Reenergizing T cells exhausted from fighting a tumor

An international team of researchers has found a possible way to reenergize T cells exhausted from fighting a cancerous tumor. In their paper published in the journal Science Immunology, the group describes their study of the impact of a decrease in enolase 1 on T cells and how bypassing it allowed them to recharge immune cells.

Prior research has shown that one of the reasons the immune system is sometimes unable to fight off a cancerous tumor is because tumor-infiltrating lymphocytes (TILs) lose energy as they attack a tumor. The tired T cells become incapable of putting up a strong fight and the tumor grows bigger. Prior research has also suggested that the reason such cells become tired is because they are outcompeted for glucose by hungry tumor cells. In this new effort, the researchers sought to find a way to overcome this problem so that TILs could continue to fight.

The researchers began by studying T cells, (CD8+ TILs) both in their dormant state and when active. They found that the cells did become exhausted after battling cancer cells for a time. More specifically, they found that T cell exhaustion was caused by a lowered amount of enolase 1, an enzyme found in the glucose metabolic pathway, due to consumption by tumor cells. The end result was a reduction in glucose metabolism and a 10-fold decrease in oxidative phosphorylation

To reenergize the T cells, the researchers chose to bypass enolase 1 altogether and instead fed the T cells pyruvates, which are end products of enzyme activity. The researchers report that doing so resulted in increased glucose metabolism and oxidative phosphorylation, which in turn resulted in improved energy levels in the T cells. Pleased with their findings, the researchers tested a variety of checkpoint inhibitors in live animals (pyruvate was not a viable option for use in test animals). They report a combined cocktail of such inhibitors caused an increase in active T cells and slowed tumor growth.

The next step for the team will be to find suitable inhibitors for use in humans, to test them and if they are successful, to enter clinical trials.

---

Explore further

Medical scientists describe optimal immune therapeutic strategies for liver cancer

---

More information: Lelisa F. Gemta et al. Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+ T cells, Science Immunology (2019). DOI: 10.1126/sciimmunol.aap9520

https://medicalxpress.com/news/2019-01-reenergize-cells-exhausted-tumor.html

Border Patrol struggles with flood of sick migrants

Border Patrol agents have spent nearly 20,000 hours since October driving asylum seekers to and from hospitals for medical evaluations, according to newly released Department of Homeland Security data.

Since Oct. 1, 2018, the Border Patrol, which works in rural areas between border crossings, has “seen an increase in the numbers of apprehended individuals requiring medical assistance.”

A total of 2,224 migrants, primarily from Guatemala and Honduras, have been hospitalized due to health issues that could not be treated on site in the last month alone, according to a CBP statement.

The department said the spike in illnesses among migrants is forcing federal law enforcement to spend less time focused on serious threats because they are facilitating hospital and urgent care trips. It’s also affecting communities that are trying to help with medical emergencies but are severely short-staffed.

For example, Hidalgo County, located in the southernmost part of New Mexico, is comprised of fewer than 5,000 residents. The average resident makes $32,000 a year, and the low incomes mean the county has less money to use. Its general budget is just $1.7 million.

Two county officials who spoke with the Washington Examiner during a recent meeting said they have seen massive groups of migrants, from 100 to 300 people each, getting dropped off in the county. The high number of arrivals wasn’t a problem at first, but by November and early December, it became a problem when many people began showing up sick and in need of professional care.

“For a while there, we were being called every day. They [Border Patrol] wanted us to do their screening because they had a lack of medical personnel,” said Hidalgo County Emergency Medical Services Director David Whipple.

Whipple only has six other staff members and five volunteers on his team, and they were responsible for responding to medical emergencies across the 5,000-square mile county. Going from the EMS headquarters in Lordsburg to Antelope Wells, then to the nearest hospital, and back to Lordsburg is a six-hour trip, he said.

The situation prompted County Manager Tisha Green to reach out to state and border representatives in late December.

In response, Border Patrol deployed members of its Border Patrol, Search, Trauma and Rescue to alleviate the stress on the county medical personnel. Since then, Whipple’s calls from Antelope Wells have dramatically decreased, partially because the number of large groups arriving there has also declined since Christmas.

However, other problems remain.

The closest Border Patrol station to Antelope Wells is located 95 miles north in Lordsburg, and all migrants who showed up to Antelope Wells had to be transported by border agents to Lordsburg.

County officials say scabies outbreaks have plagued that facility, though Border Patrol public affairs officials and Customs and Border Protection did not respond to requests for a tour and comment of either facility.

