Off to the CAR T Races: Bringing CAR T-Cell Therapies to Cancer Patients

August 30, 2017, marked a milestone for medicine: The cell-based gene therapy tisagenlecleucel became the first U.S. Food and Drug Administration (FDA)–approved treatment that re-engineers a patient’s own T cells into focused cancer killers.¹

The decision followed the FDA’s Oncologic Drugs Advisory Committee’s unanimous vote to recommend the immunotherapy for approval; in remarks, one panel member called it the “most exciting thing I’ve seen in my lifetime.”²

This approval “marks an important shift in the blood cancer treatment paradigm,” commented Kenneth Anderson, MD, president of the American Society of Hematology (ASH), in a press release. “We now have proof that it is possible to eradicate cancer by harnessing the power of a patient’s own immune system.”³

Less than two months later, tisagenlecleucel was joined by another CAR T-cell therapy: Axicabtagene ciloleucel was approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.⁴

Breakthrough treatments inevitably raise challenging issues, and chimeric antigen receptor (CAR) T-cell therapies are no exception. ASH Clinical News spoke with scientists and clinicians to better understand the science, potential, and most pressing issues surrounding CAR T-cell therapies.

“We now have proof that it is possible to eradicate cancer by harnessing the power of a patient’s own immune system.”

—Kenneth Anderson, MD

A First-in-Class Approval

A quick primer on CAR T-cell therapies: A patient’s T cells are harvested, re-engineered to express a recombinant receptor that targets a tumor-specific protein, and infused back into the patient’s body to proliferate and eradicate cancer cells.

The concept of “training” T cells to hunt and destroy cancer cells is the stuff of dreams for scientists who have spent their careers trying to take advantage of the innate immune system to combat disease. With the approval of the first CAR T-cell treatment, albeit for a discrete indication, that dream becomes a reality.

Pharmaceutical companies are racing to bring their candidate products to market. With the approval of tisagenlecleucel, Novartis was the first to reach the proverbial finish line. (For a look at the other companies and therapies attempting to follow in its tracks, see the SIDEBAR.)

Tisagenlecleucel (formerly known as CTL019 and branded as Kymriah) was developed by researchers at the University of Pennsylvania to use the 4-1BB costimulatory domain to enhance cellular responses. It is indicated for the treatment of children and young adults with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

ALL is the most common childhood cancer, and relapsed ALL is a leading cause of cancer death in children. However, five-year survival for children and adolescents has increased over time and is now estimated at 85 percent.⁵ For all the hype surrounding its approval, tisagenlecleucel is only approved for that small percentage who relapse. In the most recent data from the pivotal phase III ELIANA study, 83 percent of patients who received tisagenlecleucel achieved complete remission (CR) or CR with incomplete blood count recovery within three months.⁶

“Obviously, for the patients who need the therapy, the impact is great,” said Navneet Majhail, MBBS, MD, director of the Blood and Marrow Transplant Program at Cleveland Clinic’s Taussig Cancer Institute in Ohio. However, he added, “the larger, societal impact is going to be relatively small.”

Novartis plans additional filings for tisagenlecleucel in the U.S. and the European Union later this year, including an application for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), based on interim results from the phase II JULIET study. At three-month follow-up, the overall response rate in adults with relapsed or refractory DLBCL was less than half what was seen for children with ALL – 45 percent – with 37 percent of patients achieving CR.⁷

The company is actively studying other CAR T-cell therapies, including CTL119, a humanized anti-CD19 CAR in early development for multiple B-cell malignancies, as well as CAR T-cell therapies for myeloid leukemias, multiple myeloma, and solid tumors.

Rolling Out CAR Ts Worldwide

When the FDA announced its decision on tisagenlecleucel, Novartis introduced a new pricing model and reimbursement plan for the product. The company is also busy establishing a network of treatment centers slated to include 32 fully certified centers by the end of 2017. Only designated centers will be permitted to collect cells for tisagenlecleucel manufacturing and subsequently prescribe the product.

Dr. Majhail’s center, which was not part of the ELIANA trial but has participated in other CAR-T trials, is in the process of being approved to administer tisagenlecleucel as a commercial product.

As a transplant center that performs approximately 200 bone marrow (BM) transplants each year, he expects it to “easily accommodate” patients requiring CAR T-cell treatment. However, he suspects the complexity of the entire therapeutic process might make it difficult for non-transplant centers to become CAR T-cell providers.

“Obviously, for the patients who need the therapy, the impact is great. The larger, societal impact is going to be relatively small.”

—Navneet Majhail, MBBS, MD

“Conceptually, the process [of manufacturing and administering CAR T-cell therapy] is like a BM transplant: You have to ensure the patient is a candidate, collect the T cells by apheresis, work with the cell-processing lab to send them to a production facility, receive them back, administer lymphodepleting chemotherapy, infuse the patients, and provide post-infusion care, including preventing and treating complications. All these processes are essentially what we do in BM transplantation right now.”

