‘Super T Cells’ Engineered For Optimal Performance Drive New Gene-Therapy Approach

'Super T Cells' Engineered For Optimal Performance Drive New Gene-Therapy ApproachResearchers at Roswell Park Cancer Institute have initiated a clinical trial based on a unique two-pronged strategy for arming the immune system to more effectively attack cancer cells. Patients treated through this early-stage clinical trial, which is available only at Roswell Park, will receive one-time injections of their own cells—”super T cells” reprogrammed to make them more effective at targeting tumor cells, and armed with an added element to help them to evade one of cancer’s most resilient defenses.

The “TGF beta” clinical trial, named for one of the elements that distinguish this approach, is part of an emerging class of immunotherapies that employ adoptive cell transfer. These so-called “living drugs”—injected T cells genetically modified to better recognize and kill tumor cells through a perpetual process of cell renewal and expansion—are revolutionizing cancer treatment, with the first two FDA approvals of such gene-altering therapies occurring in just the last two months. But efforts to develop adoptive T cell therapies for solid tumors have hit upon a number of challenges; the only gene therapies to show significant benefit for patients have been in liquid tumors—forms of leukemia and lymphoma.

“What we see over and over in trying to treat some of the most aggressive and intractable cancers, including many lung, brain, ovarian, breast, melanoma and sarcoma tumors, is that the tumor fights back. The area around the tumor is a hostile environment that disarms immune cells and deprives them of the ability to kill tumor cells. We have identified a major pathway by which these kinds of cells try to disable immune cells, and formulated a strategy for exploiting that weakness,” says the study’s principal investigator, Kunle Odunsi, MD, PhD, FRCOG, FACOG, Deputy Director and Chair of Gynecology at Roswell Park, and Executive Director of its Center for Immunotherapy.

The roughly 24 patients to be treated through this phase I/IIa study will have their T cells removed in a process that’s similar to platelet removal, and takes about two hours. Approximately one week later, they will receive a single injection of those T cells, now modified with two strategic enhancements: insertion of one gene that forces them to produce a T cell receptor (TCR) that hones in on the target antigen, NY-ESO-1, and another that blocks a protein that allows cancers to grow and suppress the immune system—transforming growth factor beta (TGF-beta).

“It’s an approach that allows the immune system to be on the offense and on the defense at the same time,” says the study’s scientific lead, Richard Koya, MD, PhD, Associate Director of the Roswell Park Center for Immunotherapy. “First we arm the T cells with a receptor to help them hunt down the cancer cells, and then we add a TGF-beta blocker to suppress the suppressor. The result of this two-step gene modification—forcing expression of the receptor for NY-ESO-1, and adding a blocker gene to nullify the effect of TGF-beta—is a super T cell engineered to both more effectively kill target cancer cells and to resist the tumor’s attack.”

While preclinical studies suggest that this treatment may be effective, long-lasting and well-tolerated, the study now underway at Roswell Park marks the first time this strategy will be assessed in humans.

It is also the first time a Roswell Park team has produced a genetically engineered T cell therapy in-house. The immune cells that play such a central role in this therapy are never frozen or shipped, as they are drawn, re-engineered and reinjected within Roswell Park facilities.

To read this full article on MedicalXpress.com, please click here.

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New Medications for the Treatment of Ovarian Cancer

An article published in the Gynecologic Oncology Research and Practice reviews the current medications available for treatment of ovarian cancer.

New Medications for the Treatment of Ovarian CancerEpithelial ovarian cancer is commonly diagnosed in its advanced stages. Although current management for ovarian cancer is effective in inducing a complete remission, a large proportion of patients eventually experience recurrence.

In an article recently published in Gynecologic Oncology Research and Practice Herzog and Monk reviewed the currently available medications in the management of epithelial ovarian cancer. Platinum-containing induction chemotherapy has been the first-line treatment for women with advanced ovarian cancers. However, there have been conflicting studies on the role of maintenance chemotherapy after achieving an objective response during induction. Some studies show that maintenance chemotherapy is beneficial for patients with ovarian cancers while others say otherwise.

