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First CAR T-Cell 'Living Drug' Approved by FDA / Safety Concerns
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from Jules: the high and overly optimistic hopes that we can eradicate HIV in its elation all too often marginalizes the risks for serious adverse events associated with some of the drugs that could be used in such "cure" research. Here in this report is a discussion of such adverse effects associated with this FDA approved new therapy CAR T cells. The difference between its use in cancer vs HIV is that for these cancer patients they are at risk for death and thus risking the adverse events are an acceptable risk. But in HIV+ HAART is working well in keeping people alive and relatively healthy. Even if CAR T cells were found to cure HIV maybe or research in HIV starts how will you evaluate its long term efficacy versus HAART, a long term comparison study? The potential adverse effects make it prohibitory. Its been several years since the "cure" effort started in earnest with much resources & high expectations dedicated to this effort, I would suggest the expectations & commitment reflect over optimism, which sucks the air out of the room for very important problems facing HIV + individuals. I understand the NIH is completely devoted to the "cure" effort but maybe in a few years if and when progress does not appear people will re-evaluate this effort, come to their senses.
"However, the new approach carries with it a risk for adverse events that can become severe, and even life-threatening, and this is restricting use of the therapy to specially certified centers.
The product has a boxed warning for cytokine release syndrome (CRS), a systemic response to the activation and proliferation of CAR T cells causing high fever and flu-like symptoms, and for neurologic events. Both CRS and neurologic events can be life-threatening, the FDA warns.
Other severe side effects seen with CAR T-cell therapy include serious infections, hypotension, acute kidney injury, fever, and hypoxia.
- The FDA noted that most symptoms appear within 1 to 22 days following infusion of Kymriah. Because the CD19 antigen is also present on normal B cells, and Kymriah will also destroy normal B cells that produce antibodies, there may be an increased infection risk for a prolonged period.
- Because of the risk for CRS and neurologic events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use, the agency noted.
- The agency has also mandated that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurologic events."
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First CAR T-Cell 'Living Drug' Approved by FDA
Zosia Chustecka
August 30, 2017
http://www.medscape.com/viewarticle/884725
The first T-cell therapy that uses chimeric antigen receptor (CAR) technology has been approved today by the US Food and Drug Administration (FDA), paving the way for the other products using this novel approach that are in development.
"We're entering a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer," said FDA Commissioner Scott Gottlieb, MD.
The product is tisagenlecleucel-T (Kymriah, Novartis), approved for use in pediatric and young adult patients (age 3 to 25 years) with relapsed or refractory acute lymphoblastic leukemia (ALL).
The FDA describes the new product as a cell-based gene therapy, and more specifically as a genetically modified autologous T-cell immunotherapy, prepared individually for each patient.
"New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses," Dr Gottlieb commented. "At the FDA, we're committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving."
The FDA approval comes hot on the heels of a unanimous vote in favor of recommended approval from 10 experts convening at a recent Oncology Drugs Advisory Committee meeting, as reported by Medscape Medical News. At that meeting, David Lebwohl, MD, head of the CAR T Cell Global Program at Novartis, said that he had been involved in hematologic drug development for 20 years but has "never seen anything like this before."
The product achieves a consistently high overall rate of remission and has "the potential to be a definitive therapy — many patients do not require further therapy…. This is truly a paradigm shift in a setting of enormous medical need," he told the meeting attendees
The data that led to approval come from one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within 3 months of treatment was 83%.
"Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease," said Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research. "Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials."
Risk for Severe Adverse Events
However, the new approach carries with it a risk for adverse events that can become severe, and even life-threatening, and this is restricting use of the therapy to specially certified centers.
The product has a boxed warning for cytokine release syndrome (CRS), a systemic response to the activation and proliferation of CAR T cells causing high fever and flu-like symptoms, and for neurologic events. Both CRS and neurologic events can be life-threatening, the FDA warns.
In clinical trials, CRS has been treated successfully with an interleukin-6 blocker, tocilizumab (Actemra, Genentech), which is already marketed for use in rheumatoid arthritis. The FDA has now expanded its indication to include treatment of CAR T cell-induced severe or life-threatening CRS in patients 2 years of age or older. The agency noted that in clinical trials among patients treated with CAR T cells, 69% of patients had complete resolution of CRS within 2 weeks after one or two doses of tocilizumab.