“They’ve had big issues with scabies,” said Whipple, who did not disclose the number of cases at the Lordsburg Station. “That’s an ongoing thing.”

Scabies is an infestation of the skin by microscopic mites that lay eggs, prompting an acne-like rash and severe itching. It is contagious if a person with scabies makes prolonged skin contact with another person.

Another issue is the Border Patrol’s decision to bring migrants into local urgent care facilities, including Hidalgo County Medical Services.

“The biggest concern that I’ve heard about is not that they’re disease-ridden, but the fact that they don’t vaccinate. I mean, it would become a county epidemic,” Green said. “The comment was made that a good 20 of the immigrants walked in with Border Patrol and all of the local residents that were there waiting for appointments were kind of pushed to the side and several of the people got up and left because they didn’t want to be around any type of illness they could be bringing in.”

Green said the last call she got on this specific problem was in mid-January.

Whipple said the best offense is a good defense and that each person taken into custody should be given medical screenings by actual medical personnel.

“Certain things coming across — fevers, coughs — they need to be quarantined. We’re not seeing that,” Whipple said.

https://www.washingtonexaminer.com/news/border-patrol-struggles-with-flood-of-sick-migrants

Migrant with flesh-eating bacteria detained at US border

A man among a group of migrants detained in a desolate part of New Mexico near the border with Mexico has been diagnosed as infected with flesh-eating bacteria, the U.S. Border Patrol said Friday.

The man was taken to a hospital in recent days after telling a federal agent that he had a growing rash on his leg, U.S. Border Patrol spokesman Carlos Antunez said.

Flesh-eating bacteria are a rare condition called necrotizing fasciitis that spreads quickly and can be fatal. The bacteria usually gets into the body through a minor cut or scrape and can cause a serious infection that can destroy muscle, skin and other tissue.

A statement from border patrol officials said the unidentified migrant will require extensive medical treatment. Antunez said he could not provide more details or the man’s condition.

Sometimes surgery is needed to remove the infected area. It’s rare for the infection to spread to other people.

The man was detained near the small city of Lordsburg. His home country was not disclosed.

Another 300 migrants, mostly Central Americans, were detained Thursday south of Lordsburg near an official U.S.-Mexico border crossing, Antunez said. Some had illnesses and injuries and were taken to hospitals for treatment.

The sparsely populated, desert area has experienced a significant influx of large migrant groups recently.

Nearly 10,000 migrants have been detained at New Mexico’s three Border Patrol stations since Oct. 1, officials said.

There were 12,800 detentions at the three stations from October 2017 through September 2018.

https://apnews.com/82a4ade6d3174990b14315853b3f806f

GE Healthcare, G-CON to offer modular, prefab cell therapy manufacturing lines

GE Healthcare has begun working with G-CON Manufacturing, makers of prefabricated cleanrooms, to offer a combined and deployable platform for early-stage manufacturing of cell therapies and viral vectors.

G-CON will provide modular cleanroom infrastructure for GE’s clinical and commercial production platforms to help simplify the manufacturing process. The end goal is for drug developers and manufacturers to be able to purchase their own full production lines and cleanroom environments, which can be housed within an “off-the-shelf” warehouse-like building.

“It is well-recognized that the commercialization of the cell therapy industry requires a paradigm shift in manufacturing, because of the highly individual and complex nature of the production process,” Maik Jornitz, G-CON president and CEO, said in a statement.

With production queues at service providers spanning months to years, many innovator companies are weighing the risks and benefits of developing in-house production facilities versus contracting out, or pursuing a mix of both.

“This combination will provide manufacturers with turnkey processing capacities with speed and reliability. Such an approach will remove manufacturing bottlenecks that currently delay production of this critical new class of therapies,” Jornitz added. Both GE Healthcare and G-CON, which previously collaborated on similar processes for vaccine production, will also continue selling their products and services separately.

Last year, GE Healthcare launched its modular FlexFactory line for end-to-end cell therapy production, offering semi-automated and digitized processes at a size that can be installed into G-CON’s scalable, pod-like cleanrooms.

In addition, the collaboration will also include the cleanroom technology required for the manufacture of lentivirus and adeno-associated virus vectors, used as delivery vehicles for gene therapy treatments.

“The combination of the G-CON infrastructure along with GE Healthcare’s cell therapy and vector platform will aid in reducing the time to market for cell therapies that need vector manufacturing to be on-site and connected to the overall therapy workflow,” said Catarina Flyborg, general manager of cell and gene therapy at GE Healthcare.

“It has been designed with early-stage manufacturing processes in mind, which is the much-needed stepping stone for validating large-scale manufacturing and investment decisions in the future,” Flyborg said.

