CAR T-Cell Therapy Shows Early Potential in Triple Negative Breast Cancer

Chimeric antigen receptor (CAR) T cells targeting the tyrosine kinase receptor ROR1 can be transferred into patients safely and the cells expand in vivo, according to first in-human study of CAR T cells in patients with solid tumors.

Although post-treatment tumor biopsy revealed an influx of T cells and suggested ROR1 CAR T cells trafficked to tumor sites, CAR T cells developed an activated-exhausted phenotype at day 14 post infusion, according to findings from the ongoing phase I study presented at the 2018 San Antonio Breast Cancer Symposium.

The data presented by Jennifer Specht, MD, were from 7 patients with ROR1-expressing triple negative breast cancer (TNBC) who are being treated at up to 5 dose levels of CAR T cells. ROR1 is an orphan tyrosine kinase orphan receptor that is expressed in TNBC and non–small cell lung cancers. Enrolled patients had adequate organ function and performance status, measurable disease, and ROR1 expression in their tumors >20% by immunohistochemistry.

Embryonic expression of ROR1 is high but expression in adult cells is limited. High levels of ROR1 expression in breast cancer are associated with poor prognosis and may contribute to resistance to conventional therapies, said Specht, an associate professor in the Medical Oncology Division of the University of Washington, Seattle.

“These are early days. This study continues to enroll. We’ve treated 7 patients to date, and we’re now treating at dose level 3 of the CAR T cells, up to 3.3 x 10⁶ transfused T-cells/kg,” she said. “These were heavily pretreated patients. We have seen no significant dose-limiting toxicities to date. We have seen 1 patient recently who developed grade-3 cytokine release syndrome [CRS] that quickly responded to dexamethasone and tocilizumab. We are able to detect expansion of the CAR-T cells in most patients but not at particularly high levels, and we have not seen any significant on-target, off-tumor toxicities related to ROR1 expression.” There have been no instances of severe neurotoxicity, severe CRS, or tumor lysis syndrome.

All patients treated (age range, 27-67 years) had at least 3 lines of prior metastatic therapies. Three patients were treated with as many as 9 prior lines, and 1 received 11. Dose levels were as follows: up to 1 x 10⁵ cells/kg (dose level 0), up to 3.3 x 10⁵(level 1), up to 1 x 10⁶ (level 2), up to 3.3 x 10⁶ (level 3), and up to 1 x 10⁷ (level 4). CAR-T cells are infused following lymphodepletion with cyclophosphamide-containing regimens using a continual reassessment method for dose escalation.

The CAR-T construct being used is a second-generation product engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. The CAR-T cell product is formulated in a 1:1 ratio of CD4+ and CD8+ CAR-T cells.

Imaging assessments by RECIST 1.1 are performed at day 28 to 90, then at 6 and 12 months, and then every 6 months as clinically indicated to estimate efficacy.

“It’s [too] early to say much about responses, but clinically we have seen some patients with heavily pretreated TNBC who have prolonged stable disease [1 at 15 weeks and 1 at 19 weeks], with no subsequent therapy beyond the CAR-T cells,” Specht said. One patient with stable disease after the first infusion has had a partial response lasting 14 weeks after the second infusion.

“We have lots of things to work on in terms of potential barriers to this therapy,” Specht said. “The T-cells that persist do seem to suggest that there’s an exhausted phenotype of those T-cells, so work needs to be done to overcome that exhaustion. We also are trying to understand better how the T cells are trafficking to tumor cells. It’s very different from hematologic malignancies where your cells of interest are easily accessible.”

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Specht JM, Lee SM, Turtle C, et al. A phase I study of adoptive immunotherapy for ROR1+ advanced triple negative breast cancer (TNBC) with defined subsets of autologous T cells expressing a ROR1-specific chimeric antigen receptor (ROR1-CAR). Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. P2-09-13.

https://www.onclive.com/conference-coverage/sabcs-2018/initial-results-of-car-tcell-therapy-study-show-tolerability-in-vivo-expansion-in-tnbc

Biotech week ahead, Dec. 10

Biotech stocks pulled back in last week. Incidentally, some large-cap biotech stocks were hitting new peaks even amid the sectoral downturn.

New molecular entity approval hit a new peak at 55 thus far this year, compared to 46 in 2017.

With that said, here are some catalytic events that can move biotech stocks this week.

