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July 11, 2014

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New Approach Identifies Cancer Mutations as Targets of Effective Melanoma Immunotherapy

July 1, 2014
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PHILADELPHIA —A new approach demonstrated that the recognition of unique cancer mutations appeared to be responsible for complete cancer regressions in two metastatic melanoma patients treated with a type of immunotherapy called adoptive T-cell therapy. This new approach may help develop more effective cancer immunotherapies, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Steven A. Rosenberg, MD, PhD

Steven A. Rosenberg, MD, PhD

“This study provides the technical solution to identify mutated tumor targets that can stimulate immune responses, which is one of the major bottlenecks in developing a new generation of adoptive T-cell therapy,” said Steven A. Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute (NCI) in Bethesda, Maryland. “The two targets identified in this study play important roles in cancer cell proliferation.

“Immunotherapy has the potential to successfully treat cancer by targeting tumor mutations. We’ve moved one step closer because of this study,” Rosenberg added.

Adoptive T-cell therapy is a type of immunotherapy in which the immune cells infiltrating a patient’s tumor, so called tumor-infiltrating lymphocytes (TILs, which are T cells), are harvested, activated and expanded in the laboratory, and transferred back to the patient. Such activated cells are capable of efficiently attacking tumor cells.

“In a clinical trial, up to 72 percent of the patients with metastatic melanoma experienced tumor regression after adoptive T-cell transfer. However, not all patients benefited. This is because the specificity of the TILs remains largely unclear. Our goal was to establish an efficient method to identify the specificity of these cells,” explained Rosenberg.

The researchers took tumor samples from two patients who had benefited from the therapy and pursued two screening approaches to identify the tumor targets recognized by the clinically effective T cells. First, they used a conventional screening method called cDNA library screening to identify nonmutated targets. Second, they used a novel method called tandem minigene library screening to identify mutated targets that cannot be found by the conventional method of screening.

For the second approach, the researchers used next-generation DNA sequencing to sequence the coding regions of the DNA from the two patients’ tumors, and identified mutations. Next, they generated a library of these mutations. Instead of synthesizing the entire mutated gene, they synthesized only a small region surrounding the mutation (hence the name “minigene” library). They then screened the minigene library to identify those targets in the patients’ tumors that were recognized by their TILs.

Using cDNA library screening, the researchers identified three novel nonmutated tumor targets, and four previously known non-mutated tumor targets.

Using tandem minigene library screening, they identified two novel mutated tumor targets, KIF2C and POLA2, which play important roles in cell proliferation.

With the minigene library approach, Rosenberg and colleagues recently reported another novel tumor target recognized by the activated T cells of a patient with bile duct cancer, who responded to adoptive T-cell transfer.

This study was funded by the NCI Director’s Innovation Award, the NCI Intramural Research Program, the Adelson Medical Research Foundation, the Milstein Family Foundation, and the European Research Council. Rosenberg declares no conflicts of interest.​

Continued Use of Low-dose Aspirin May Lower Pancreatic Cancer Risk

June 26, 2014
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PHILADELPHIA — The longer a person took low-dose aspirin, the lower his or her risk for developing pancreatic cancer, according to a study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Harvey A. Risch, MD, PhD

Harvey A. Risch, MD, PhD

“We found that the use of low-dose aspirin was associated with cutting the risk of pancreatic cancer in half, with some evidence that the longer low-dose aspirin was used, the lower the risk,” said Harvey A. Risch, MD, PhD, professor of epidemiology in the Department of Chronic Disease Epidemiology at the Yale School of Public Health in New Haven, Connecticut. “Because about one in 60 adults will get pancreatic cancer and the five-year survival rate is less than 5 percent, it is crucial to find ways to prevent this disease.”

Men and women who took low-dose aspirin regularly had 48 percent reduction in their risk for developing pancreatic cancer. Protection against pancreatic cancer ranged from 39 percent reduction in risk for those who took low-dose aspirin for six years or less, to 60 percent reduction in risk for those who took low-dose aspirin for more than 10 years.

“Older studies of aspirin use have been clouded by the use of [regular- or high-dose] aspirin for pain relief from conditions that themselves might be related to the risk for pancreatic cancer. Only recently have people been using low-dose aspirin for long enough times [to prevent cardiovascular disease] that the use might bear on risk of pancreatic cancer development,” explained Risch.