Other severe side effects seen with CAR T-cell therapy include serious infections, hypotension, acute kidney injury, fever, and hypoxia.
The FDA noted that most symptoms appear within 1 to 22 days following infusion of Kymriah. Because the CD19 antigen is also present on normal B cells, and Kymriah will also destroy normal B cells that produce antibodies, there may be an increased infection risk for a prolonged period.
Because of the risk for CRS and neurologic events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use, the agency noted.
The agency has also mandated that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurologic events.
Additionally, the certified healthcare settings are required to have protocols in place to ensure that Kymriah is given to patients only after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurologic toxicities following infusion — and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.
One Shot, Potentially Curative
This is incredibly exciting, with unbelievable potential," commented Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in a recent interview, as previously reported by Medscape Medical News.
"This is just the tip of the iceberg," he predicted.
Next likely to reach the market is Kite's axicabtagene ciloleucel (KTE-C19) for lymphoma, and CAR T cells aimed at other leukemias and for multiple myeloma are under development.
"It's a one-shot therapy that looks to be curative," he said.
The first patient treated with tisagenlecleucel has been leukemia free for more than 5 years, and 5 years is often used as the benchmark in cancer as to whether the patient has beaten the disease. "We are getting there, we are in that range," he said.
"It's still early days," he added, noting that in the pivotal trial that was the basis of approval, the overall survival (OS) rate at 12 months was 80% with tisagenlecleucel-T. This is double what has been previously reported (40% with blinatumomab and 20% with clofarabine monotherapy; the median OS durations were 16.6 months, 7.5 months, and 3 months, respectively).
"To get this sort of response in a relapsed/refractory ALL population is absolutely remarkable," Dr Greenberger commented.
For this patient population, CAR T-cell therapy offers a last chance — patients in the pivotal trial had already undergone a median of three prior therapies, and more than half had undergone hematopoietic stem cell transplantation.
These are patients with few options and a very poor prognosis, Dr Greenberger said. For these patients, the therapy is lifesaving.
"Living Drug" Made Individually for Each Patient
The product is made individually for each patient. After blood is taken from the patient, it undergoes a process that involves extracting T cells, subjecting the cells to CAR cell engineering, and then infusing the engineered T cells back into the patient.
Because they grow and expand in the body and then lie dormant, CAR T cells have been described as "livings drugs."
The "living drug" description is apt, said Malcolm Brenner, MD, PhD, founding director of the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, who has been working with these therapies for the past 20 years.
"It's an important concept," he told Medscape Medical News.
"What you start off with isn't what you end up with," he added.
"I wouldn't say this is a new concept, as bone marrow transplant is also a living drug...but this is quite a different concept from usual drugs, which are gradually cleared out of the body."
"These cell therapies are potentially very long-lived...which is good, as you want to keep the leukemia at bay, but if you develop side effects, they can also last a very long time, and also, because the cells are growing and expanding, the side effects can become worse," he noted. "These therapies need very careful monitoring," he added.
Elizabeth Budde, MD, PhD, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Hospital in Duarte, California, agrees. She has been involved in several trials of CAR T cells, and in an interview with Medscape Medical News, she emphasized the importance of close monitoring with an experienced eye, "as these patients can crash at any time."
The worst of the side effects occur within a week or two of infusion, when the cells are expanding and attacking the leukemia. Some of the side effects can be very severe, even life-threatening. The two most concerning side effects are CRS, which was severe in about half of the patients in the pivotal trial, and neurologic toxicity, which developed in nearly half of the patients (44%).
In early trials with CAR T-cell products, these side effects resulted in several deaths, but clinicians have since learned how to manage these adverse events, for example by using tocilizumab for CRS and steroid for neurologic toxicity. There were no deaths due to treatment in the pivotal trial with tisagenlecleucel-T.
Although these side effects are severe, they are not more severe than those associated with bone marrow transplants; however, the side effects are different, Dr Brenner commented. "You certainly get severe multiorgan toxicity and also neurological toxicity after a transplant."
Overall, bone marrow transplant causes a bigger shock to the system than does CAR T-cell therapy.