Conferences

• 26th Euro Congress and Expo on Dental & Oral Health – Dec. 10-11, in Rome, Italy
• 11th World Congress on Hormonal Imbalance and hormone Replacement Therapy – Dec. 13-14, in Dubai, UAE
• 13th International Conference on Allergy and Clinical Immunology – Dec. 13-14, in London, UK
• International Conference on Mental Health in Adults and Childhood – Dec. 13-14, in Abu Dhabi, UAE
• 4th International Anesthesia and Pain Medicine Conference – Dec. 13-14, in Abu Dhabi
• 13th Annual Conference on Dementia and Alzheimers Disease – Dec. 13-15, in Abu Dhabi
• 12th World Pediatric Congress – Dec. 13-15, in Abu Dhabi, UAE
• ESMO Immuno-oncology Congress 2018 – Dec. 13-16, in Geneva Switzerland

Clinical Trial Results

Denali Therapeutics Inc DNLI 3.27% is scheduled to present Phase 1 data for its Alzheimer’s disease candidate DNL747 at its R&D Day Monday, Dec. 10. The company released positive results from the trial Nov. 19. Denali said it plans to evaluate the candidate in multiple indications, including Alzheimer’s, amyotropic sclerosis and multiple sclerosis.

Bellicum Pharmaceuticals Inc BLCM 5.05% is expected to report preliminary results from the lower-dose cohorts of the Phase 1/2 study of BPX-601 in patients with advanced pancreatic cancer at the ESMO Immuno-oncology conference scheduled for Dec. 13-16.

Apellis Pharmaceuticals Inc APLS 1.5% is due to present an update on the Phase 3 study of APL-2 in geographic atrophy related to age-related macular degeneration in the first-half of December.

Idera Pharmaceuticals Inc IDRA 0.33% will present an update on its ILLUMINATE 204 Phase 1/2 trial in the first-half of December. The trial is evaluating its intratumoral tilsotolimod in combination with either ipilimumab or pembrolizumab in patients with PD-1 refractory/relapsed metastatic melanoma

Earnings

Monday, Dec. 10

• Avid Bioservices Inc CDMO 1.15% (after the market close)

Tuesday, Dec. 11

• Arrowhead Pharmaceuticals Inc ARWR 3.74% (after the market close)

Thursday, Dec. 13

• Pure Bioscience, Inc. PURE 5.77% (after the market close)

https://www.benzinga.com/general/biotech/18/12/12807823/the-week-ahead-in-biotech-conferences-clinical-trials-and-earnings

Dutch hospitals to drop U.S. body brokers, cite ethical concerns

Two major Dutch hospitals say they will stop importing human body parts from American firms, which they have been doing without any regulation for a decade.

The hospitals told Reuters in recent weeks they made their decisions on ethical grounds. The move comes amid investigations by U.S. law enforcement into some so-called body brokers – companies that obtain the dead, often through donation, dissect them and sell the parts for profit.

Earlier this year, Reuters reported that one broker under scrutiny by the U.S. Federal Bureau of Investigation – Portland, Oregon-based MedCure – has used a Dutch hub to distribute tens of thousands of kilograms of human body parts across Europe since 2012. U.S. authorities suspect MedCure sold body parts tainted with disease to American and foreign customers, a concern triggered in part by such shipments to Canada and Hong Kong, according to people familiar with the investigation.

Reuters found that importers of U.S. body parts included two Dutch hospitals. The news agency uncovered no evidence body parts used in the Netherlands were infected, but the Dutch hospitals said they would drop the suppliers in response to reporting by Reuters which raised questions about how the brokers acquired body donations.

The country’s largest hospital, Amsterdam’s Academic Medical Center (AMC), said it bought between 300 and 500 heads from U.S. brokers, which in the past included MedCure, to cover a shortfall. The parts, used for research and training courses, were bought as early as 2008 and as recently as Nov. 21, the hospital said.

Erasmus Medical Center in Rotterdam said it bought knees and shoulders from a U.S. supplier but declined to provide details. The hospital said it used the parts for research and training courses which were not designed to make profits.

The health ministry declined to comment on the hospitals’ decision, and said there is no specific regulatory body which oversees the use of such samples.

From 2012 to 2016, according to manifest records reviewed by Reuters, MedCure shipped body parts valued at a total of more than $500,000 from the United States to the Netherlands. MedCure said it helps connect donors and scientific, research and medical entities. “We are an accredited and regulated institution and adhere to the best-in-class industry standards for safety ethics, and transparency,” the company said in a statement to Reuters.

Dutch laws govern the use of donated organs, the transportation of bodies and cremation, but there are none pertaining to body parts used for training or research, Dutch Minister for Medical Care Bruno Bruins told parliament in April.

The health ministry said it saw no need to regulate the trade in body parts because hospitals take precautions.

