HemOnc Today's PharmAnalysis
HemOnc Today's PharmAnalysis
September 25, 2017
15 min read

CAR T-cell therapy approval huge step for oncology, but only ‘beginning of story’

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The FDA’s approval of tisagenlecleucel for the treatment of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia represents a watershed moment for cancer care.

Tisagenlecleucel (Kymriah, Novartis) — a chimeric antigen receptor (CAR) T-cell therapy — provides unprecedented benefits to poor-prognosis patients who have exhausted all other treatment options.

However, as the first gene therapy available in the United States, the implications of its regulatory success extend far beyond the population for which it is indicated.

“The best way I can characterize it is by saying it is similar to the first step on the moon,” Hetty E. Carraway, MD, MBA, staff physician in hematologic oncology and blood disorders at Taussig Cancer Institute at Cleveland Clinic, told HemOnc Today. “Now we really have an opportunity to expand this type of application — not just to other types of cancers, but potentially to autoimmune diseases and other medical disorders that could benefit from such technology.”

The implications of tisagenlecleucel’s approval will extend far beyond the population for which it is indicated, according to Hetty E. Carraway, MD, MBA.
The implications of tisagenlecleucel’s approval will extend far beyond the population for which it is indicated, according to Hetty E. Carraway, MD, MBA. “Now we really have an opportunity to expand this type of application — not just to other types of cancers, but potentially to other autoimmune diseases and medical disorders,” Carraway said.

Source: Cleveland Clinic, ©Russell Lee 2014.

Formidable challenges remain, however.

Although researchers have made progress predicting and treating adverse events, CAR T-cell therapy still carries the potential for life-threatening toxicity.

Cost also is a concern. A single infusion of tisagenlecleucel will cost $475,000. Consequently, clinical trials and real-world evidence must show the therapy and subsequently approved CAR T-cell products priced at similar levels induce meaningful, long-term responses, experts said.

In addition, the manufacturing and delivery of these agents must be improved to broaden the eligible patient population and potentially reduce costs, Carraway said.

“As optimistic as everyone is about this type of therapy, it’s clear the innovation is not yet done,” Carraway said. “This is the beginning of the story, not the end.”

HemOnc Today spoke with investigators and clinicians about the significance of tisagenlecleucel’s approval for the hematology/oncology community; the benefits it may provide for difficult-to-treat patients; the status of other CAR T-cell therapies in development; and the hurdles that must be overcome as the clinical community adopts this treatment approach.

‘Persistence pays off’

Patients with relapsed or refractory B-cell precursor ALL often undergo several treatments, including chemotherapy, radiation, targeted therapy or stem cell transplant. Treatment options improved only modestly during the past several decades and prognoses remained poor, as more than 90% of patients died within 5 years.


However, the FDA has approved three new therapies for relapsed/refractory ALL in the past 3 years.

Blinatumomab (Blincyto, Amgen) — a bispecific T-cell engager — received accelerated approval in December 2014 and full approval earlier this year for second-line treatment of Philadelphia chromosome-negative disease.

In mid-August, the FDA approved inotuzumab ozogamicin (Besponsa, Pfizer) — a CD22-directed antibody-drug conjugate — for use in adults.

On Aug. 30, the FDA approved tisagenlecleucel — a novel, customized immunocellular therapy — for the treatment of patients aged up to 25 years with refractory B-cell precursor ALL, as well as those whose disease is in second or later relapse.

“Because we know that traditional cytotoxic chemotherapy is very unlikely to work for these patients, being able to offer one or more of these options from unique drug classes provides a lot more hope and optimism about the potential outcome,” Ryan D. Cassaday, MD, assistant professor in the division of hematology at University of Washington and assistant member in the clinical research division at Fred Hutchinson Cancer Research Center, told HemOnc Today.

Ryan D. Cassaday, MD
Ryan D. Cassaday

Novartis and University of Pennsylvania entered into a global collaboration in 2012 to research, develop and commercialize CAR T-cell therapies — including tisagenlecleucel — for the treatment of cancers.

Tisagenlecleucel — formerly known as CTL019 — is comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells.

Each patient’s T cells are collected and sent to a manufacturing center, where they are re-engineered to include a new gene that contains a CAR that directs T cells to target and kill CD19-expressing leukemia cells. The modified cells then are infused back into the patient.

