FDA panel unanimously endorses Novartis T-cell cancer therapy pioneered at Penn

Updated: JULY 12, 2017 — 6:09 PM EDT

For the estimated 600 children who battle terminal leukemia each year in the U.S., there is new hope.

And for the fledgling field of T-cell immune therapies, there is new excitement.

In a resounding vote of confidence for a first-of-its-kind cancer treatment, a U.S. Food and Drug Administration advisory committee on Wednesday unanimously recommended approval of Novartis Pharmaceutical’s T-cell therapy for acute lymphocytic leukemia (ALL).

Novartis’ technology, which genetically engineers each patient’s immune system T-cells to recognize and attack cancer cells, was developed at the University of Pennsylvania by a team led by gene therapy pioneer Carl June. The leukemia therapy was clinically tested in studies at Children’s Hospital of Philadelphia beginning in 2012, and in a pivotal study of 68 children at 25 medical centers around the world.

The living drug, called tisagenlecleucel, has shown unparalleled effectiveness. It put 83 percent of patients in the global trial into complete remission, even though they had relapsed again and again with conventional treatments, according to Novartis’ data. After six months, 75 percent of the patients who responded remained cancer-free.

That’s why FDA scientists asked the panel not to focus on whether the therapy works, but on its unprecedented safety and manufacturing challenges. Each child’s T cells must be collected at a participating hospital, frozen, and shipped to Novartis’ cellular manufacturing plant in Morris Plains, N.J. There the cells are thawed, genetically manipulated, multiplied over three weeks, tested for potency and purity, refrozen, and sent back to the hospital to be thawed and given intravenously to the child. (Novartis hasn’t discussed the pricetag for this feat, but analysts guess the therapy could cost as much as $600,000.)

After infusion, the T cells go on an attack that overstimulates the child’s immune system, triggering flu-like symptoms — or much worse. In the global trial, 82 percent of children had at least mild overstimulation, and 47 percent had life-threatening overreactions, such as high fevers, low blood pressure, seizures, liver abnormalities, and heart irregularities.

No child has ever died of these side effects, but a frighteningly close call with the very first patient more than five years ago —  Emily Whitehead of Philipsburg, Pa. — helped CHOP doctors develop the monitoring and response plan that includes use of an immune-dampening rheumatoid arthritis drug.


Emily, now 12, attended the meeting at FDA offices in Silver Spring, Md., with her father, Tom. He assured the panel that those transient side effects, however scary, were a small price to pay for seeing his daughter beat a disease that was days away from killing her.

“Our daughter was going to die, and now she leads a normal life,” Whitehead told the panel, choking up. “We are honored to attend this hearing and be a part of this process.”

Another parent who testified, Don McMahon, of Alpharetta, Ga., told how his son Connor, now 16, fought leukemia beginning at age 3. Last year, as Connor faced his third relapse, he qualified for the T-cell therapy at Duke University.

“Connor ….had fevers of over 104 for 8 days,” McMahon said. “But then he walked out of the hospital. He finished the hockey season… For the sake of these children, approve this T cell therapy.”

The 10 panel members praised Novartis for developing strategies to manage and minimize the risks. The company plans to limit to 35 the number of U.S. medical centers that will be allowed to offer the therapy, and will provide intensive training of care providers, plus education for families.

In addition, the company will create a registry to follow patients for up to 15 years, watching for possible rare, delayed side effects. One theoretical risk that has not been detected so far: secondary cancers could be caused by the viral vector that genetically modifies the T cells.

“In the data presented today, the clinical responses are remarkable,” said panel member Catherine Bollard, a pediatrician and immunologist at Children’s National Medical Center in Washington, D.C. “I think Novartis has done a great job of mitigating the risks going forward.”

“This is a major advance and ushers in a new era of treatment of acute lymphocytic leukemia,” said Malcolm Smith, a pediatric oncologist with the National Cancer Institute.

The FDA is expected to follow the panel’s advice and formally approve the therapy by this fall. Novartis, which is also seeking European approval of the leukemia therapy, is clearly in the lead in the high-stakes race to develop T-cell treatments, which are seen as an exciting new chapter in immunotherapy. Other companies, including Kite Pharma Inc. and Juno Therapeutics, are also developing such therapies for various blood malignancies. All the players hope the technology ultimately will work in solid tumor cancers, which pose more daunting obstacles than the blood cancers.

About 6,000 children and young adults are diagnosed with acute lymphocytic leukemia each year in the U.S. and Europe. About 85 percent are cured with conventional treatments, but those who repeatedly relapse face a grim prognosis, even with relentless rounds of highly toxic chemotherapy.

“It’s clear to all of us in oncology that, even though pediatric ALL is a success story, the patients who are left behind are in tough shape and really difficult to treat,” Stephan Grupp, the CHOP oncologist who led the global trial, told the advisers. “It means hitting them with heavy chemo over and over. They spend weeks and months in the hospital. So the current treatment options are just not adequate.”

After the panel’s unanimous endorsement, Grupp sounded elated.

