Key Role Of T Cells Is Highlighted By The Mapping Of Ovarian Cancer Tumor Cell Microenvironment

Dr. Enrique Jacome

Understanding the chemokine landscape of papillary serous ovarian cancer, the most common form of the disease, is important for the development of new immunotherapy strategies where the goal is to increase the presence and function of T cells in the tumor microenvironment. New research examining the molecular environment of ovarian cancer is the first to map the presence of chemokines, immune-system proteins that mobilize T cells in this disease. The study was conducted at the Perelman School of Medicine at the University of Pennsylvania and led in part by Emese Zsiros, MD, PhD, FACOG, a Penn fellow at the time the research was conducted and now an Assistant Professor in the Department of Gynecologic Oncology at Roswell Park Cancer Institute (RPCI). Findings have been published online ahead of print in the journal Clinical Cancer Research.

"Ovarian cancer patients who have T cells within their tumor at the time of diagnosis live significantly longer. These patients show an immune response to their disease, which slows down tumor progression and recurrence," said Dr. Zsiros. "The trafficking of T cells and other immune cells is mainly governed by chemokines, which are small signaling proteins that determine cell migration."

In this study, T cells were equipped with chemotherapy agents that target metastases in a complex multistep process. The ability of these re-engineered T cells to infiltrate is regulated by patients' own tumors and their chemokine environment. In their analysis of the papillary serous ovarian cancer environment, researchers found that, for a significant number of patients, the chemokine landscape is very diverse but exhibited a high number of known T cells that recruit chemokines.

Successful immunotherapy depends on the ability of the re-engineered T cells to travel into the tumor environment. The scientists also report that tumors lacking T cells also may express some of these quasi-universal chemokines. The challenge is to manipulate the ovarian cancer chemokine landscape in a way that promotes recruitment of tumor-specific T cells, while repressing the recruitment of other immune cells that dampen the patient's antitumor response.

Researchers also report that the ovaries, the primary disease site for these tumors, have the same chemokine expression as metastatic deposits outside the pelvis - an important factor to consider when designing immunotherapy trials targeting chemokines or chemokine receptors on T cells.

"Chemokines are important regulators of circulation, homing and retention of T cells, and thus the characterization of the tumor chemokine microenvironment is key to developing effective immunotherapy against solid tumors such as ovarian cancer," said principal investigator and senior author George Coukos, MD, PhD, faculty leader in tumor biology at the Ludwig Centre of the University of Lausanne. Dr. Coukos is an adjunct professor of Obstetrics and Gynecology at the Perelman School of Medicine at the University at Pennsylvania, where this research was conducted.

Roswell Park researchers will continue to focus on developing and testing new chemokine and chemokine-receptor-blocking agents to enhance the patients' own immune response with a goal of achieving longer survival and better quality of life for patients diagnosed with ovarian cancer.

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BU Study Finds Underlying Subfertility May Affect ART Birth Outcomes

Dr. Enrique Jacome

Birth outcomes for babies whose mothers used assisted reproductive technology (ART) are better in some cases, and worse in others, than for subfertile women who did not use ART, according to a first-of-its-kind study led by Boston University School of Public Health researchers.

Those findings, published online in the journal Fertility and Sterility, suggest that underlying subfertility, distinct from the use of ART, may account for some of the elevated risks in birth outcomes attributed to the use of in vitro fertilization and other ART procedures.

Researchers found that the risks of preterm birth and low birth weight were higher for singletons (single babies) born to mothers who had ART than for those who had fertility problems but did not use ART. But the risks of perinatal death - stillbirths or deaths within one week of birth -- were no higher for mothers with ART than for fertile women, while they were significantly higher for singletons born to subfertile mothers. And for twins, the risks of death among ART births were significantly lower than for either subfertile or fertile women.

The study is the first population based U.S. comparison of birth outcomes for women who received fertility treatment and those with subfertile indicators who did not use ART. The growth in the use of ART has raised concerns about a range of perinatal outcomes, including an excess of preterm births, low birth weight, and neonatal death. But because previous studies have compared ART birth outcomes with spontaneous conceptions, it has remained unclear whether differences in outcomes are related to underlying subfertility or other factors, such as the older average age of mothers.

The new study suggests that both underlying subfertility and ART itself may influence outcomes. Among singletons, the differences in rates of preterm birth and low birth weights were more pronounced when comparing the ART group to fertile women than to subfertile women, indicating that underlying fertility problems may play a role in those outcomes.

"Overall, these (findings) suggest an underlying risk associated with subfertility, distinct from that which may result from ART," the authors said.

Among twins, the study suggests that babies born after ART appear to have better outcomes. ART twin births compared with subfertile births had a longer mean gestational age, lower rate of very premature delivery and very low birth weight, and a much lower rate of perinatal death.

While the authors reached no conclusions, they said one possible explanation for the better ART outcomes was "the special baby" hypothesis, which posits that extra attention given to ART births by both parents and caregivers may contribute to more favorable outcomes. Mothers in the ART group tended to be older and more likely to deliver by cesarean section than the other groups studied.

"It may be possible that ART-related births involved greater attention to care, " the authors said, adding that "more sensitive and comprehensive measures of prenatal care than are currently available on a population basis will be necessary to determine if a 'special baby' hypothesis is supported."

The study is the first one published by a collaboration dubbed MOSART - for the Massachusetts Outcomes Study of Assisted Reproductive Technologies - which brings together BU School of Public Health childbirth experts with researchers from five other institutions to probe how ART influences health outcomes for women and children. The collaboration is funded through a five-year grant from the National Institutes of Health's National Institute of Child Health and Development.