When it comes to cancer recurrence, both platinum-based and combination chemotherapy have been used to address this issue. However, nearly all patients eventually become resistant to platinum-based medications which render the chemotherapy ineffective. Poly-ADP ribose polymerase (PARP) inhibitors such as olaparib are currently being studied for its role in recurrent and platinum-resistant ovarian cancers. However, the use of these medications is also associated with various adverse effects.

Overall, the medications used for ovarian cancer provide opportunities for improving response rates and prolong progression-free intervals. However, complexities in drug interaction can affect the selection process in which medication to use. Platinum-based therapy is still recommended as first-line therapy in women diagnosed with advanced epithelial ovarian cancers. PARP inhibitors are recommended in patients who develop resistance to platinum-based medications. Bevacizumab is another option for some patients with recurrent ovarian cancer.

Currently, there are limited treatment options for patients who are resistant to platinum-based medications and have contraindications to PARP inhibitors or bevacizumab.  This unmet need is currently being addressed through the accelerated FDA approval process of two drugs, olaparib and rucaparib, for the treatment of recurrent disease.

Reference: Herzog, T.J. & Monk, B.J. (2017). Bringing new medicines to women with epithelial ovarian cancer: what is the unmet medical need? Gynecologic Oncology Research and Practice 4(13). doi: 10.1186/s40661-017-0050-0

To read this article on MedicalNewsBulletin.com by Karla Sevilla, please click here.

Attention, Women: You Might Be Missing This Common Sign of Ovarian Cancer

Attention, Women: You Might Be Missing This Common Sign of Ovarian CancerWhen it comes to cancer types that disproportionately affect women, breast cancer gets a lot of buzz. And by all means, continue your regular self-exams and mammograms, please! Still, it’s important to tune in to the signs of ovarian cancer, too. The American Cancer Society reports that ovarian cancer affects over 20,000 women in the U.S. each year, and about 40 women die every day from the disease. But according to new research from Target Ovarian Cancer, most women wouldn’t recognize one major red flag.

The British charity surveyed 1,000 women to determine their knowledge of the risk and protection factors of ovarian cancer. Overall, just one percent knew that feeling the frequent need to urinate is a symptom of the disease.

Why does ovarian cancer make you pee a lot? “Needing to wee more often or more urgently—and indeed, all of the symptoms of ovarian cancer—can occur because a mass in the abdominal area is pushing on the surrounding organs, includinoverg the bladder,” according to Katherine Pinder, Deputy Director of Services at Target Ovarian Cancer.

Granted, there are lots of other reasons for taking a bathroom break more frequently than normal. Increasing your water consumption, becoming pregnant, or suffering from a condition like diabetes can all boost your urge.

But it’s still important to be aware of the small possibility that your frequent urination could mean something more serious—especially if you’re experiencing other common signs of ovarian cancer like abdominal bloating, appetite loss, or pelvic and/or abdominal pain. If you display any of these symptoms, it’s always best to book an appointment with your doctor or gynecologist as soon as possible.

Ovarian cancer isn’t the only cancer with unusual symptoms. Don’t miss the cancer symptoms that women are likely to ignore.

To read this entire article on Reader’s Digest, please click here.

New Options Are Being Explored in Ovarian Cancer

New Options Are Being Explored in Ovarian CancerA NOVEL ANTIBODY-DRUG conjugate is being investigated as a single-agent treatment for patients with advanced, platinum-resistant epithelial ovarian cancer that expresses a certain protein, in an effort to provide an effective option for a population facing a difficult prognosis.

The drug is mirvetuximab soravtansine (IMGN853), and the phase 3 FORWARD 1 trial is testing it in patients whose cancers have medium to high expression levels of the protein folate receptor–alpha (FR-alpha).

That’s because the drug targets FR-alpha, a cell-surface glycoprotein found on approximately 80 percent of epithelial ovarian cancer tumors; its overexpression may be associated with negative outcomes in patients treated with chemotherapy. The study also includes women with primary peritoneal and fallopian tube cancers that express the protein.

