average 0.6 bowls of water pipe tobacco per person.

The researchers found that the elevated levels of nicotine, cotinine, and NNAL, which were detected immediately after the water pipe-smoking session, remained significantly elevated in the next-day urine samples, compared with the “before” samples: Nicotine was 10.4-fold higher; cotinine, 3.2-fold; and NNAL, 2.2-fold.

Water pipe-smoking duration correlated significantly with the increase in post-exposure urine nicotine levels, and number of bowls smoked per person significantly correlated with the increase in post-exposure and next-day urine cotinine levels, respectively. The average increase in nicotine levels was comparable to levels obtained after smoking at least one cigarette, explained St.Helen.

“I have seen entire families, including young children, smoking water pipes. I have even been offered a smoke by my friend who thought water pipe smoking was ‘totally safe,’” St.Helen added. “Our study provides evidence that water pipe smoking leads to significant intake of tobacco-related addictive and harmful substances, and is therefore not without risk, particularly among children and youths.”

This study was funded by the National Institutes of Health and the California Tobacco-related Disease Research Program. St.Helen declares no conflicts of interest.

Pam Ballinger Appointed Senior Director of Meetings and Exhibits for the American Association for Cancer Research

May 13, 2014
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PHILADELPHIA — The American Association for Cancer Research (AACR) has appointed Pam Ballinger, CMP, as senior director of meetings and exhibits. In her role, Ballinger will oversee the planning and implementation of all meeting logistics for more than 25 AACR annual conferences and educational workshops, including the AACR Annual Meeting, which attracts more than 18,500 attendees, making it the world’s largest scientific meeting in cancer research.

“I am extremely pleased to welcome Pam to the AACR’s senior management staff. Her extensive experience and expertise in coordinating large-scale meetings for medical professionals will be invaluable in our efforts to ensure the seamless operation of the AACR’s expanding meetings and events program,” said Margaret Foti, Ph.D., M.D. (h.c.), chief executive officer of the AACR. “Pam’s innate creativity and innovativeness, coupled with her outstanding leadership skills, will further enhance the experience of participants in our meetings and help the AACR to accelerate the dissemination of new research findings to the cancer community as well as the public at large.”

Prior to joining the AACR, Ballinger served for 14 years as vice president of meeting services at Association Headquarters (AH), an association management company for nonprofits in Mount Laurel, N.J., where she managed AH’s largest meetings, including the American Transplant Congress and the joint annual meeting of the American Society of Transplant Surgeons and the American Society of Transplantation. Previously she was director of meetings at Slack Inc., a medical publishing and communications company.

“I am excited to accept the challenge of developing innovative ways to help scientists share their findings, learn from each other, and advance the cause of cancer research,” Ballinger said. “I hope to build upon and improve what is already a world-class meetings program.”

Ballinger holds the designation of Certified Meeting Professional (CMP) from the Convention Industry Council and is past president and a member of the board of directors of the Greater Philadelphia chapter of the Professional Convention Management Association. She serves on the customer advisory boards of convention and visitors bureaus in several cities.
 
Before going into association meeting management, Ballinger was a medical editor for J.B. Lippincott and Slack Inc. She holds a bachelor’s degree from the University of Maine.

AACR to Host Two Press Teleconferences at Pancreatic Cancer Conference

May 8, 2014
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NEW ORLEANS — The American Association for Cancer Research (AACR) will host two press teleconferences at its special conference on Pancreatic Cancer: Innovations in Research and Treatment, May 18-21 at the Hyatt Regency New Orleans.

A press kit containing embargoed news releases and highlighted abstracts will be available to media May 13.

First Teleconference
The first teleconference will be held Monday, May 19, 10 a.m. CT. Reporters can dial in at 866-297-6395 (United States/Canada) or 847-944-7317 (international), and should offer confirmation code 37195596 when prompted. It will include:

  • Analyses projecting paradigm-shifting pancreatic cancer mortality rates;
  • Updated results of a phase Ib trial combining gemcitabine with a new radioimmunotherapy for metastatic pancreatic cancer;
  • Development and validation of a blood-based biomarker panel for detection of early-stage pancreatic cancer; and
  • Preclinical results indicating CD47 may be a therapeutic target for pancreatic neuroendocrine tumors and pancreatic ductal adenocarcinoma.

Second Teleconference
On Wednesday, May 21, 10 a.m. CT, conference leaders David Tuveson, M.D., Ph.D., The Lustgarten Foundation and Cold Spring Harbor Laboratories; Christine Iacobuzio-Donahue, M.D., Memorial Sloan Kettering Cancer Center; and Alec Kimmelman, M.D., Ph.D., Dana-Farber Cancer Institute, will offer analysis of the conference, including discussion of exciting new research areas and potential treatment options.

Reporters who join that press teleconference should dial 866-297-6395 (United States/Canada) or 847-944-7317 (international) and offer confirmation code 37264783 when prompted.

Read the conference program.

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John Leonard Joins Board of Trustees of the AACR Foundation

May 8, 2014
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PHILADELPHIA — The American Association for Cancer Research (AACR) is pleased to announce that John E. Leonard, Ph.D., has joined the board of trustees of the AACR Foundation.

Leonard has worked in the biotechnology industry since 1988 and has held numerous leadership positions, including senior vice president of development at Vaccinex Inc., where he has served as an officer since 2009. Leonard is also the president and chief executive officer of the John and Elizabeth Leonard Family Foundation, which provides support for several grants and scholarships including a fellowship in basic cancer research in partnership with the AACR.

“I am absolutely delighted that Dr. Leonard has accepted our invitation to join the AACR Foundation board of trustees,” said Margaret Foti, Ph.D., M.D. (h.c.), chief executive officer of the AACR. “Dr. Leonard brings a wealth of experience in the biotechnology industry to the foundation. His guidance, expertise, and enthusiasm for the foundation’s mission will be invaluable as we expand our efforts to fund urgently needed cancer research and gives new hope to cancer patients.”

In the biotechnology industry, Leonard specialized in therapeutic antibody development. While at IDEC Pharmaceuticals and then Biogen Idec, he served in leadership positions on product development teams for drugs including rituximab (Rituxan), used to treat B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis; ibritumomab tiuxetan (Zevalin), for B-cell non-Hodgkin lymphoma; and natalizumab (Tysabri), for multiple sclerosis and Crohn’s disease.

“Translational research can improve the lives of patients with life-threatening diseases,” Leonard said. “Especially now, when cancer research funding from the federal government is insufficient, private funding has an even greater role to play. I look forward to helping the AACR address this need.”

Leonard received his doctorate in biochemistry from the University of California, Riverside. He served in the U.S. Army Reserve’s Medical Service Corps and retired as a colonel; he is a veteran of the 1990-91 Gulf War.

Leonard is a co-holder of five patents and author or co-author of numerous articles published in peer-reviewed journals. He has been a member of the AACR since 1986.

He and his wife, Elizabeth, in 2011 set up and funded the John and Elizabeth Leonard Family Foundation, a 501(c)(3) nonprofit organization, to support translational research, promote education in mathematics and the sciences, aid the disadvantaged, and address environmental issues. 

The mission of the AACR Foundation supports that of the AACR—to prevent and cure cancer through research, education, communication, and collaboration. Through its programs and services, the AACR fosters cancer research and related biomedical science; accelerates the dissemination of new research findings among scientists and others dedicated to the conquest of cancer; promotes science education and training; and advances the understanding of cancer causes, prevention, diagnosis, and treatment throughout the world. The foundation funds programs deemed by the AACR to be of the highest priority and impact in achieving this shared mission.