In the Netherlands and much of Europe, people who bequeath their bodies to research do so as a charitable donation, with no payment involved. In the United States, many brokers offer donor families free cremation in return for donating a body – a potential saving of up to $1,000.

AMC’s current supplier Science Care, one of the largest body brokers in America, is not under FBI investigation, the company told Reuters; an FBI spokeswoman said policy prevents the agency saying whether a company is or is not being scrutinized. But Science Care’s business model rankles some Dutch lawmakers and doctors.

Freek Dikkers, the professor of ear, nose and throat medicine at the AMC whose department bought the heads, said it was stopping after learning that the company solicits donors at hospices and old age homes and that its former owners earned millions from the trade. Dikkers said that was “unacceptable.”

One frozen head from Science Care that passed through Dutch airport customs belonged to a 53-year-old who died in April 2017 after treatment to remove a brain tumor. Although the declared value of the head on the customs form was $25, the going rate for a human head in the U.S. market is currently around $500, Reuters found. Science Care did not respond to a request for comment about the price of body parts.

Neither of the hospitals would say how much they paid for the parts. The heads were used, sometimes multiple times, to train young doctors before they operated on live patients, said Dikkers.

“It was a rising trend in recent years, initially around 30, and then increasing to 50 (per year), in four shipments,” he said in an interview with Reuters and Dutch TV program Nieuwsuur.

The AMC said documents provided by U.S.-based brokers indicated the heads the hospital bought tested negative for disease. A hospital spokeswoman said it had not carried out its own tests, but doctors always wear protective clothing.

Science Care said it follows all regulations and has been accredited by the American Association of Tissue Banks (AATB). The company uses “an extensive medical screening process for our donors, including testing for Hepatitis B, Hepatitis C, HIV-1, and HIV-2, to reduce potential risks.” All specimens are packaged and shipped according to international standards, it said.

The Rotterdam hospital, Erasmus, said it imported body parts – mostly sample knee and shoulder joints – for orthopedic surgery courses. It declined to say how long it has imported the parts, which company or companies supplied them, or how many it has bought.

Even though the hospitals say they plan to stop using the U.S. suppliers, the business of sending body parts through the Netherlands continues.

Rhenus Logistics, a Dutch company, transported and stored body parts for MedCure between 2015 and 2018. The contract ended this year, said Rhenus spokeswoman Ellen Visser, when MedCure set up its own Dutch distribution hub.

A month later, a new company was established in the Netherlands: Rise Labs, with three people affiliated to MedCure listed as board members. From two addresses in Amsterdam, it offers “services to donors leaving their whole body and providing services to medical professionals working in the field of anatomical research.”

The company did not respond to requests for comment. A receptionist at one Rise Labs’ address did not open the door when a reporter called for comment. MedCure declined to comment.

https://www.reuters.com/article/us-usa-bodies-dutch-exclusive/exclusive-dutch-hospitals-to-drop-u-s-body-brokers-cite-ethical-concerns-idUSKBN1O70RT

With Tesaro off the block, will Clovis be next PARP cancer med maker taken out?

GlaxoSmithKline stepped into the PARP inhibitor space big-time on Monday when it agreed to pay $5.1 billion to buy Zejula maker Tesaro. The $75-per-share valuation marked a 62% premium over Tesaro’s share price, which had already rocketed up on rumors of a deal.

Now, some biopharma watchers are wondering whether Clovis Oncology will be the next PARP maker to command a high premium from an asset-hungry Big Pharma player. Clovis markets Rubraca, a head-to-head competitor to Zejula, but the drug has struggled to keep up with the PARP competition, particularly AstraZeneca and Merck’s first-to-market Lynparza. In the third quarter, Clovis turned in Rubraca sales of just $22.8 million, missing the consensus analyst estimate of $31.3 million and pushing the company’s stock down 30% to $11.63.

But earlier this month, Clovis nabbed breakthrough status from the FDA for prostate cancer, setting it up to be the first PARP on the market in that indication—possibly making the company just a bit more attractive as an acquisition target. And at least some analysts figure Rubraca would be better off as part of a larger company’s portfolio.

Clovis enjoyed a more recent piece of good news that has helped its share price rebound to $20. Tuesday, the company announced that the European Patent Office upheld key claims on Rubraca, allaying fears that if the same claims were to be challenged in the U.S., Clovis could face generic competition even before its patents run out in 2023.