“Not long ago, the idea that T cells can be reprogrammed and harnessed to attack cancer was seen as too far-fetched to reach clinical application,” Richard Koya, MD, PhD, associate director of the Center for Immunotherapy at Roswell Park Cancer Institute, told HemOnc Today. “[This approval] shows that persistence despite early disappointments often pays off in important ways in cancer research.”

A new standard

Tisagenlecleucel — the first CAR T-cell therapy to demonstrate early, deep and durable remission in patients with relapsed/refractory ALL — likely will become the new standard of care for this population, according to Stephan A. Grupp, MD, PhD, Yetta Deitch Novotny professor of pediatrics at Perelman School of Medicine at University of Pennsylvania and director of the Cancer Immunotherapy Frontier Program at Children’s Hospital of Philadelphia.

Stephan A. Grupp, MD, PhD
Stephan A. Grupp

“Relapsed and especially refractory ALL patients have terrible treatment options,” Grupp told HemOnc Today. “Most of these patients can’t even get to bone marrow transplant and, even if they do, transplant doesn’t work very well for them. Consequently, they have very little long-term prospect of remaining in remission and almost no potential for cure. This is a group with a very high unmet medical need.”

Researchers conducted three trials to assess the efficacy and safety of tisagenlecleucel in children and young adults with relapsed/refractory B-cell ALL.

The FDA based its approval on results of the phase 2 ELIANA trial. The Novartis-sponsored open-label, single arm study — the first pediatric global CAR T-cell therapy registration trial — took place at 25 centers in the United States, Canada, Europe, Australia and Japan.

Sixty-eight patients underwent tisagenlecleucel infusion, and 63 were evaluable for efficacy.

Fifty-two patients (83%; 95% CI, 71-91) achieved complete remission or complete remission with incomplete blood count recovery within 3 months of infusion. Median duration of remission had not been reached (95% CI, 7.5 months to not estimable).

Researchers detected no minimal residual disease — a blood marker that can signal potential relapse — among responding patients.

“We have been very impressed by how well this approach works for this patient population,” Grupp, lead investigator of the ELIANA trial, said in an interview. “Short term, it works very well to get patients into remission. We’re also starting to see long-term efficacy.

“The first patient we treated 5 years ago remains in remission, and the event-free survival for patients who respond is around 60% at 1 year,” Grupp added. “There are a lot of patients who are getting long-term disease control, and we hope there is actually some permanence to their disease control from this one-time therapy.”

Potential for toxicity

CAR T-cell therapy has been associated with severe — and, in some cases, fatal — toxicities in clinical trials.

JCAR015 (Juno Therapeutics), an experimental CAR-modified T-cell therapy intended to treat adults with relapsed or refractory B-cell ALL, had been placed on hold twice — once by its manufacturer and once by FDA — after a combined five patients died of cerebral edema.

In March, Juno officials announced their decision to cease development of JCAR015.

Tisagenlecleucel’s label carries a boxed warning about the risk for fatal or life-threatening adverse events, including cytokine release syndrome — caused by an overactive immune response — and neurological toxicities.

Forty-nine percent of patients in the ELIANA trial experienced grade 3 or grade 4 cytokine release syndrome.


“Cytokine release syndrome is a significant toxicity,” Grupp told HemOnc Today. “Those T cells are growing very rapidly, and they produce a lot of inflammatory proteins.”

Over time, researchers have improved their ability to identify which patients may be at greatest risk for this complication.

“Patients with small amounts of leukemia don’t get significant cytokine release syndrome,” Grupp said. “In patients with large amounts of leukemia — in some cases, literally pounds of leukemia in their body — these engineered T cells grow to the extent they need to grow to get on top of the disease, so we still see these patients with high disease burdens go into remission.

“But, along the way, those T cells are growing very rapidly, and they produce a lot of inflammatory proteins,” Grupp added. “Those patients can be quite ill, but we have learned how to deal with that using the interleukin-6 pathway.”

On the same day the FDA approved tisagenlecleucel, the agency expanded the indication of tocilizumab (Actemra, Genentech) — a humanized interleukin-6 receptor antagonist administered via IV injection — to include treatment of CAR T-cell therapy-induced severe or life-threatening cytokine release syndrome in patients aged 2 years or older.