Preparing the body for transplant requires intensive chemotherapy and, in some cases, whole-body radiotherapy to wipe out the bone marrow before the transplant. Both are extreme therapies with severe side effects; indeed, this treatment itself can sometimes be fatal, Dr Greenberg commented.
"With CAR T cell therapy, you do need to make room for the cells, so there is also a chemotherapy pretreatment, but it is not nearly as toxic and as risky," said Dr Greenberg.
The difference between the two approaches was summarized in an interview with Mary Horowitz, MD, conducted previously by Medscape Medical News. Dr Horowitz is scientific director at the Center for International Blood and Marrow Transplant Research and chief of the Division of Hematology and Oncology at the Medical College of Wisconsin, in Milwaukee. She commented that whereas bone marrow transplant is like carpet bombing a city in order to destroy a specific building, CAR T cells are like smart bombs that seek out and destroy just the building.
Another difference is that after transplant, there is a high risk for infection and also a risk for graft-vs-host disease, both acute and long term, which may require immunosuppression, sometimes long term.
In contrast, CAR T-cell treatment is a "one-shot therapy," Dr Greenberg emphasized. "Yes, it's a shock to the immune system, and the adverse events during the acute phase can be severe, and even life-threatening, but once it's over, it's done. That's it. No more treatment."
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COMMENTARY
Safety With CAR T-Cell Therapy
Stephan A. Grupp, MD, PhD
http://www.medscape.com/viewarticle/883664?nlid=117502_3901&src=wnl_newsalrt_170830_MSCPEDIT&uac=27194HK&impID=1421987&faf=1
August 30, 2017
Hi. My name is Dr Stephan Grupp. I am the director of the Cancer Immunotherapy Program at the Children's Hospital of Philadelphia. I am also a professor of pediatrics at the University of Pennsylvania School of Medicine. I'm here today to talk about some news that has come across in the chimeric antigen receptor (CAR) T-cell field. It's been an exciting couple of weeks because we have had the first presentation to the US Food and Drug Administration (FDA) about an engineered CAR T-cell therapy. We went before the Oncology Drug Advisory Committee (ODAC) with the group from Novartis, which is the drug company that is seeking approval for CTL019, the CD19-directed CAR T-cell therapy that has been designed for pediatric and young adult patients with acute lymphoblastic leukemia (ALL).
This therapy is certainly going to have other uses, but this is the first time that it has gone in front of the FDA. We were excited to present the data, and we were even more excited at the end of the day when the advisory panel voted 10-0 to recommend approval to the FDA. At this point, we are waiting for the next steps.
We spent a lot of time talking about the issue of risk-benefit in these patients. These were patients with refractory disease in many cases (relapsed in all, or primary refractory) who had no other treatment options available to them. The data across multiple trials have shown efficacy ranging from 83% to 95% complete response rates, and the vast majority of these patients are also minimal residual disease negative. Those are all real positives in terms of the risk-benefit.
Of course, there are unique toxicities associated with CAR T-cell therapy, the most notable of which is cytokine release syndrome. However, in our global registration trial, we showed that we could do this safely across 25 centers in 11 countries. Many centers hadn't treated patients with cell therapy before, but they were very good centers that had significant transplant and intensive care unit experience. So, we were able to do this safely across the globe in a way that was comparable to the results that we had locally in a single-institution trial.
There was also a lot of discussion at the FDA about long-term safety. This is a gene therapy, and for the first time, these patients have the potential to survive for many years after receiving this treatment. The safety follow-up that would be required was something the agency was really focused on. Is it necessary to do genetic testing for replication-competent lentivirus? The sense was that it probably was not, because it didn't seem to be a realistic risk in the absence of many clinical events that would suggest otherwise. There also were concerns about oncogenicity—in other words, activation of T-cell proliferation with the CAR T-cell gene that has been inserted into these T cells. We don't see any evidence of that at all across many hundreds of patients, so that was actually quite reassuring.
This is a cellular immunotherapy—a brand-new way of treating cancer and of applying immunotherapy. All of the really striking results, including this trial, which led to this successful ODAC vote, have been in patients with hematologic malignancies, specifically ALL, non-Hodgkin's lymphoma, and to a certain extent, chronic lymphoblastic leukemia as well. These are all CD19-positive malignancies. Data are also emerging in multiple myeloma.