Still, Clovis’ status as a one-trick pony makes it particularly vulnerable, particularly in the PARP market. Part of the problem is that the overall market has been growing more slowly than PARP sellers had hoped it would. At the recent European Society for Medical Oncology meeting, Tesaro’s chief medical officer Marty Huber, M.D., reported that only about half of women with ovarian cancer who are eligible for PARP drugs are receiving them as maintenance therapy. This despite the release of multiple clinical trials supporting their use in that setting.

As if that isn’t making the marketing task challenging for Clovis already, there’s now a fourth player in the PARP market—a giant, no less—vying for oncologists’ attention. In October, Pfizer won FDA approval for its PARP inhibitor, Talzenna, for BRCA-mutated, HER2-negative breast cancer.

During a conference call with analysts after its third-quarter earnings report, Clovis CEO Patrick Mahaffy said “a perceived lack of differentiation” among PARP inhibitors is proving to be a challenge. To address the problem, “we are currently launching significant patient and branded resources into the marketplace across all of our customer channels,” he said.

The disappointing Q3 numbers led SunTrust Robinson Humphrey analyst Peter Lawson to slash his price target on Clovis’ shares from $90 to $20, based largely on a peak sales estimate for Rubraca of $900 million. “While Rubraca looks well positioned, downside risks relate to failure to commercialize, competition, and failure to expand into other cancers,” he wrote in a note.

That said, Lawson tabs Clovis as “well positioned” for a potential acquisition, he wrote—and he’s not alone in that opinion. JPMorgan analyst Cory Kasimov said in a note released after the third-quarter earnings report that Rubraca is a “very good drug” that “may trigger some bottom fishing.”

Kasimov added that the next opportunity for positive Rubraca data won’t come until late 2019, when the company is expected to release highly anticipated results from clinical trials in bladder cancer. That could be all the more reason for Clovis to turn up on someone’s M&A target list.

“It strikes us that this asset would be much better off in a larger organization,” Kasimov said, “where it can more quietly grow as part of an oncology portfolio, as opposed to being judged on a quarterly basis within a single-product company (as is currently the case).”

https://www.fiercepharma.com/pharma/tesaro-off-block-will-clovis-be-next-parp-maker-to-get-swallowed-up

With pricing outcry raging, US drug spending up less than 1% last year: CMS

Congress and the Trump administration are riled up about pharma prices and promising to drive them down, but a new U.S. government report shows growth in retail drug spending screeched to a halt in 2017.

The data, released by the Centers for Medicare & Medicaid Services Thursday, show growth in spending on pharmacy-dispensed drugs slowed to 0.4% last year, down sharply from 2.3% in 2016—and even more sharply from the increases in 2015 and 2014, CMS reported. Drug costs for those years grew 8.9% and 12.4%, respectively.

Why the slowdown? For one thing, drugmakers pushed through lower price hikes, CMS said. Prescription growth also slowed, while more patients started on generics and generic prices dropped, the agency said.

The new CMS data hit as drug prices continue to occupy center stage in Washington. After years of scrutiny on pharma’s pricing practices—and annual increases in prices and costs—Congress and the Trump administration have made the issue a priority. The FDA is approving generics at a record pace and prioritizing applications for drugs with little to no competition. The administration is working to force drugmakers to include prices in TV ads and lower certain U.S. prices closer to international levels, among a slew of other proposals.

Meanwhile, uncomfortable in the spotlight, many drugmakers have pumped the brakes on price hikes. Pfizer, for instance, raised prices this summer but backpedaled—at least temporarily—after the president slammed the company on Twitter. Trump tweeted that Pfizer “should be ashamed” about the move, and the company decided to defer price hikes. It now appears ready to raise them again in early 2019.

During the Pfizer controversy, other large drugmakers such as Novartis and Roche said they wouldn’t raise prices again in 2018.

https://www.fiercepharma.com/pharma/pharma-spending-grew-just-4-last-year-due-to-lower-price-hikes-and-more-cms

Internet therapy apps reduce depression symptoms

In a sweeping new study, Indiana University psychologists have found that a series of self-guided, internet-based therapy platforms effectively reduce depression.

The work, which reviewed 21 pre-existing studies with a total of 4,781 participants, was published in the November issue of the Journal of Medical Internet Research. The study was led by Lorenzo Lorenzo-Luaces, a clinical professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences.

In the past several years, many internet-based apps and websites have made claims to treat depression. The subjects of the IU study were specifically those applications that provide treatment with cognitive behavioral therapy, a form of psychotherapy that focuses on changing thought patterns and behavior to alleviate symptoms of depression and other mental disorders.