Grupp and colleagues began using tocilizumab to treat cytokine release syndrome about 5 years ago.

“That really saved the field of active cell therapy,” Grupp said.

Tocilizumab — approved in 2010 for the treatment of certain adults with moderate to severe rheumatoid arthritis — is the first FDA-approved treatment for cytokine release syndrome.

The FDA based the expanded approval on results of a retrospective analysis of pooled data from multiple trials that evaluated CAR T-cell therapies for hematologic malignancies. Forty-five pediatric and adult patients received tocilizumab with or without additional high-dose corticosteroids for severe or life-threatening cytokine release syndrome.

Thirty-one patients (69%; 95% CI, 53-82) achieved response, defined by three criteria: resolution of cytokine release syndrome within 14 days of their first dose; no more than two tocilizumab doses required; and no drugs aside from tocilizumab and corticosteroids used during treatment.

Researchers reported no adverse reactions related to tocilizumab.

Even when cytokine release syndrome is controlled, other complications can occur during or after CAR T-cell therapy.

Eighteen percent of patients in the ELIANA trial experienced grade 3 or grade 4 neurologic events within 8 weeks of treatment. The most common neurologic events included headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%) and tremor (9%).

Other adverse reactions that occurred in more than 20% of patients included hypogammaglobulinemia, infections, pyrexia, decreased appetite, hypotension, bleeding, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue and acute kidney injury.


Novartis announced its plan to establish a network of certified treatment centers across the United States, at which personnel will be trained to use tisagenlecleucel and provide appropriate care to patients who undergo infusion. The initial network will include 32 hospitals and clinics.

“There has been a great deal of discussion about toxicities — specifically cytokine release syndrome — and for very good reason,” Carraway said. “However, these toxicities do appear manageable, especially when this type of therapy is given in the appropriate setting with the necessary staff and support.”

Cost considerations

Novartis uses each patient’s T cells to manufacture tisagenlecleucel at a Novartis facility in Morris Plains, New Jersey.

The company — which to date has manufactured CAR T cells for more than 250 patients worldwide for various indications — anticipates it will have the necessary resources to meet anticipated demand.

The process, which takes 22 days from T-cell collection to infusion of the genetically engineered therapy, is labor intensive.

It also is costly. Novartis set the price at $475,000 per treatment.

“If you are saving children, and they get back into society and do great things for us long term and never need another treatment, how do you put a price on that?” Elizabeth M. Jaffee, MD, president-elect of the American Association for Cancer Research and deputy director of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, told HemOnc Today. “That is the challenge with all of these new therapies, and it is quite frustrating. Now that [CAR T-cell therapies] are available, we are going to see a lot more economic assessments.”

Elizabeth M. Jaffee, MD
Elizabeth M. Jaffee

The per-treatment cost is considerably less than the $750,000 some investors and industry analysts projected. It also is less than Novartis’ own internal value-based assessments, according to a company-issued press release.

The company has developed patient access programs and plans to collaborate with CMS on an outcomes-based approach designed to only charge patients who respond to tisagenlecleucel within the first month of infusion.

“Novartis has been at the forefront of outcomes-based pricing and is very pleased to work with CMS on this first-of-its-kind collaboration with a technology that has the potential to transform cancer care,” Joseph Jimenez, CEO of Novartis, said in the press release.

Others say the price cannot be justified.

“[Although] Novartis’ decision to set a price at $475,000 per treatment may be seen by some as restraint, we believe it is excessive,” David Mitchell, founder and president of Patients For Affordable Drugs, an independent organization that strives to reduce the prices of prescription drugs through policy changes, said in a statement. “Novartis should not get credit for bringing a $475,000 drug to market and claiming they could have charged people a lot more.”


The pricing structure and outcomes-based payment approach will ensure patient access while providing Novartis a return on investment, company officials said.

Mitchell, however, noted that U.S. taxpayers have invested more than $200 million in CAR T-cell therapy’s discovery. He said Novartis has “not yet acknowledged the significance of taxpayers’ investment” and has declined to provide details about its own investment.