“There seems to be enough evidence that people who are considering aspirin use to reduce the risk for cardiovascular disease can feel positive that their use might also lower their risk for pancreatic cancer, and quite certainly wouldn’t raise it,” Risch added.

Study subjects were recruited from the 30 general hospitals in Connecticut between 2005 and 2009. There were 362 pancreatic cancer cases and 690 controls. Study subjects were interviewed in person to determine when they started using aspirin, the number of years they used aspirin, the type of aspirin they used (low versus regular dose), and when they stopped using aspirin, among other things. Confounding factors, including body mass index, smoking history, and history of diabetes, were taken into account.

Of the study participants, 57 percent were men, about 92 percent were non-Hispanic white, about 49 percent were former or current smokers, and 19 percent had been diagnosed with diabetes within the three years prior to this study.

A dose of 75 to 325 mg of aspirin per day was considered as low-dose aspirin (usually taken for heart-disease prevention), and a dose higher than that, generally taken every four to six hours, was considered as regular-dose aspirin taken for pain or anti-inflammation purposes.

Of the participants, 96 percent of low-dose aspirin users and 92 percent of regular-dose aspirin users reported daily aspirin use.

The earlier a person started regularly taking low-dose aspirin, the greater the pancreatic cancer risk reduction, ranging from 48 percent reduction in those who started three years before the study, to 60 percent in those who started taking it 20 years before the study. On the other hand, discontinuation of aspirin use within two years prior to the study was associated with a threefold increased risk for pancreatic cancer compared with continuing use.

“People who are developing pancreatic cancer have various physiologic changes, including taste disorders, starting to occur two to three years before pancreatic cancer is diagnosed. Such individuals are more likely to quit using aspirin. So it may be tricky to separate the various aspects of patterns of aspirin use and risk of pancreatic cancer,” noted Risch.

“Aspirin use has potential risks of its own, and thus the risks and benefits for each person have to be evaluated based on personal characteristics and considerations,” added Risch. “For the small subset of individuals with strong family histories of pancreatic cancer or who otherwise have been evaluated to be at substantially increased risk of pancreatic cancer, aspirin use could be part of a regimen designed to reduce their risk.”
 
This study was funded by the National Cancer Institute. Risch declares no conflicts of interest.

Combination Tumor Imaging Can Distinguish Malignant and Benign Breast Tumors, Help Avoid Unnecessary Biopsies

June 24, 2014
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PHILADELPHIA — Imaging breast tumors using four approaches together can better distinguish malignant breast tumors from those that are benign, compared with imaging using fewer approaches, and this may help avoid repeat breast biopsies, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Katja Pinker, MD

Katja Pinker, MD

“By assessing many functional processes involved in cancer development, a multiparameter PET-MRI of the breast allows for a better differentiation of benign and malignant breast tumors than currently used DCE-MRI alone. Therefore, unnecessary breast biopsies can be avoided,” said Katja Pinker, MD, associate professor of radiology in the Department of Biomedical Imaging and Image-guided Therapy at the Medical University of Vienna in Austria.

The new imaging technique, called multiparametric (MP) 18FDG PET-MRI, which used four imaging approaches, was 96 percent accurate in distinguishing malignant breast tumors from those that were benign, and provided better results than combinations of two or three imaging approaches. The study estimates that this technique can reduce unnecessary breast biopsies recommended by the commonly used imaging method, the DCE-MRI, by 50 percent.

“DCE-MRI is a very sensitive test for the detection of breast tumors, but is limited in visualizing the functional properties cancer cells acquire during development. Therefore, there is still room for improvement,” explained Pinker. “PET-MRI mirrors cancer biology and allows accurate diagnosis of breast cancer without a biopsy. Additionally, the more accurately we understand a tumor’s biology, the better we can tailor therapy to each breast cancer patient’s individual needs.

“Provided that a hospital is equipped with a PET-CT and an MRI scanner or a combined PET-MRI, the technique we have described can be immediately implemented in clinics,” said Pinker.

Pinker and colleagues recruited 76 patients to the study who had suspicious or inconclusive findings from a mammography or a breast ultrasonography. They performed a MP 18FDG PET-MRI on all the patients. In addition, all patients’ breast tumor biopsies were evaluated by histopathology.

To determine the combination of imaging parameters that yielded the most accurate results, Pinker and colleagues combined the imaging data from two parameters, three parameters, and all four parameters. All two-parameter and three-parameter evaluations included DCE-MRI.