If successful, the novel drug would offer an alternative to patients who have not responded to platinum-based chemotherapy, and possibly to individuals who have become resistant to chemotherapy.

“This would be another agent available for patients with platinum-resistant disease, for which, outside of combination chemotherapy and Avastin (bevacizumab), there are really no therapies with an expected response rate,” said Kathleen N. Moore, M.D., associate director for clinical research and director of the TSET Phase I Drug Development Unit at the Stephenson Cancer Center in Oklahoma, and a co-principal investigator on the study.

“If they can’t get bevacizumab — which a lot of patients can’t (due to issues such as risk factors for cardiac or gastrointestinal side effects) — then this may be their first line in platinum-resistant cancer. It gives another, better option with a higher chance of working over a longer period of time without as many adverse effects. It moves up the line in terms of options for patients with platinum-resistant ovarian cancer,” she added.

It is estimated that 23,000 women are diagnosed annually with ovarian cancer in the U.S. Patients with ovarian cancer who are also resistant to platinum-containing chemotherapy comprise a population with an unmet need, as they are difficult to treat and they need more options after first- and second-line therapy.

The global FORWARD I trial (NCT02631876) is currently enrolling patients at 79 locations, including many in the United States. It seeks to randomize 333 women in a 2:1 ratio to either the experimental mirvetuximab soravtansine arm or to chemotherapy consisting of investigator’s choice of paclitaxel, pegylated liposomal doxorubicin or topotecan. Eligible patients will have advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer with FR-alpha-positive tumor expression. Patients must also have platinumresistant disease, and must have received at least one, but no more than three, prior treatments. Patients with low-grade ovarian cancer or clear-cell ovarian cancer are not eligible, mainly because the investigators don’t think they will get any benefit from the therapy.

Mirvetuximab soravtansine acts like a “targeted bomb,” according to Moore, that is programmed to target FR-alpha and carries very potent molecules of chemotherapy that are very dissimilar to anything the patients will have previously received. The chemotherapy is going directly to the cancer cells, instead of to the whole body, as with typical systemic chemotherapy, which goes wherever there is a blood vessel.

The cancer cell accepts the drug into the cell, like a Trojan horse, and when the medicine gets there, it releases its payload of chemotherapy and the cell dies. The chemotherapy molecules can then disperse to other cells locally and infect them, as well.

Although the drug is generally well tolerated, one of its most common side effects is low-grade diarrhea in 30 to 40 percent of patients, according to Moore. Like other antibody– drug conjugates, the drug can also cause keratopathy, damage to the limbus of the cornea that causes transient blurry vision and is observed in about 10 percent of patients. Because preventing dry eyes often prevents keratopathy, lubricating eyedrops are mandatory in the study.

Should keratopathy occur, persist or become more severe, the dose of the drug is either lowered or withheld entirely, and patients can resume the treatment after it’s resolved. Due to this risk, any patients who have a history of corneal abnormalities, which Moore noted is uncommon, will be excluded from the study.

According to a pooled analysis of phase 1 expansion cohorts that was presented at the 2017 Annual Meeting of the American Society of Clinical Oncology, mirvetuximab soravtansine demonstrated a favorable toxicity profile and encouraging clinical activity. “The early-phase data is very strong in terms of the response rate and the duration of response, as well as the tolerability of the drug, so we are excited to move this drug into the marketplace, and we hope patients are excited about it,” Moore said.

There were 113 patients with epithelial ovarian cancer in the pooled analysis, including a cohort of 36 patients who met the inclusion criteria for FORWARD I. In all pooled patients from the phase 1 analysis, the confirmed overall response rate (ORR) was 30 percent, and included three complete responses and 31 partial responses. The confirmed ORR was 47 percent in the group eligible for FORWARD I, including one complete response and 16 partial responses.

