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Monday, December 17, 2018

A University of Virginia School of Medicine researcher is developing a two-fisted, antibody-based approach to destroy ovarian cancer—an approach he believes could also be modified to kill breast, prostate, and other solid tumors (Cancer Cell 2018; doi:10.1016/j.ccell.2018.07.005).

The dual-pronged approach being developed by Jogender Tushir-Singh, PhD, aims to overcome obstacles that have undermined otherwise promising immune therapies for ovarian cancer. If the approach proves successful, it may even rescue some failed therapies, allowing doctors to move them from the scrap heap to the clinic, where they could benefit patients.

"There are a lot of efforts in terms of cancer immune therapy, but the success of these are really limited in solid tumors," said Tushir-Singh, of UVA's Department of Biochemistry and Molecular Genetics and the UVA Cancer Center. "I strongly believe, and with my own experience while working in the pharmaceutical industry, that this advancement will allow us to rescue and give a second lease on life to a lot of antibodies that have failed in the clinic. This is all based on large amount of clinical data, and we have strategically exploited this information to improve the therapeutic efficacy against ovarian cancer."

Targeted Treatment for Ovarian Cancer

In developing his approach, Tushir-Singh realized that a major problem with immune therapies for ovarian cancer is that the immune cells intended to kill the cancer cells cannot infiltrate the solid tumor bed effectively.

"I found that one of the problems is with the solid tumor microenvironment," he explained. "The microenvironment is highly hypoxic, anergic and, particularly in the case of ovarian cancer, some unusually large receptors form a protective fence around tumor cells, so even if the immune cells reach there, there are many obstacles."

Tushir-Singh decided to find a way to make the tumor environment more attractive despite the protective fence around it. So he engineered an antibody that he likens to a "two-headed arrow." "The antibodies need to find a home," he recalled thinking, "so let's design one head to bind to a receptor that is highly expressed in ovarian tumors."

But getting the antibody there wasn't enough. Previous clinical trials had shown the need for antibodies that were more effective at killing ovarian cancer cells. So Tushir-Singh sought to amplify his antibody's cancer-killing power. The result: One head of the "arrow" strikes what is known as the "death receptor" on the cancer cells, telling them to die, while the other head strikes a receptor known as FOLR1, a well-established marker that suggests a poor prognosis among ovarian cancers.

Tushir-Singh's engineered antibodies are more than 100 times more effective at killing cancer cells than the antibodies that have made it to clinical trials, his lab work suggests. Further, his approach avoids toxicity issues that have plagued previous antibody therapies, he said. "Liver toxicity has been the biggest problem for a lot of antibodies—they are taken out of the blood too fast and accumulate where not needed. But by providing a good home for the antibodies in the tumor, we are keeping these antibodies away from the liver."

Tushir-Singh's approach is still in the early stages of therapeutic development, but he is eager to test his two-headed arrow in people. "Ultimately," he said, "a clinical trial in ovarian cancer patients is my big goal, and, with the help of the UVA Licensing & Ventures Group, we are looking for industrial partners, too."

"UVA is a great institution and a very fertile ground to do good science," Tushir-Singh said. "With Dr. Sanchita Bhatnagar's lab being next door, we are a collaborative husband-and-wife team. We joined UVA just 3 years ago.

"Being a young professor, I am highly thankful and admire the leadership in my department, which is chaired by Dr. Anindya Dutta, and at UVA Cancer Center, which is headed by Dr. Tom Loughran. I have been fortunate to have a great basic research team such as Dr. Kodi Ravichandran along with many others, and an effective clinical collaborator, Dr. Charles 'Chip' Landen."

 


Monday, December 17, 2018

New types of combined oral contraceptives (containing both lower doses of estrogens and newer progestogens) are associated with a reduced risk of ovarian cancer, in young women, finds a large study published by The BMJ (2018; doi:10.1136/bmj.k3609).

The results show that this positive effect strengthened with longer periods of use and persisted for several years after stopping, providing important reassurance for women, according to the researchers.

At least 100 million women worldwide are using hormonal contraception every day. Previous research has shown a reduced risk of ovarian cancer in women who take combined oral contraceptives, but most of the evidence relates to the use of older products, containing higher levels of estrogen and older progestogens.

Women who use newer oral contraceptives and other hormonal contraceptive methods also want to know whether they are likely to experience the same benefit.

So researchers at the University of Aberdeen in Scotland and the University of Copenhagen in Denmark investigated the influence of newer hormonal contraceptives (combined and progestogen-only products) on overall and specific types of ovarian cancer in women of reproductive age.

Using national prescribing and cancer registers, they analyzed data for nearly 1.9 million Danish women aged 15-49 years between 1995 and 2014.

Women were categorized as never users (no record of being dispensed hormonal contraception), current or recent users (up to 1 year after stopping use), or former users (more than 1 year after stopping use) of different hormonal contraceptives.