“This is the first engineered cell therapy in human history,” he said in an interview. “It’s been a decade of work with wonderful people at Penn. What could be better? This is a once-in-a-lifetime experience.”

Source: http://www.philly.com/philly/health/health-news/novartis-t-cell-cancer-therapy-pioneered-at-penn-chop-gets-fda-hearing-20170712.html



Scientists have discovered an important gene whose loss lies behind follicular lymphoma, an incurable cancer

Follicular lymphoma is an incurable cancer that affects over 200,000 people worldwide every year. A form of non-Hodgkin lymphoma, follicular lymphoma develops when the body starts making abnormal B-cells, which are white blood cells that in normal conditions fight infections. This cancer is associated with several alterations of the cell’s DNA, but it has been unclear which gene or genes are involved in its development. EPFL scientists have now analyzed the genomes of more than 200 patients with follicular lymphoma, and they discover that a gene, Sestrin1, is frequently missing or malfunctioning in FL patients. The discovery opens to new treatment options and it is now published in Science Translational Medicine.

One of the common features of follicular lymphoma is a genetic abnormality between two chromosomes (14 and 18). In an event known as “chromosomal translocation” the two chromosomes “swap” certain parts with each other. This triggers the activation of a gene that protects cells from dying, making cells virtually immortal — the hallmark of a tumor.

Moreover, approximately 30% of follicular lymphoma patients lose also a portion of chromosome 6, affecting multiple genes involved in suppressing the emergence of a tumor. These patients typically have poor prognosis. Another 20 % of patients have alterations causing chromosomal disorganization and the consequent malfunctioning of several genes and proteins. The bottom line is that for both group of patients it is very difficult to pinpoint which of all the affected genes are actually causing the disease.

The lab of Elisa Oricchio at EPFL, with colleagues from the US and Canada, analyzed the genomes of over 200 follicular lymphoma patients. Their analyses revealed that a specific gene, Sestrin1, can be harmed by both loss of chromosome 6 and silenced in patients.

Sestrin1 helps the cell defending itself against DNA damage — for example after exposure to radiation — and oxidative stress. In fact, Sestrin1 is part of the cell’s anti-tumor mechanism that stops potentially cancerous cells from growing.

Disruption of a region in chromosome 6 or epigenetic modifications of the DNA block Sestrin1 expression and these contribute to the development of Follicular Lymphoma.

Beyond identifying the Sestrin1 gene as frequently altered in FL patients, the scientists demonstrated that Sestrin1 is able to suppress tumors in vivo. They showed that Sestrin1 exerts its anti-tumor effects by blocking the activity of a protein complex called mTORC1, which is well known for controlling protein synthesis as well as acting as a sensor for nutrient or energy changes in the cell.

Finally, the identification of loss of Sestrin1 as a key event behind the development of follicular lymphoma is particular important because it helps identifying patients that will benefit from new therapies.Indeed, this study shows that the therapeutic efficacy of a new drug that is currently in clinical trial depends on Sestrin1. Importantly, this dependency can be extended beyond follicular lymphoma to other tumor types.

Source: https://www.sciencedaily.com/releases/2017/06/170628144909.htm



CAR-T news — June 2017

“One of the leading CAR T-cells immunotherapy company, Cellectis dosed the first blood cancer patient with the allogeneic, “off-the-shelf” CAR-T therapy, UCART123 at Weill Cornell Medicine and NewYork-Presbyterian Hospital…”

Scientists Get Closer to First CAR T-Cells Based Immunotherapy for Humans

Cellectis’ off-the-shelf CAR-T Cancer Therapy has Entered the Clinic

Cellectis’ Press Release…

First in Human Administration of UCART123 in Cellectis’ AML Phase I Clinical Trial at Weill Cornell Medicine, NewYork-Presbyterian Hospital | Cellectis

A journalist from Bloomberg News is working on a story similar to the one below:

For experimental cancer therapy, a struggle to ensure supply keeps up with demand | Science | AAAS

“The sky-high cost of producing CAR T cells, and limitations on the availability and regulatory qualification of reagents can be barriers to making CAR T cell therapy accessible…”

Biotechin.Asia- Driving CAR T-Cell Therapy From Bench to Bedside

CAR-T Value Calculation In The Firing Line | Seeking Alpha

Work continues on applying CAR-T to solid tumors:

Unleashing CAR-T Therapies on Solid Tumors: Are We There Yet? | BIOtechNow

Buy Celyad And Get In On The CAR-T Space In Solid Tumors: Medicine’s Next Frontier – Celyad (NASDAQ:CYAD) | Seeking Alpha

A history of all reported deaths (clinically described as a “Grade 5 Adverse Event”) thus far from CAR-T:

EP Vantage – Spotlight – Putting a number on CAR-T deaths

Neurotoxicity needs separate treatment from CRS in CAR T-cell therapy  | (Free registration required)

Engineering CAR-T cells

CAR-T coverage in PC Magazine(!)

How Scientists Are Hacking Cancer | News & Opinion | PCMag.com