“It was a good opportunity to look at a large number of patients who have been treated with the drug, then to try to narrow it down to the population who benefited the most, and that was the population that had three prior regimens and medium to high expression,” said Moore. “That’s not to say other groups don’t benefit at all; someday we may go back and look at this in other populations, in lower expressers in different histologies.”

There seems to be a lot of promise for the drug, and it is under investigation in other settings, as well. “There are several phase I studies running in combination with a number of chemotherapies, as well as with pembrolizumab (Keytruda) and bevacizumab,” Moore said.

Mirvetuximab soravtansine is being developed by ImmunoGen.

To read this entire article on CureToday.com, please click here.

New Blood Test Developed To Diagnose Ovarian Cancer

New Blood Test Developed To Diagnose Ovarian CancerInvestigators from Brigham and Women’s Hospital and Dana-Farber Cancer Institute are leveraging the power of artificial intelligence to develop a new technique to detect ovarian cancer early and accurately. The team has identified a network of circulating microRNAs – small, non-coding pieces of genetic material – that are associated with risk of ovarian cancer and can be detected from a blood sample. Their findings are published online in eLife.

Most women are diagnosed with ovarian cancer when the disease is at an advanced stage, at which point only about a quarter of patients will survive for at least five years. But for women whose cancer is serendipitously picked up at an early stage, survival rates are much higher. Currently, no FDA-approved screening techniques exist for ovarian cancer, making it challenging to diagnose the disease early in either women with a genetic predisposition for the disease or in the general population.

Ovarian cancer is relatively rare compared to other benign gynecological conditions such as ovarian cysts. But early detection tests, such as ultrasound or detection of the protein CA125, have a high false positive rate for ovarian cancer. And clinical trials have found that when these tests are used to try to detect early-stage ovarian cancer, they do not have a meaningful impact on survival rates. The Dana-Farber and BWH team sought a tool that would be more sensitive and specific in detecting true cases of early-stage disease.

The team looked at a set of molecules called microRNAs – non-coding regions of the genome that help control where and when genes are activated.

“microRNAs are the copywrite editors of the genome: Before a gene gets transcribed into a protein, they modify the message, adding proofreading notes to the genome,” said lead author Kevin Elias, MD, of BWH’s Department of Obstetrics and Gynecology.

“This project exemplifies the synergy of the two institutes DFCI and BWH and the power of clinicians working closely with lab-based scientists. My lab has been working on miRNAs for a decade and when Kevin came to us with the patient samples, it was a no-brainer to initiate this project” said the senior author Dipanjan Chowdhury, PhD, Chief of the Division of Radiation and Genomic Stability in the Department of Radiation Oncology at DFCI.

In the lab, Elias and Chowdhury and their colleagues determined that ovarian cancer cells and normal cells have different microRNA profiles. Unlike other parts of the genetic code, microRNAs circulate in the blood, making it possible to measure their levels from a serum sample. The team sequenced the microRNAs in blood samples from 135 women (prior to surgery or chemotherapy) to create a “training set” with which to train a computer program to look for microRNA differences between cases of ovarian cancer and cases of benign tumors, non-invasive tumors and healthy tissue. Using this machine-learning approach, the team could leverage large amounts of microRNA data and develop different predictive models. The model that most accurately distinguished ovarian cancer from benign tissue is known as a neural network model, which reflects the complex interactions between microRNAs.

“When we train a computer to find the best microRNA model, it’s a bit like identifying constellations in the night sky. At first, there are just lots of bright dots, but once you find a pattern, wherever you are in the world, you can pick it out,” said Elias.

The team then tested this sequencing model in an independent group of 44 women to determine the accuracy of the test. Once the accuracy of the model was confirmed, the team deployed the model across multiple patient sample sets, using a total of 859 patient samples to measure the sensitivity and specificity of the model. The new technique was far better at predicting ovarian cancer than an ultrasound test. Whereas using ultrasound fewer than 5 percent of abnormal test results would be ovarian cancer, almost 100 percent of abnormal results using the microRNA test actually represented ovarian cancer. Finally, the group put their final model into practice, using the microRNA diagnostic test to predict the diagnoses of 51 patients presenting for surgical care in Lodz, Poland. In this population, 91.3 percent of the abnormal test results were ovarian cancer cases – a very low false positive rate. Negative test results reliably predicted absence of cancer about 80 percent of the time, which is comparable to the accuracy of a Pap smear test.