Most (86%) of the hormonal contraceptive use related to combined oral products.

After taking account of several factors, including age and parity, the researchers found that the number of cases of ovarian cancer were highest in women who had never used hormonal contraception (7.5 per 100,000 person years), whereas among women who had ever used hormonal contraception, the number of cases of ovarian cancer were 3.2 per 100,000 person years.

There was no firm evidence to suggest any protective effect among women who used progestogen-only products, although the researchers point out that few women were exclusive users of these products. This limits the ability to detect an effect.

The reduced risk for combined products was seen with nearly all types of ovarian cancer, and there was little evidence of important differences between products containing different types of progestogens.

Similar results were also found among women followed up to their first switch in contraceptive type.

Based on these figures, the researchers say that hormonal contraception prevented an estimated 21 percent of ovarian cancers in this group of women.

This is an observational study, so no firm conclusions can be drawn about cause and effect, but they do support the findings of studies of older products. The researchers point out that they did not study older women, among whom most cases of ovarian cancer occur. However, this was a large study with a long follow-up period, and the researchers were able to adjust for a range of potentially influential factors.

"Based on our results, contemporary combined hormonal contraceptives are still associated with a reduced risk of ovarian cancer in women of reproductive age, with patterns similar to those seen with older combined oral products," said the authors.

"The reduced risk seems to persist after stopping use, although the duration of benefit is uncertain. Presently, there is insufficient evidence to suggest similar protection among exclusive users of progestogen-only products," they concluded.

 


Monday, December 17, 2018

In nearly 80 percent of women with ovarian cancer, the disease has already spread to the omentum before it was diagnosed. Within the omentum—a large, energy-dense fat pad that covers the intestines—the cancer grows even faster (Cell Metab 2018; doi:10.1016/j.cmet.2018.08.007).

A multi-center research team based at the University of Chicago Medicine describes how rapidly spreading ovarian cancer cells take the next steps. Once they infiltrate the omentum and begin to deplete the fat cells there, the tumor recruits cancer-associated fibroblasts (CAFs). These cells accelerate cancer proliferation and spread by enhancing the mechanisms that cancer cells use, such as increasing blood flow to the tumor, to generate additional energy sources.

In their current study, "Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis," the researchers used a technique called quantitative phosphoproteomics to characterize the reciprocal signaling between human ovarian cancer cells and the CAFs that hasten the spread of abdominal cancers.

When the researchers grew human ovarian cancer cells together with CAFs in the lab, they were able to detect key components of their cellular crosstalk. This allowed the researchers to unravel the role of glycogen in the metabolism and rapid spread of ovarian cancers.

"This is the first time that the role of glycogen in cancer metastasis has been thoroughly investigated," said the study's senior author, Ernst Lengyel, MD, PhD, the Arthur L. and Lee G. Herbst Professor and Chairman of Obstetrics and Gynecology at the University of Chicago.

"No systematic study of the signaling pathways initiated by human cancer cells and cancer-associated fibroblasts has been performed," he added. "We think this could have significant clinical implications."

The authors summarized the cascade of events that fuel disease spread: fibroblast-derived chemical signals help mobilize glycogen in cancer cells, which is then metabolized into glucose. This is used by cancer cells as a source of energy, helping those cells invade other tissues. It also boosts tumor aggressiveness, enhancing proliferation, invasion, and metastasis.

The authors suggest, however, that inhibition of one step in the process, blocking glycogen mobilization in cancer cells by interfering with enzymes mobilizing glycogen, or inhibiting signaling pathways that prevent the glycogen mobilization stimulated by CAFs, "might be a therapeutic strategy for the reduction of tumor dissemination in abdominally metastasizing cancers after optimal tumor reduction."


Friday, December 14, 2018

Nova Southeastern University (NSU) researchers recently discovered that by testing the level of NER (nucleotide excision repair) gene expression, pediatric oncologists can determine the likelihood of early relapse (less than 3 years) in their acute lymphoblastic leukemia (ALL) patients.

This is a critical finding because NER gene expression levels can now help guide doctors in their rationale for appropriate treatment targeted to each patient's disease.

ALL is the most common childhood cancer. Treatment has improved dramatically due to evolving methods of determining risk factors and genetic analysis. Five-year survival rates have increased substantially from 57 percent in 1975-1977 to 92 percent in 2006-2012. Yet, the current genotoxic chemotherapy regimens are still extremely debilitating.

"Our research found a correlation between high NER expression levels and early relapse of ALL among relapsing patients," said Jean Latimer, PhD, Director of the NSU AutoNation Institute for Breast and Solid Tumor Cancer Research and Associate Professor and cancer research scientist in NSU's College of Pharmacy. "Being able to identify patients with the highest risk of early recurrence who are not detectable using present clinical measures and then treating them with a more targeted therapy is crucial to overcoming the cancer."

