Mayo Clinic to Offer CAR T-Cell Therapy for Relapsed Non-Hodgkin Lymphoma

October 31, 2017  Newswise — ROCHESTER, Minn. – Mayo Clinic announced today that its Rochester campus is one of 16 cancer centers nationally selected to provide chimeric antigen receptor T-cell therapy (CAR T-cell therapy) for adults with B-cell non-Hodgkin lymphoma who have not responded to, or have relapsed, after two or more lines of treatment. The therapy, called axicabtagene ciloleucel (Yescarta), is approved to treat subtypes of lymphoma, including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, diffuse large B-cell lymphoma arising from follicular lymphoma, and high-grade B-cell lymphoma.

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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.


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.

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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.”



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.




Checking These Areas for Lumps Can Help Catch Lymphoma Early
This video from TakeaPITStop uses a Barbie doll to demonstrate how lymphoma patients often discover their lumps.


This video from uses a Barbie doll to demonstrate how lymphoma patients often discover their lumps. During Barbie’s usual beauty routine of shaving, moisturizing and applying fake tan she notices a lump near her collarbone.
Although she thought it could be just a cyst she decides to get it checked out by her doctor and after several tests, she’s diagnosed with Hodgkin’s lymphoma. The video goes on to detail some of the common symptoms of the disease including fatigue, persistent lumps in the neck, armpits or groin, intensive itching, and night sweats. It explains that lymphoma is the most common cancer in people under the age of 30 and advises young people to check their neck, armpits, and groin regularly for any lumps and get anything unusual checked out by their doctor.