“The key is that this test is very unlikely to misdiagnose ovarian cancer and give a positive signal when there is no malignant tumor. This is the hallmark of an effective diagnostic test,” said Chowdhury.

The team also looked for evidence of biological relevance for the distinguishing microRNAs. They found changes in the quantity of these microRNAs in blood samples collected before and after surgery, suggesting that the microRNA signal decreases after the cancerous tissue is removed. They also took actual patient samples and imaged the microRNAs in the cancerous cells, demonstrating that the serum signal was coming from the cancerous tissues.

To move the diagnostic tool out of the lab and into the clinic, the research team will need to verify how the microRNA signature changes over time as risk of ovarian cancer increases. To do so, they will need to use prospectively collected, longitudinal samples following women over time. They are particularly interested in determining if the tool will be useful for women at high risk of ovarian cancer as well as the general population.

To read this entire article on MedicalXpress.com, please click here.

Maintenance Poly (ADP-ribose) Polymerase Inhibitor Therapy for Ovarian Cancer: Precision Oncology or One Size Fits All?

Maintenance Poly (ADP-ribose) Polymerase Inhibitor Therapy for Ovarian Cancer: Precision Oncology or One Size Fits All?Platinum/taxane combinations are the most effective regimens for treatment of epithelial ovarian cancer. Response varies between patients, but because the molecular basis for resistance is not defined, patients receive so-called one size fits all therapy. In contrast, elucidation of the molecular events that cause cancer and regulate its progression has led to the development of precision therapies for cancer. One early example is trastuzumab, an anti–human epidermal growth factor receptor 2/neu antibody used to treat breast cancers that overexpress this receptor tyrosine kinase. Immunohistochemical and fluorescence in situ hybridization tests for human epidermal growth factor receptor 2/neu guide its use. Patients lacking overexpression are spared the toxicity and cost of an expensive drug that is unlikely to provide benefit. In the wake of early successes in precision oncology, the US Food and Drug Administration (FDA) promulgated a model in which companion diagnostic (CDx) tests would be developed and approved in parallel with targeted therapies.

Inherited mutations in the BRCA1 and BRCA2 genes are responsible for most high-penetrance genetic susceptibility to epithelial ovarian cancer. These genes are involved in the homologous recombination (HR) pathway of double-stranded DNA repair. In cancers lacking functional BRCA genes, there is therapeutic synergy with poly (ADP-ribose) polymerase (PARP) inhibitors that prevent repair of single-stranded DNA damage. This formed the basis for the development of PARP inhibitor therapy. On the basis of a 34% objective response rate and a median duration of response of 7.9 months, the PARP inhibitor olaparib received accelerated FDA approval in December 2014 for patients with germline BRCA1/2 mutations who had received at least three prior lines of therapy.1 Parallel approval was given to the Myriad Genetics BRACAnalysis CDx test that identifies germline BRCA mutations using a blood sample.

In December 2016, the PARP inhibitor rucaparib received accelerated FDA approval for treatment of ovarian cancer after two lines of prior therapy for patients with germline or somatic BRCA mutations, on the basis of a 54% response rate with a median duration of response of 9.2 months.2,3 The FoundationFocus CDxBRCA test that sequences these genes in tumor tissue was approved with rucaparib. This further extended the number of patients that could be treated with PARP inhibitors to include those with either germline or somatic BRCA mutations, which together comprise approximately 20% of high-grade serous ovarian cancers. In the future, BRCA testing of women with ovarian cancer may increasingly be performed on the cancer itself, with reflex germline testing when a mutation is found to determine if relatives should be offered testing.