Previous studies had examined the effectiveness of individual internet-based cognitive behavioral therapy apps, or iCBT, using a range of methods. Until this study, however, no review had examined whether the effects of these treatments were inflated by excluding patients with more severe depression or additional conditions such as anxiety or alcohol abuse.

“Before this study, I thought past studies were probably focused on people with very mild depression, those who did not have other mental health problems, and were at low risk for suicide,” Lorenzo-Luaces said. “To my surprise, that was not the case. The science suggests that these apps and platforms can help a large number of people.”

For Lorenzo-Luaces, internet-based cognitive behavioral therapy apps are an important new tool for addressing a major public health issue: that individuals with mental health disorders like depression far outnumber the mental health providers available to treat them.

“Close to one in four people meet the criteria for major depressive disorder,” he said. “If you include people with minor depression or who have been depressed for a week or a month with a few symptoms, the number grows, exceeding the number of psychologists who can serve them.”

People with depression are also expensive for the health care system, he added.

“They tend to visit primary-care physicians more often than others,” Lorenzo-Luaces said. “They have more medical problems, and their depression sometimes gets in the way of their taking their medication for other medical problems.”

By conducting a “meta-regression analysis” of 21 studies, Lorenzo-Luaces and collaborators decisively determined that internet-based therapy platforms effectively alleviate depression. A central question was determining whether previous studies distorted the strength of these systems’ effects by excluding people with severe depression.

The conclusion was that the apps worked in cases of mild, moderate and severe depression.

Many of the studies in the analysis compared use of internet-based cognitive behavioral therapy apps to placement on a wait list for therapy or the use of a “fake app” that made weak recommendations to the user. In these cases, the iCBT apps worked significantly better.

“This is not to say that you should stop taking your medication and go to the nearest app store,” added Lorenzo-Luaces, who said both face-to-face therapy and antidepressants may still prove to be more effective than the iCBT apps alone.

“People tend to do better when they have a little bit of guidance,” he said. But he added that a 10- to 15-minute check-in may be sufficient for many people, freeing health care providers to see more patients.

App-based therapy also has an advantage in situations where access to face-to-face therapy is limited due to logistical barriers, such as long distances in rural areas or inflexible work schedules.

“ICBT apps take the methods we have learned and make them available to the many people who could benefit from them,” Lorenzo-Luaces said. “It’s an exciting development.”

 Explore further: Cognitive behavioral therapy delivered online effective for treating depression

More information: Lorenzo Lorenzo-Luaces et al. The Generalizability of Randomized Controlled Trials of Self-Guided Internet-Based Cognitive Behavioral Therapy for Depressive Symptoms: Systematic Review and Meta-Regression Analysis, Journal of Medical Internet Research (2018). DOI: 10.2196/10113

https://medicalxpress.com/news/2018-12-internet-therapy-apps-depression-symptoms.html

Pregnant Women Commonly Refuse Vaccines

Pregnant women commonly refuse vaccines, including influenza vaccine and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine, according to research published online Dec. 4 in Obstetrics & Gynecology.

Sean T. O’Leary, M.D., M.P.H., from the University of Colorado Anschutz Medical Campus in Aurora, and colleagues surveyed a nationally representative network of obstetrician-gynecologists (331 respondents) from March 2016 to June 2016 to understand providers’ strategies when encountering vaccine refusal.

Providers perceived that pregnant women more commonly refuse influenza vaccine than Tdap vaccine, according to the researchers. The majority of respondents (62 percent) reported ≥10 percent of pregnant women they care for in a month refuse influenza vaccine compared with 32 percent who reported the same for Tdap vaccine. Providers said the most common reasons they heard for vaccine refusal were patients’ belief that influenza vaccine makes them sick (48 percent), belief they are unlikely to get a vaccine-preventable disease (38 percent), general worries about vaccines (32 percent), desire to maintain a natural pregnancy (31 percent), and concern that their child could develop autism as a result of maternal vaccination (25 percent). To address refusal, providers reported most commonly using strategies such as stating vaccines in pregnancy are safe (96 percent), explaining that not getting the vaccine puts the fetus or newborn at risk (90 percent), or explaining that not getting the vaccine puts the pregnant woman’s health at risk (84 percent). Providers perceived that the most effective strategy is telling patients that not getting vaccinated puts the fetus or newborn at risk.

“Ob-gyns perceive vaccine refusal as common among pregnant women and report they spend significant time discussing vaccine concerns with pregnant patients,” the authors write.

Abstract/Full Text (subscription or payment may be required)

https://www.physiciansbriefing.com/obgyn-women-s-health-11/pregnancy-news-543/pregnant-women-commonly-refuse-vaccines-740362.html