The key question for all of us is whether this therapy will be applicable to solid tumors. It will be the work of the next 5 years to see whether we can apply what we've learned in hematologic malignancies to the solid tumor world. That's another level of understanding that we will need. More technological development will be required before this is successful, but this is something we are all very excited about.
And, of course, most exciting is the fact that if the FDA approves this [Editor's note: FDA approved CTL019 (tisagenlecleucel) on August 30, 2017] then it would be the first engineered cell therapy available for prescription in the United States. Novartis intends a very careful rollout to specific trained centers, and there will be a certification process. This is a new approach to delivering this brand-new therapy, but we've learned a lot from the registration trials that will allow us to figure out how to do this safely across multiple centers.
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Oncologists Optimistic About Prospects for CAR T-Cell Therapy
Alicia Ault
August 23, 2017
http://www.medscape.com/viewarticle/884506?nlid=117502_3901&src=wnl_newsalrt_170830_MSCPEDIT&uac=27194HK&impID=1421987&faf=1
CAR T-cell therapies for hematologic cancers are a promising development that most oncologists expect to use in their practice, according to a new Medscape survey of clinicians.
In the survey, all the respondents said they believed that products manufactured from patients' chimeric antigen receptor (CAR) T cells would prove to be effective in the long term, and 95% said the products would prove to be safe.
Not all of the 41 oncologists who responded to the Medscape email query in August were familiar with the therapies, although half said they are affiliated with a hospital that is approved as a CAR T-cell therapy center.
Medscape first asked whether the respondents knew of the two therapies currently under review at the US Food and Drug Administration (FDA): tisagenlecleucel (previously known as CTL019; developed by Novartis); and Kite Pharma's axicabtagene ciloleucel (KTE-C19).
Thirty-seven percent had some familiarity with tisagenlecleucel, and about 15% knew basic information about the product. More than a quarter knew the name, but 37% had never heard of tisagenlecleucel. Forty-four percent had never heard of axicabtagene ciloleucel, while 22% had heard the name, and 34% had some familiarity with it.
The respondents then were given trial information sourced from the manufacturers that showed that 83% of patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia who were treated with tisagenlecleucel achieved complete remission. For patients with refractory aggressive B-cell non-Hodgkin lymphoma who were treated with axicabtagene ciloleucel, the complete response rate was 39%.
After reading the trial data, 90% of the oncologists said CAR T-cell therapies would be important or very important in hematologic malignancies.
All of the respondents ultimately agreed that, on the basis of available data, the therapies will prove to be effective in the long term, and 83% said it would be applicable in their practice if approved.
"Excited"
"This is a wonderful, novel therapeutic, which is not only effective for refractory patients but also can cure patients without the need of irradiation," said one pediatric oncologist, who has been practicing for more than 25 years. "It also avoids many transplant-related toxicities," he said, adding that "short-term toxicities are manageable."
Another oncologist, noting that his hospital was selected by Novartis as a regional center for the treatment, said, "The head of the program here has discussed the data with me extensively ― I am excited about the prospects for CAR T."
Seventy-five percent of the respondents agreed that the benefits outweigh the risks for patients for whom all other options have been exhausted, but a majority also said the therapies should only be available in centers that have been approved to offer it. Fewer than 3 in 10 said they would be very comfortable treating CAR T adverse events.
Although safety has been a concern regarding the drugs, 95% said they believe the therapy will be safe in the long term.
"Experience is key, and as it is used more, one will obtain a higher degree of confidence," commented one hematologist.
A majority of the clinicians said they thought CAR T would eventually be used earlier in the disease process. Almost as many agreed that there was a need for reliable manufacturing and production processes.
Almost half of the respondents envision that CAR T will come to replace stem cell transplants, but access to the therapy would be limited to appropriate candidates. A third said the cost of CAR T would be prohibitive.
The manufacturers have not discussed pricing for the therapies, but industry watchers have estimated that costs will range from $300,000 to $500,000.
An FDA advisory panel unanimously backed approval of tisagenlecleucel on July 12, which suggests US approval may not be far off.
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