All results were compared with histopathology diagnosis to evaluate which combination was most efficient in making an accurate diagnosis. Of the 76 tumors, 53 were malignant and 23 were benign, based on histopathology.
 
The researchers found that none of the two- or three-parameter combinations reached the same level of sensitivity and specificity as the four-parameter method, which had an AUC of 0.935. (An AUC of 0.9 to 1 means the method is excellent, and an AUC of 0.5 means the method is worthless.)

“Performing a combined PET-MRI is currently less cost-effective than existing breast imaging methods,” said Pinker. “However, a significant reduction in unnecessary breast biopsies by using this combined method may improve the cost-effectiveness.”

MP 18FDG PET-MRI allowed tumor imaging by four parameters: DCE-MRI, DWI, 3D 1H-MRSI, and 18FDG-PET.

Thomas Helbich, MD, MBA, is the senior author of this study and head of this study group.

This study was funded by the Austrian Society of Senology Scientific Funding Award, the Austrian National Bank “Jubiliaemsfond” Project, and the Medical Scientific Fund of the Mayor of Vienna Project. Pinker declares no conflicts of interest.

A Vaccine May Cause Pancreatic Cancer to Respond to Immunotherapy

June 18, 2014
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PHILADELPHIA — Pancreatic ductal adenocarcinomas (PDAC) do not typically respond to immunotherapy, which limits treatment options for this cancer. By priming with a therapeutic vaccine and a low-dose chemotherapy combination prior to surgery, researchers converted PDACs into immunogenic cancers that may respond to immunotherapy, according to a study published in Cancer Immunology Research, a journal of the American Association for Cancer Research (produced in collaboration with the Cancer Research Institute).

Lei Zheng, MD, PhD

Lei Zheng, MD, PhD

“The only curative treatment for pancreatic cancer is complete surgical resection, and approximately 80 percent of patients who undergo surgery relapse and die from the disease within five years, suggesting a need for effective strategies,” said Lei Zheng, MD, PhD, assistant professor of oncology and surgery at the Sidney Kimmel Comprehensive Cancer Center and the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care at the Johns Hopkins University School of Medicine in Baltimore.

In this clinical trial, pretreatment of PDAC patients with the vaccine GVAX and low doses of the chemotherapy cyclophosphamide caused the aggregation of immune cells inside the patients’ tumors, and many of these immune cells expressed proteins that may make these cancers amenable to immunotherapies such as PD-1 inhibitors.

“Pancreatic cancer is one of a number of malignancies that typically lack tumor-infiltrating effector lymphocytes and have been considered ‘nonimmunogenic’ neoplasms,” added Zheng. “This situation has drastically slowed the development and application of immune-based therapies for these cancers.

“Our study shows for the first time that treatment with a vaccine-based therapy directly reprograms the pancreatic cancer microenvironment, allowing the formation of lymphoid aggregates, which are organized, lymph node-like, functional immune structures, and which convert an immunologically quiescent tumor into an immunologically active tumor,” Zheng said.

Between 2008 and 2012, Zheng and colleagues enrolled 59 patients with PDAC to this study and randomized them among three arms: Patients in arm A received GVAX alone, patients in arm B received GVAX plus a single intravenous dose of cyclophosphamide at 200 mg/m2, and patients in arm C received GVAX plus 100 mg oral doses of cyclophosphamide once daily, on alternate weeks.

About two weeks after vaccination, all patients underwent surgery to remove their pancreatic tumors. Of the 59 patients, 39 remained grossly free of disease after surgery and underwent further treatment with chemotherapy and radiotherapy, and their tumors were analyzed in this study.

In addition to tumor samples from the 39 patients, the researchers used, for the comparative analyses, tumor samples from 58 patients from other studies: Four were unvaccinated patients and 54 were patients whose tumor samples were collected prior to vaccination.

They found that the vaccine-chemotherapy combination resulted in the formation of lymphoid aggregates within the tumors in 33 of the 39 patients within two weeks of vaccination.

Extensive analysis of the various immune cell types found in the tumors after vaccination revealed an increase in the ratio of effector T cells to regulatory T cells. According to Zheng, this meant that the tumors had become immunogenic and the immune cells in the tumor area were capable of fighting the cancer cells. An increase in the ratio was associated with better survival.

The researchers also found that the tumors from patients who survived for more than three years after vaccine therapy had enhanced signaling pathways that promote immune responses, compared with those who survived for less than 1.5 years following vaccination.