Earlier this month, the FDA said it was expecting a new wave of cell and gene therapy applications in the coming years, projecting at least 200 new IND submissions annually by the end of 2020. By 2025, the agency expects to be approving 10 to 20 therapies each year.

FDA Commissioner Scott Gottlieb and CBER Director Peter Marks outlined plans to hire at least 50 new clinical reviewers focused in the space, as well as issue new guidance, including on how changes in manufacturing techniques for CAR-T therapies can be introduced without sponsors performing new clinical investigations or bridging studies, and instead possibly submit real-world data.

https://www.fiercebiotech.com/medtech/ge-and-g-con-to-offer-modular-pre-fab-cell-therapy-manufacturing-lines-and-cleanrooms

Bellerophon to Present on Endpoint to Detect Pulmonary Fibrosis Improvement

Bellerophon Therapeutics, Inc. (Nasdaq: BLPH) (“Bellerophon” or the “Company”), a clinical-stage biotherapeutics company, today announced that data from the Company’s ongoing INOpulse® Phase 2b clinical trial (iNO-PF) for the treatment of Pulmonary Hypertension associated with Interstitial Lung Disease (PH-ILD) that supports actigraphy as a clinically meaningful endpoint will be the subject of a poster presentation at the 13^th Annual Pulmonary Vascular Research Institute World Congress on Pulmonary Vascular Disease, which will take place January 31 through February 3, 2019, in Barcelona, Spain.

Actigraphy (medical wearable continuous activity monitoring) provides highly sensitive objective real-world physical activity data that correlates to patient functional abilities and health outcomes.  Bellerophon is currently utilizing actigraphy to evaluate multiple clinically meaningful activity parameters in the iNO-PF study.  In addition, actigraphy is currently being utilized as the primary endpoint in several pivotal clinical trials in other cardiopulmonary indications, such as heart failure and Chronic Obstructive Pulmonary Disorder.

“Evaluating real-world physical activity in patients suffering from cardiopulmonary diseases provides invaluable insight in assessing disease progression and overall patient well-being,” said James Loyd, M.D., Professor of Medicine at Vanderbilt University Medical Center, an author of the poster to be presented and a principal investigator in the iNO-PF study. “Having enrolled more than 10 patients into the iNO-PF study, including the first patient into Cohort 2, I believe that actigraphy provides clinically meaningful data sensitive to functional change following treatment with INOpulse.  Based on my experience and the clinical data generated to date, I am confident that INOpulse has the unique potential to become the first therapy to treat PH-ILD, a disease with a serious unmet medical need.”

The data to be presented was generated in Cohort 1 of the iNO-PF trial, which consisted of 41 subjects who were randomized to iNO 30 (30 mcg/kg IBW/hr) vs. placebo, with a one-week run-in period, followed by an eight-week double-blinded treatment period.  Statistically significant improvements in multiple clinically meaningful activity parameters were observed in the treatment arm. Subjects on pulsed inhaled nitric oxide (iNO) demonstrated an increase of 8% in moderate activity (walking, stairs, yardwork, etc.) versus a 26% decrease for subjects on placebo (p=0.04). Subjects on iNO showed no decline in their overall activity levels versus a 12% decline for subjects on placebo (p=0.05).  Cohorts 2 and 3, which are ongoing, will assess higher doses, iNO 45 and iNO 75, as well as a longer 16-week treatment period.

Presentation Details

Title: Actigraphy as a clinically meaningful endpoint to detect change after treatment with iNO (30 mcg/kg-IBW/hr) in patients at risk of Pulmonary Hypertension associated with Pulmonary Fibrosis

Date/Time: Saturday, February 2, 2019 (6:15-7:30 PM)

Session: Moderated Poster Session

https://www.marketscreener.com/BELLEROPHON-THERAPEUTICS-20708472/news/Bellerophon-to-Present-Clinical-Data-Supporting-Actigraphy-as-a-Clinically-Meaningful-Endpoint-to-De-27926262/

Novartis: Cosentyx improved psoriasis quality of life measures early as Week 4

Novartis announced today results from a pooled analysis of four Phase 3 clinical trials demonstrating patients with moderate-to-severe plaque psoriasis (PsO) treated with Cosentyx^® (secukinumab) 300 mg reported improvements in mobility, self-care, and usual activities components of the EQ-5D-3L questionnaire as early as Week 4 when compared to placebo in patients who reported problems at baseline.¹ The results were presented at the 15^th Annual Maui Derm for Dermatologists 2019.

