Gene therapy for cancer halted after patient death

Gene therapy for cancer halted after patient death

11 September 2017

By Ebtehal Moussa

Appeared in BioNews 917

Two trials assessing gene therapy for blood cancer have been put on hold by the US Food and Drug Administration (FDA), following a patient fatality.

The therapy, known as ‘off-the-shelf’ CAR-T immunotherapy, used genetically modified immune system T cells to target cancer, yet unlike other trials the cells were taken from a healthy donor instead of the patient. It was hoped this therapy would prove easier and less expensive to produce.

Allogeneic production of CAR-T cells is cost-effective and results in remarkable off-the-shelf product, capable of being distributed worldwide’, the manufacturer Cellectis had suggested in a video presentation.

The early-stage trials of the therapy, called UCART123, aimed to treat two types of blood cancer, blastic plasmacytoid dendritic cell neoplasm (BPDCN) and acute myeloid leukaemia (AML), in patients who did not respond to typical treatment or relapsed.

The 78-year old male patient who died was first to be treated in the BPDCN study. He experienced side effects in the form of lung infection and moderate cytokine release syndrome (CRS) at day five, severe CRS and blood vessel leakage on day eight, and death on day nine. CRS results from the excessive release of immune components called cytokines from targeted cancer cells and immune system cells.

The first patient in the AML study, a 58-year old female patient, received the same treatment at the same dose, and experienced similar side effects. Although intensive care treatment resolved the side effects, the AML study has also been put on hold until the development of appropriate safety measures.

Two days following the reported patient fatality, the FDA made a recommendation to lower the immunotherapy and supporting drug dosage.

‘Cellectis is working closely with the investigators and the FDA in order to resume the trials with an amended protocol including a lowered dosing of UCART123,’ the company said in a statement.

Cellectis’s shares fell by 23 percent following the FDA’s notice. It is not the first to report patient death through CAR-T therapy trials. In March 2017, the pharmaceutical company Juno Therapeutics reported five patient deaths in response to personalised CAR-T therapy targeting acute myeloid leukaemia, a type of blood cancer. Similarly, Kite Pharma’s trial on aggressive non-Hodgkin lymphoma has reported one patient death.



Some of the logistics, manufacturing and pricing details in the aftermath of Novartis gaining FDA approval of CAR-T

Wow, where to start? So much has been written about CAR-T while I was away this past week. The stories below just scratch the surface. I’m sure I’ll have more in the next few days. So, in no particular order…

Details of Novartis’ manufacturing process:


Kite’s manufacturing process (Kite Pharmaceuticals anticipates being next to receive FDA approval for their CAR-T therapy):


From Novartis, a video of its manufacturing process:


About that $475,000 price tag … This was guaranteed to stir controversy. Novartis’ rationale is that CAR-T can supplant an allogeneic stem cell transplant (SCT), which can cost $550 – 800K, with greater mortality risk and probably less curative potential.  Also controversial is Novartis’ decision not to refund the cost if the patient has achieved a Complete Remission (CR) in the first month, when many patients may relapse afterwards.  A 3-month or even 6-month CR would be more indicative of a potential cure.


Speaking of costs, the twittersphere is buzzing about this quote from Dr. Carl June at U. Penn back in 2012:

Dr. June said that producing engineered T-cells costs about $20,000 per patient — far less than the cost of a bone-marrow transplant. Scaling up the procedure should make it even less expensive, he said, but he added, “Our costs do not include any profit margin, facility depreciation costs or other clinical care costs, and other research costs.”


A profile of Carl June and his immunotherapy research in the Wall Street Journal:


Some of CAR-T’s success can be attributed to insights gained by the publicly-funded National Institutes of Health (NIH):


From Memorial Sloan-Kettering – from transplants to breakthroughs such as Steven Rosenberg at the NIH, etc…


This didn’t get quite as much press, but the FDA simultaneously “approved an expanded indication for Actemra to treat CAR T cell-induced severe or life-threatening CRS in patients ages two and older on Wednesday”. Actemra is an IL-6 inhibitor typically used to treat Rheumatoid Arthritis.  It was famously used as a last resort to reduce the CRS and thereby save the life of CAR-T’s first patient, 6-year-old Emily Whitehead, at U. Penn in 2012.  I’m now planning to ask my own oncologist, during my next visit in January, whether it was ever considered to control my CRS after my CAR-T infusion in July 2015.  (I spent five days in ICU after my infusion.)


I know I’ve posted about this before.  The Fred Hutchinson Cancer Center in Seattle is attempting to bypass the entire T-cell collection and manufacturing process by modifying the patient’s T cells in situ:


From journalist Michelle Cortez at Bloomberg News… it details some other attempts to bypass the $$ T-cell collection and manufacturing process, including equipping the hospitals and cancer centers to conduct it themselves:




This Science Magazine article contains links to other interesting articles…


From AP News (links to other CAR-T demo videos):

FDA has just approved the first CAR-T therapy!