“We are further dissecting the immune signatures within the lymphoid aggregates to study the TGF-beta and Th17 signaling pathways. TGF-beta and Th17 pathways may also be key targets, in addition to PD-1/PD-L1, for treatments that enhance vaccine-induced antitumor immune responses in pancreatic cancer,” said Zheng.

“Our study has suggested a new model for developing more effective immunotherapy for traditionally nonimmunogenic tumors like pancreatic cancer,” Zheng added. “We will next investigate immunotherapies that include both cancer vaccines and treatments that boost the ‘good’ immune-regulatory signals or block the ‘bad’ immune-regulatory signals.”

This study was funded by the National Institutes of Health, the Johns Hopkins School of Medicine Clinical Scientist Award, the American Society of Clinical Oncology Young Investigator Award, the Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins, the National Pancreas Foundation, the Lefkofsky Family Foundation, the Lustgarten Foundation, the Sol Goldman Pancreatic Cancer Center, and the AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award. Zheng declares no conflicts of interest.

Childhood Cancer Survivors Hospitalized Frequently Years After Cancer Treatment

June 12, 2014
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PHILADELPHIA — Survivors of childhood cancers were hospitalized more often and for longer durations because of blood disorders and other problems, many years after cancer treatment was completed, compared with the general population, according to a study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Anne C. Kirchhoff, PhD, MPH

Anne C. Kirchhoff, PhD, MPH

“Our findings demonstrate that childhood cancer survivors face ongoing problems that can lead to hospitalization, even for those who are decades past their original cancer diagnosis. This can negatively impact their quality of life,” said Anne C. Kirchhoff, PhD, MPH, assistant professor of pediatrics at the Huntsman Cancer Institute of the University of Utah in Salt Lake City.

“Regular cancer-focused health care is important for identifying health problems for survivors throughout their lives,” Kirchhoff added. “Patients and families who have experienced childhood cancer should obtain a cancer treatment summary and recommendations for follow-up care from their oncologist, and coordinate their follow-up care with their oncology and primary care doctors to ensure their health care needs are being managed.”

In this study, survivors were 52 percent more likely to be hospitalized, and their number of admissions was 67 percent higher, compared with age and sex-matched individuals who did not have cancer. Survivors were also 35 percent more likely to have stayed longer every time they were hospitalized, compared with controls.

“The Affordable Care Act has several provisions that will improve insurance for cancer survivors, including expanding coverage to dependents up to age 26, prohibiting insurance denials based on health status, and eliminating lifetime limits on coverage,” noted Kirchhoff. “Better insurance coverage should hopefully help survivors identify and manage health problems at earlier, less costly stages.”

Kirchhoff and colleagues identified 1,499 childhood cancer survivors treated between 1975 and 2005 who were at least five years past their original cancer diagnosis from the Utah Population Database (UPDB) and the Utah Cancer Registry. They collected information including demographics, type of cancer, and type of treatment. Data on subsequent hospitalizations were obtained from the Utah Department of Health hospital discharge records. Using UPDB, they also identified 7,713 subjects who did not have cancer, who served as age and sex-matched controls in this study.

About 50 percent of the survivors included in this study were female, and 98 percent were non-Hispanic white. The researchers found that both female survivors and male survivors were more likely to have been hospitalized than their respective controls. Female survivors also had a longer average length of hospital stay than female controls.

More than 10 percent of survivors of central nervous system tumors, neuroblastoma, or malignant bone tumors were hospitalized five or more times during the follow-up period, and the hospital admission rates were approximately two times higher for survivors of neuroblastoma and bone tumors, respectively, compared with controls. “We saw higher rates of hospitalization across most cancer types, but not for all cancers, which gives us clues as to which groups of survivors may need better surveillance in the long term,” said Kirchhoff.

Common reasons for hospitalizations for survivors compared with the controls included conditions like blood disorders (such as anemia) and cancer, although it is unclear if this was for their original cancer diagnosis or new cancers. Infections, nervous system problems, and respiratory problems were other leading reasons for hospitalization.

Kirchhoff and colleagues will conduct further analyses to better understand the reasons survivors are hospitalized and their hospital-related costs.

This study was funded by a Huntsman Cancer Institute Cancer Control and Population Sciences Research Award, the Huntsman Cancer Foundation, a Primary Children’s Medical Foundation Career Development Award, the Utah Cancer Registry, and the National Institutes of Health. Kirchhoff declares no conflicts of interest.

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