In the study that led to approval of rucaparib, patients with germline BRCA mutations had the best progression-free survival (PFS).2 In addition, a group with intermediate response was defined by a high frequency of loss of heterozygosity (LOH) in their cancers, which was used as a surrogate for genomic instability as the result of loss of HR pathway function. Those without BRCA mutations or high LOH had the worst outcomes. Foundation Medicine will probably seek approval of their LOH test as a complementary diagnostic. This term was created by the FDA for tests that may be used to guide selection of patients for therapy, but that were not codeveloped and approved with the drug.

Likewise, Myriad Genetics has developed the myChoice HRD test that, in addition to identifying BRCA mutations, uses > 50,000 markers across the genome to assess HR deficiency (HRD) in the cancer. The test uses three markers of genomic instability: LOH, telomeric allelic imbalance, and large-scale state transitions. These measures are combined to create an HRD score. More than 95% of BRCA1/2-mutant breast cancers had a score > 42, which was established as the cutoff.4 Some patients lacking BRCAmutations had HRD scores > 42, suggesting that HRD may result from other alterations in the HR pathway. In this regard, germline and somatic mutations in several HR pathway genes, including RAD51C, RAD51D, BRIP1, and PALB2, occur in breast and ovarian cancers, but at a much lower frequency than BRCA1/2 mutations. Finally, it has been suggested that HR pathway gene inactivation may occur as the result of promoter methylation or other mechanisms.2 

References

1. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244250, 2015 Link
2. Swisher EM, Lin KK, Oza AM, et al: Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): An international, multicentre, open-label, phase 2 trial. Lancet Oncol 18:7587, 2017 Crossref, Medline
3. Clovis Oncology: Rubraca demonstrated responses in patients with germline or somatic BRCA-mutant advanced ovarian cancer. http://rubraca.com/clinical-data/efficacy
4. Telli ML, Timms KM, Reid J, et al: Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22:37643773, 2016 Crossref, Medline

To read this full article on the Journal of Clinical Oncology, please click here.

Genetic Analysis Indicates Ovarian Cancer May Originate In Fallopian Tubes

Genetic Analysis Indicates Ovarian Cancer May Originate In Fallopian TubesMany of the most severe ovarian cancer cases may originate in the fallopian tube (FT), based on data from an analysis of nine patients published online in Nature Communications.

“Our data suggest that FT neoplasia is the origin of ovarian serous carcinogenesis, and can directly lead to cancer of the ovaries and of other sites,” wrote Sana Intidhar Labidi-Galy, MD, of Dana-Farber Cancer Institute, Boston, and her colleagues (Nature Commun. 2017 Oct 23. doi: 10.1038/s41467-017-00962-1).

Preliminary evidence suggests that fallopian tube cancers may develop into high-grade serous ovarian carcinoma (HGSOC), but evolutionary evidence is limited, the researchers said.

They conducted genetic sequencing on 37 tumor samples from five adult patients with HGSOC. They identified changes in the TP53 tumor suppressor gene in all cases of HGSOC. They also studied serous tubal intraepithelial carcinomas from four patients.

“As expected, we identified sequence changes in the TP53 tumor suppressor gene, a well-known driver gene in HGSOC, in all cases,” the researchers wrote.

“The TP53 alterations were identical in all samples analyzed for each patient including in the p53 signatures, the [serous tubal intraepithelial carcinoma] lesions, and other carcinomas,” Dr. Labidi-Galy and her associates said. Although TP53 was the only gene analyzed in this study, the researchers also noted changes in areas of several known ovarian cancer genes, including BRCA1 and BRCA2.

The study findings were limited by the small size of the tumor samples and small number of cells, the researchers noted.

The results, however, suggest an avenue for further research to help guide early detection and treatment of ovarian cancer, such as the potential removal of fallopian tubes rather than the ovaries in some cases, they concluded.

The research was supported by multiple foundations and organizations, including the National Institutes of Health. One of the investigators is a founder of Personal Genome Diagnostics and a member of its scientific advisory board and board of directors. The other researchers had no financial conflicts to disclose.

To read this full article on Ob.Gyn.News., please click here.