This is critical, according to the research recently published in the peer-reviewed journal, BMC Medical Genomics, because while ALL is much more treatable than in the past, the survival rate after relapse is poor (2018; doi:10.1186/s12920-018-0422-2).

"By being able to accurately predict if a child's cancer is likely to recur early or not, we may also spare many children who have low NER levels from the most toxic chemo regimens,'" said Latimer.

The AutoNation research team also included Stephen Grant, PhD, Project Director and Associate Professor, Public Health, Dr. Kiran C. Patel College of Osteopathic Medicine; Homood As Sobeai, PhD, Assistant Professor, College of Pharmacy, King Saud University, and Omar Ibrahim, post-doctoral fellow. 

Thursday, December 6, 2018

By Brandon May

Preliminary data from an ongoing phase I study presented by Samer K. Khaled, MD, at the 2018 ASH Annual Meeting shows that a CD19-targeted chimeric antigen receptor (CAR) T-cell platform—a naïve/memory T cell–enriched T-cell product that expresses CD28 costimulatory CAR (CD19:28z-CAR)—was associated with low rates of toxicities and high rates of response in a small cohort of adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL).

"The study uses a unique T-cell population, a more naïve T-cell population, and the idea is to use a unique kind of T cell to manufacture the T-cell product," Khaled explained to Oncology Times. "In this trial, 11 out of 11 patients experienced complete remission, it dramatically increased activity, and the toxicity was very low. Based on these findings, we believe that this platform has very promising results that can be used to manufacture CD19 or even other targeted CAR T cells."

A total of 16 adult patients with ALL were enrolled and subsequently received a lymphodepleting treatment regimen consisting of 1.5-3 gm/m2 cyclophosphamide during a 2- to 3-day period as well as 25-30 mg/m2 fludarabine for a total of 3 days. T cells were not administered to three patients who experienced infection of a lack of CD19+ disease.

At time of enrollment, the median age of the cohort was 33 years (24-72 years), and 100 percent of patients had active bone marrow disease. Approximately 62 percent (n=8) and 38 percent of patients had high disease burden (i.e., 15%-91% bone marrow blasts) and low disease burden (≤5% bone marrow blasts), respectively. Patients had a history of heavy pretreatment, including a median of 5 prior treatment regimens. Specifically, six patients, nine patients, and one patient had previously received an allogeneic transplant (HSCT), blinatumomab, and CD19 CAR T cells, respectively.

During the phase I treatment phase, the investigators administered a flat 200 million (M) dose of CD19:28z-CAR T cells, including 11 and 2 autologous and allogeneic donor products, respectively. Only 2 out of 13 patients who received 200 M CAR+ T cells were ineligible for dose escalation or evaluation for disease response. Ineligibility was attributed to one patient who received <80 percent of the initially prescribed treatment dose of 100 M, whereas the other ineligible patient was categorized as having CD19-negative extramedullary disease.

The researchers sought to evaluate the safety and activity of the Tn/mem-enriched CD19:28z CAR T-cell platform in the enrolled relapsed/refractory ALL patients. Additionally, the researchers sought to identify a phase II recommended dose and examined rates of toxicity and disease response in the cohort.

No dose-limiting toxicities were observed in the 13 patients treated with the CAR T-cell platform. Toxicities possibly or definitely related to study treatment were considered mild, and all toxicities were reversible. Cytokine release syndrome (CRS) of grade 2 was observed in two patients, and CRS of grade 3 was observed in another two patients. Additionally, a total of three patients and two patients had grade 2 and grade 3 neurotoxicity, respectively.

In 11 patients who were deemed evaluable for response, complete responses were observed in four patients by minimal residual disease (MRD) negativity by flow. Similarly, complete remission with incomplete blood count recovery was observed in seven patients, with six of these patients demonstrating MRD negativity. The researchers observed a median response duration of 81 days (39-286 days) at time of last follow-up or HSCT start. Eight patients received HSCT at median of 69 days (39-103 days) following infusion with CAR.

Limitations of the study include its small patient cohort, the lack of a comparator or placebo group, and the limited follow-up.

"We were amazed at the difference between the early arm 1 on this study to [after treatment] in regard to activity just by tweaking the manufacturing platform," Khaled added when asked about what findings surprised him during the study. Additionally, he noted that, while the findings were promising, challenges still remain in studying this cohort of patients.

"Most of the patients had a very early relapse or refractory disease, so one challenge that we had is that the patients were referred to us very late in the disease, which makes it very hard to collect cells and make the product," he said. Most of the patients in the cohort were also heavily pretreated, he stated, so these preliminary findings may not generalize to treatment-naïve patients with ALL.

Brandon May is a contributing writer.