“The drug pricing system in America is completely broken,” Mitchell added. “Until policy in this country changes, the vicious cycle of patients struggling under high drug prices will continue.”

Novartis intends to submit additional regulatory filings this year in the United States and Europe for use of tisagenlecleucel for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma. More filings are expected next year, according to the company’s press release.

Mitchell said his organization will watch to see if Novartis reduces tisagenlecleucel’s price as the number of patients eligible for the therapy increases, as well as whether patients in the United States are charged more for tisagenlecleucel than patients in other countries where it is approved.

For the foreseeable future, cost will remain an essential component of conversations between clinicians and their patients, Carraway said.

“This is not a new conversation,” she said. “Unfortunately, many of our patients are in a position where they can’t afford medical care for diabetes, never mind cancer. We struggle with this every day. This is never an easy conversation, but it’s one we need to be thoughtful about.”

Other therapies for hematologic malignancies

After more than a decade of research and hundreds of millions of dollars invested, the first approval of a CAR T-cell therapy in the United States has substantial implications for clinicians and researchers regardless of whether they treat leukemia, Cassaday said.

“Beyond the impact this will have for patients with B-cell ALL, this approval is truly a landmark achievement in translational medicine and drug development,” Cassaday told HemOnc Today. “Considering the enthusiasm about this treatment approach, not only in the scientific and medical community but also in the popular press, this announcement is — among other things — a vindication of sorts.”

Still, many questions remain unanswered, including whether CAR T-cell therapy can benefit patients with other types of cancers.

“Although the importance of this [approval] is difficult to overstate, I think we still have much more to learn and understand about this technology and how it can be used — particularly in other cancers, including other hematologic malignancies,” Cassaday said.

Use of CAR T-cell therapies for other blood cancers appears encouraging.


The FDA granted priority review to axicabtagene ciloleucel (Kite Pharma) — an anti-CD19 CAR T-cell therapy — for treatment of patients with refractory aggressive non-Hodgkin’s lymphoma.

Results from the phase 2 ZUMA-1 trial showed 82% of patients achieved objective response after a single infusion (P < .0001). After median follow-up of 8.7 months, 44% of patients remained in ongoing response, including 39% of patients in complete response.

The FDA is expected to make a decision on axicabtagene ciloleucel by Nov. 29.

LCAR-B38M (Legend Biotech) — a B-cell maturation antigen-specific CAR T-cell therapy — induced a 100% objective response rate in 35 patients with myeloma, according to a study by Fan and colleagues presented at this year’s ASCO Annual Meeting. Ninety-four percent of patients showed evidence of clinical remission within 2 months of infusion, and five patients followed for more than 1 year remained in stringent complete response with no sign of residual disease in bone marrow.

Jeremy S. Abramson, MD, clinical director of the Center for Lymphoma at Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School, and colleagues conducted the TRANSCEND NHL trial to evaluate treatment with JCAR017 (Juno Therapeutics), a CD19-directed CAR T-cell product.

The analysis included 28 patients (median age, 63 years; median prior therapies, 4; range, 1-8) with relapsed or refractory diffuse large B-cell lymphoma.

Sixteen of 20 patients treated at the first dose level — 5 x 107 cells per kg — achieved response, and 60% achieved complete response, according to results presented at ASCO.

“Though our follow-up is still relatively brief, many of these remissions are proving durable and will hopefully prove curative,” Abramson told HemOnc Today at the time the results were presented.

Broader applications

Researchers initially envisioned use of genetically modified cells as a treatment for solid tumors. Early solid tumor targets for CAR T-cell therapy included melanoma, gynecologic cancers and neurologic malignancies.

Although some studies have been encouraging, advances in solid tumors considerably lags the progress observed in hematologic malignancies.

“We have shown this works in kids with ALL,” Grupp said. “We are going to be seeing more data soon in adults with lymphoma, and we probably will see another FDA approval in that area later this year. This is being extended to patients with other blood cancers, like multiple myeloma.

“The big challenge for the field now is this: Can we see any way to see these approaches which work so well in blood cancers extended to patients with common adult malignancies like lung cancer, pancreatic cancer and breast cancer?” Grupp added. “Right now, that’s not happening. That’s what we need to see over the next 5 years.”