“Moderate-to-severe plaque psoriasis can impact every aspect of a person’s life,” stated Steven R. Feldman, M.D., Ph.D, Wake Forest School of Medicine*. “These findings suggest that helping patients feel better through improved quality of life and ability to function should be a goal as important as skin clearance in psoriasis management.”

Plaque psoriasis is characterized by painful red, raised, dry patches of skin usually covered by silvery or white scales.² The disease typically involves the extensor areas of the forearms and shins, along with hard-to-treat areas like the scalp, palms of the hand, soles of the feet and finger nails.^2,3 Many patients with psoriasis also live with concurrent psoriatic arthritis (PsA), an inflammatory form of arthritis causing stiffness, pain, and swelling in the joints. When left untreated, PsA can cause irreversible joint damage and lead to physical limitations.⁴ For patients experiencing symptoms of PsO and PsA the physical limitations can lead to psychological problems that can affect every day social activities and work causing embarrassment, lack of self-esteem, anxiety and depression.^2,4-5

The pooled analysis of the ERASURE, FIXTURE, FEATURE, and JUNCTURE trials included patients with moderate-to-severe plaque psoriasis who were randomized to receive placebo or Cosentyx 300 mg and who reported problems with mobility, self-care, or usual activities (e.g. work, study, housework, family or leisure activities) at baseline, as recorded by the EQ-5D questionnaire. The percentages of patients reporting problems in the EQ-5D-3L mobility, self-care, or usual activities domains were compared at weeks 4, 8, and 12 between patients receiving placebo (n=282) and Cosentyx 300 mg (n=309).¹

• Change in Mobility: The percentage of patients reporting no problems in mobility at Week 4 was higher with Cosentyx 300 mg compared with placebo (60.7% vs 38.5%); similar trends were observed at Weeks 8 (73.6% vs 48.1%) and 12 (71.4% vs 46.6%).¹
• Change in Self Care: The percentage of patients reporting no problems in self-care at Week 4 was higher with Cosentyx 300 mg compared with placebo (71.4% vs 40.9%); similar trends were observed at Weeks 8 (79.2% vs 42.3%) and 12 (87.1% vs 43.0%).¹
• Change in Usual Activities: The percentage of patients reporting no problems in usual activities at Week 4 was twice higher with Cosentyx 300 mg compared with placebo (63.8% vs 31.1%); similar trends were observed at Weeks 8 (74.4% vs 35.7%) and 12 (82.7% vs 42.6%).¹

Cosentyx is the first and only fully human IL-17A antagonist approved to treat moderate to severe plaque psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS).⁶ To date, over 14,630 unique prescribers have experience with Cosentyx, and have prescribed Cosentyx to more than 105,000 US patients to date across all indications.⁷

https://www.biospace.com/article/releases/novartis-data-show-psoriasis-patients-treated-with-cosentyx-reported-improvements-in-quality-of-life-measures-as-early-as-week-4/

Biocept Liquid Biopsy Targets Circulating Tumor DNA

Biocept, Inc. (NASDAQ: BIOC), a leading commercial provider of liquid biopsy tests designed to provide physicians with clinically actionable information to improve the outcomes of patients diagnosed with cancer, announces the availability of research-use-only (RUO) kits, which are intended to enable molecular laboratories around the world to utilize Biocept’s Target Selector™ circulating tumor DNA (ctDNA) assays to perform liquid biopsy testing.  Biocept’s Target Selector™ platform is patent protected in the United States and in 10 major international territories. The first available kit is for the high-sensitivity detection of EGFR oncogene mutations, which are among the most frequently evaluated biomarkers for lung cancer. Additional RUO test kits for other oncogene mutations are planned for launch in the future.

Biocept’s Target Selector™ ctDNA platform utilizes patented primers, reagents, and methodologies to enrich the specimen for mutations of interest, resulting in very high assay sensitivity and specificity versus methods currently used in most laboratories.

“The launch of our liquid biopsy kit strategy has been a priority for Biocept, and we are excited to now have the ability to leverage the value of our patents as we enable laboratories around the world to utilize our proprietary Target Selector technologies,” said Michael Nall, President and CEO of Biocept. “Key objectives for this new business line are to create a leading global brand of research-use-only products, including kits and blood collection tubes, in the liquid biopsy market and to generate additional revenues in addition to those generated by our U.S.-based clinical laboratory business.”

https://www.biospace.com/article/releases/biocept-launches-liquid-biopsy-kits-intended-to-broaden-use-of-its-proprietary-technology-platform-for-high-sensitivity-detection-of-circulating-tumor-dna/