Truly a momentous day in the long and winding history of this life-saving therapy.  It’s initially approved for Acute Lymphoblastic Leukemia (ALL).  Can approval for Lymphoma be far behind?

Press Announcements > FDA approval brings first gene therapy to the United States

Novartis wins a landmark FDA approval with first CAR-T cancer drug

EP Vantage – World’s first CAR-T approval sweeps away more cell therapy doubts

Kite Seeks EU Approval for CAR T-Cell Therapy in 3 Lymphoma Subtypes (August 3, 2017)

Kite Pharma submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA) requesting the approval of its CAR T-cell therapy, axicabtagene ciloleucel, as treatment for patients with certain lymphomas.

The include relapsed or refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL), who cannot receive autologous stem cell transplants.

This is the first application for a CAR T-cell therapy ever submitted to the EMA.

Full article:

Support LLS, via a dear friend…

Not exactly "CAR-T news" per se, but…

A dear friend of ours, Laura Housley, was diagnosed with leukemia 17 years ago, and was saved by an allogeneic stem cell transplant (SCT).  In fact, she indirectly saved my life as well.  Almost five years ago, Laura recommended that I begin seeing the transplant specialist at the John Theurer Cancer Center of Hackensack Hospital.  It was he who in 2014 first recommended my enrollment in a CAR-T trial, over his own SCT treatment.  (I'd never even heard of CAR-T the first time he mentioned it.)  I owe Laura and him my life.

Since her recovery, Laura has gone on to do a lot of fundraising for The Leukemia & Lymphoma Society, and was nominated and named their Woman of the Year, for her role as a spokeswoman and fundraiser for the Society. She still offers support to patients about to undergo a SCT.  You can read her blog post for LLS here:

In November, Laura's daughter Sara, who is now in college, will be running for The Leukemia & Lymphoma Society's team, in the New York City Marathon.  If you're interested in donating, please see Sara's fundraising page:

(LLS is truly a worthy cause for present and future leukemia and lymphoma patients.  Donations to LLS contributed to CAR-T's development, and they have a very informative, helpful CAR-T page here.)

— Ben



Kite Seeks EU Approval for CAR T-Cell Therapy in 3 Lymphoma Subtypes

Kite Seeks EU Approval for CAR T-Cell Therapy in 3 Lymphoma Subtypes

by Alice Melão

Kite Pharma submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA) requesting the approval of its CAR T-cell therapy, axicabtagene ciloleucel, as treatment for patients with certain lymphomas.

The include relapsed or refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL), who cannot receive autologous stem cell transplants.

This is the first application for a CAR T-cell therapy ever submitted to the EMA.

“The MAA submission of axicabtagene ciloleucel marks an important global milestone in the development of engineered T-cell therapy,” Arie Belldegrun, MD, president and CEO of Kite, said in a press release.

He said the company is excited to be working with the EMA’s Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) “to help bring this potentially transformative therapy to patients in the EU.”

Axicabtagene ciloleucel, formerly known as KTE-C19, is a CAR (chimeric antigen receptor) T-cell therapy. The treatment consist of collecting the patient’s own T-cells and modifying them to express a CAR protein that recognizes the surface protein CD19, a molecule that is widely expressed by B-cell lymphomas and leukemias.

Kite’s application includes primary data from the ZUMA-1 trial (NCT02348216), a Phase 1/2 trial testing axicabtagene ciloleucel in treatment-resistant or relapsed aggressive non-Hodgkin’s lymphoma patients. The trial included 101 patients with DLBCL, PMBCL, or TFL, most with advanced-stage disease.

Data presented late June at the 22nd Congress of the European Hematology Association (EHA), showed that 82 percent of patients responded to treatment after a single infusion of axicabtagene ciloleucel. This positive response was sustained in 44 percent of patients after a median follow-up time of 8.7 months. At that time, 39 percent of patients exhibited a complete response.

The most common severe treatment-related adverse events reported in ZUMA-1 included cytokine release syndrome and neurologic events, which were generally reversible after suitable management.

Axicabtagene ciloleucel has been designated a breakthrough therapy by the U.S. Food and Drug Administration for the treatment of DLBCL, TFL, and PMBCL, and received priority medicines (PRIME) regulatory support in the European Union. These designations are meant to support a drug’s development and accelerate its regulatory review.

The FDA is reviewing Kite’s biologics license application (BLA) submitted for axicabtagene ciloleucel for the treatment of refractory aggressive non-Hodgkin’s lymphoma. A final decision is expected by Nov. 29.

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.”