The study linked detailed clinical information on ART treatment from all ART clinics in Massachusetts from 2004-2008 with data on births, fetal deaths and hospital records in the state. The subfertility comparison group was developed by means of an algorithm that conservatively identified births to women with indicators of subfertility, either through diagnosis codes or maternal reporting.

Lead author Eugene Declercq, professor of community health sciences at BUSPH, said the study is an important first step in "extricating the possible risks of ART from underlying infertility or maternal demographic and health risks." He encouraged further research taking advantage of the power of linking clinical and population data to examine ART outcomes for both infants and mothers.

Infertility affects an estimated 12 to 15 percent of women of reproductive age. The use of in vitro fertilization and other fertility-enhancing treatments has risen steadily in the U.S. Treatment with assisted reproductive technologies resulted in 65,160 live born infants in the U.S. in 2012, representing 1.6 percent of all U.S. births.

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FDA Approves LILETTA - Levonorgestrel Releasing Intrauterine System

Dr. Enrique Jacome

Actavis plc, a leading global specialty pharmaceutical company, and Medicines360, a nonprofit women's health pharmaceutical company, have announced the approval of LILETTA (levonorgestrel-releasing intrauterine system) by the U.S. Food and Drug Administration (FDA) for use by women to prevent pregnancy for up to three years. LILETTA is placed in the uterus by a healthcare professional and works by continuously releasing levonorgestrel, a progestin, to prevent pregnancy.

Actavis and Medicines360's groundbreaking partnership will allow women, regardless of income and insurance coverage, to access this new and effective contraceptive option. Through the collaboration, LILETTA will be available in the U.S. commercially as well as at a lower cost to public health clinics enrolled in the 340B Drug Pricing Program.

"At Actavis, we are committed to developing alternative forms of contraceptive options. With the FDA's approval of LILETTA, we are pleased to offer women a novel IUD which provides three years of safe and effective contraception," said David Nicholson, PhD., Executive Vice President, Actavis Global Brands R&D.

"The FDA's approval of LILETTA marks an important milestone for women, providers, and the reproductive health community. LILETTA was designed from the beginning to be accessible by women, regardless of socioeconomic status," said Pamela Weir, Chief Operating Officer, Medicines360. "In the past, many barriers including expensive upfront costs or lack of insurance coverage have prevented women from obtaining IUDs." 

The approval of LILETTA was based on the largest hormonal IUD trial, ACCESS IUS (A Comprehensive Contraceptive Efficacy & Safety Study of an IUS), conducted in the U.S. with 1,751 enrolled women receiving LILETTA. LILETTA was safe and effective for a broad range of women, with a cumulative three year efficacy rate of 99.45 percent. LILETTA is indicated for women regardless of parity or BMI.

LILETTA is a small, flexible plastic T-shaped system which is 32 mm x 32 mm in size. It works to prevent pregnancy by slowly releasing levonorgestrel (LNG), a progestin, at an initial release rate of 18.6 mcg/day with an average in vivo release rate of LNG of approximately 15.6 mcg/day over a period of three years. Generally, LILETTA can be inserted at any time if the provider is reasonably certain that the woman is not pregnant. While LILETTA is intended for use up to three years, it can be removed by a healthcare professional at any time. LILETTA can be replaced at the time of removal with a new LILETTA, if continued contraceptive protection is desired.

"This new hormonal IUD was proven more than 99 percent effective in the largest ever IUD trial conducted in the U.S. It offers a long-term, highly-effective yet reversible option to prevent pregnancy for many women regardless of whether or not they've had a child before," said David L. Eisenberg, M.D., assistant professor of obstetrics and gynecology at Washington University in St. Louis and principal investigator and lead author of the ACCESS IUS study. "This long-acting reversible contraceptive is a desirable option for women looking to prevent pregnancy."

Actavis and Medicines360 expect that LILETTA will be available for use in the U.S. by Q2 2015.

About the Clinical Trial for LILETTA

The approval of LILETTA is supported by the largest hormonal IUD trial (ACCESS IUS) conducted in the U.S. designed to reflect the U.S. population. This multicenter open-label clinical trial included 1,751 women who received LILETTA. LILETTA was found to be 99.45 percent effective in preventing pregnancy in women regardless of age, parity (previous births), or BMI. The trial is ongoing to evaluate the use of LILETTA for up to four, five and seven years.

LILETTA was studied in women aged 16-45, with a BMI range of 15.8kg/m2 - 61.6kg/m2 (26.9 kg/m2 mean BMI) across women of various races and ethnicities. Most women were Caucasian (78.4 percent) or Black/African American (13.3 percent); 14.7 percent of women were of Hispanic ethnicity. Nearly 58 percent of trial participants were nulliparous (had not previously given birth), the largest percentage of nulliparous IUD patients ever studied. 

In an analysis of women who discontinued the study early, 97 percent returned to menses within three months after LILETTA was removed. Furthermore, in a group of women trying to conceive, 87 percent became pregnant within one year of removal. Additionally, some women were able to conceive as soon as two weeks after removal (12 days). Approximately 19 percent of women treated with LILETTA experienced amenorrhea (absence of menstruation) within one year of treatment and more than one-third experienced amenorrhea by the third year of treatment.

The incidence of ectopic pregnancy in the clinical trial with LILETTA, which excluded women with a history of ectopic pregnancy who did not have a subsequent intrauterine pregnancy, was approximately 0.12 percent per 100 woman-years.

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