The nature of CAR T-cell therapy may hinder the transition from hematologic malignancies to solid tumors, Jaffee said.

“This therapy isn’t specific for cancerous B cells; it depletes all B cells, and this has long-term consequences,” Jaffee said. “The challenge in moving this therapy to other cancers is to figure out the difference between normal cells and the cancer that develops from those normal cells in other organs.

“In colon cancer or liver cancer, we can’t deplete all colon cells or all liver cells,” Jaffee added. “We have to figure out, in those other cancers, what are the differences between the normal cells and the cancer cells that the immune system can see so all we’re doing is getting at the malignant cell. That is a big challenge, and it is not something we are going to address easily.”

The ability to reach the tumor microenvironment also may be an obstacle.

“Even if you can make these T cells supercharged, it’s easy for them to get access in leukemia because leukemia cells are circulating into the blood,” Jaffee said. “To get those T cells into a solid tumor, such as a colon cancer sitting in the liver, you also need to be able to unleash those checkpoints that are sitting in the tumor microenvironment that prevent the T cells from getting in there and functioning. Long term, I see this as something we’ll be able to do for more patients, and it will work in conjunction with checkpoint inhibitors.”

The durability of response may determine the speed at which CAR T-cell therapy is adopted in other areas of cancer care, Carraway said.

“We are seeing exciting response rates but, given the upfront cost, we really want to have meaningful, long-term durations of responses,” Carraway said. “If that isn’t the case, the next phase of research will have to focus on making sure these remissions are durable.

“It’s also important to emphasize that [tisagenlecleucel] does not cover a large number of patients. We are talking about a small group that may be eligible for this treatment, or even get to the point where they can receive it given how progressive their disease is,” Carraway added. “Given the pioneering work that has been done so far, the next step is to try to improve the efficacy, safety and delivery of these agents so more of our patients have access.”

The extent to which smaller practices can adopt this treatment modality may influence costs, Cassaday said.


“It is unclear how readily available these therapies will be to patients outside the reach of major medical centers that have the resources and infrastructure to manage their administration and potential toxicities,” Cassaday said. “Additionally, if we are successful in bringing CAR T cells to more common diseases, there could be significant financial implications to their broad application. We in the medical community will need to wrestle with these challenging topics as this story unfolds.” – by Mark Leiser and Chuck Gormley


Abramson JS, et al. Abstract 7513. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Fan F, et al. Abstract LBA3001. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Grupp SA, et al. Blood. 2016;128:221.

Locke FL, et al. Abstract CT019. Presented at: American Association for Cancer Research Annual Meeting; April 1-5, 2017; Washington, D.C.

Maude SL, et al. Abstract 2801. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Novartis. Novartis receives first ever FDA approval for a CAR-T cell therapy, Kymriah (CTL019), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice. Available at: www.novartis.com/news/media-releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapy-kymriahtm-ctl019. Accessed on Sept. 4, 2017.

For more information:

Jeremy S. Abramson, MD, can be reached at Massachusetts General Hospital Cancer Center, 55 Fruit St., Boston MA 02114; email: jabramson@partners.org.

Hetty E. Carraway, MD, MBA, can be reached at Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave, R-35, Cleveland, OH 44195; email: carrawh@ccf.org.

Ryan D. Cassaday, MD, can be reached at University of Washington, 825 Eastlake Ave. E, Box 358081, Mailstop G6075, Seattle, WA 98109; email: cassaday@uw.edu.

Stephan A. Grupp, MD, PhD, can be reached at Children’s Hospital of Philadelphia, Oncology/BMT, CTRB 3006, 3501 Civic Center Blvd., Philadelphia, PA 19104-4318; email: grupp@email.chop.edu.

Elizabeth M. Jaffee, MD, can be reached at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 401 N. Broadway, Baltimore, MD 21231; email: ejaffee@jhmi.edu.

Richard Koya, MD, PhD, can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263; email: richard.koya@roswellpark.org.

Disclosures: Cassaday reports research support from Gilead, Incyte, Merck, Pfizer and Seattle Genetics, as well as consultant roles with Adaptive Biotechnologies, Amgen and Pfizer. Grupp reports research support from Novartis. Abramson, Carraway, Jaffee and Koya report no relevant financial disclosures.