Manufacturing Marvels

Manufacturing CAR T-cell therapies is no simple feat, requiring several carefully executed steps. “These products must be temperature-controlled at all times during preparation, shipping, and administration, and can only be manipulated under aseptic conditions,” explained Marcela V. Maus, MD, PhD, of the Massachusetts General Hospital, and Sarah Nikiforow, MD, PhD, of the Dana-Farber Cancer Institute, in a recent paper published in the Journal for ImmunoTherapy of Cancer.⁸

Drs. Maus and Nikiforow (a 2014 ASH Scholar Award recipient) are members of the Foundation for the Accreditation of Cellular Therapy, an organization established by the International Society for Cellular Therapy and the American Society of Blood and Marrow Transplantation for voluntary inspection and accreditation in the field of cellular therapy. The agency established new standards for the use of immune effector cells, specifying the clinical and quality infrastructure required for safe administration of those therapies.

In the early days of tisagenlecleucel, cell processing was performed at the University of Pennsylvania, the academic center where it was developed. Once tisagenlecleucel advanced to later-phase trials, Novartis transferred manufacturing to their facility in Morris Plains, New Jersey; to date, more than 250 patients in 11 countries across various indications have received T-cell products manufactured at the Novartis site.⁹

The manufacturing process includes cryopreservation of a patient’s harvested cells, giving treating physicians and centers greater flexibility to initiate CAR T-cell therapy based on the individual patient’s condition.

“Cryopreservation also allows for manufacturing and treatment of patients from around the world,” according to the pharmaceutical company, which also has a manufacturing facility in Leipzig, Germany.

Manufacturing failure does happen. In the most recent data on tisagenlecleucel, seven of 88 patients (8%) enrolled in the trial were not infused as a result of insufficiently formulated CAR T-cell product.⁵ Early reported manufacturing failure rates in hematology/oncology studies using several different CAR T-cell products ranged from 2 percent to 14 percent.¹⁰

The most common reason for manufacturing failure was “inability to achieve targeted dose,” most commonly caused by an inadequate number of T cells in the incoming apheresed product, poor selection of T cells on day zero of manufacturing, or irreversibly impaired T cells (i.e., no response to stimulation in culture). In addition, more general causes, such as microbial contamination, equipment-related cell loss, high endotoxin level, and accidents, can ruin CAR T-cell products for clinical use.

“We have much more difficulty growing these cells in culture with certain diseases, and that is usually related to the amount of prior therapy that the patients have received,” Adrian P. Gee, PhD, professor in the Department of Pediatrics, Section of Hematology-Oncology at Baylor College of Medicine in Houston, Texas, told ASH Clinical News. Indeed, the cited 14 percent failure rate was seen in an early study that enrolled heavily treated lymphoma patients.

Dr. Gee also directs the Clinical Applications Laboratory and the Cell Processing and Vector Production Core Laboratory at the Center for Cell and Gene Therapy at Baylor, which is conducting preclinical and early clinical research in CAR T cells for multiple indications, including neuroblastoma. They produce their own de novo CAR T cells in their facility.

One sure way to simplify and more readily scale up manufacturing is to develop an “off-the-shelf” allogeneic CAR T-cell product that uses immune cells from a healthy donor. It would be “very attractive to just generate the cells from healthy donors, and then they’d be immediately available to treat a patient,” said Dr. Gee.

This process also would eliminate the time and costs involved in production: Allogeneic products could potentially be manufactured in bulk, ready to use whenever a patient needs them. Experimental allogeneic CAR T-cells are being evaluated in clinical trials but have shown little success. On September 4, Cellectis reported that the FDA had placed a clinical hold on its phase II studies of UCART23 in patients with blastic plasmacytoid dendritic cell neoplasm and acute myeloid leukemia following a patient death after the development of cytokine release syndrome (CRS) and lung infection.¹¹ A potential explanation for the severity of CRS in that patient is that T cells from healthy donors may be more potent than those from sick patients. The company is working with the investigators and the FDA to resume the trials with an amended protocol.

When the Cure Creates a Disease

Sending a patient’s own T cells to boot camp may seem relatively innocuous, but safety issues have plagued the development of this revolutionary approach. Several other trials have been delayed or halted due to patient deaths, and numerous investigational CAR T-cell products have been abandoned because of toxicities.

The adverse events (AEs) commonly associated with CAR T-cell therapy – tumor lysis syndrome, neurotoxicity, and CRS – are not well understood.¹²

CRS, an inflammatory response indicative of high immune activity, is the most frequently observed toxicity. Most patients who develop CRS experience mild or moderate flu-like symptoms that subside over time, but some experience severe CRS that can lead to life-threatening multi-organ dysfunction. Symptoms of CRS can appear weeks after infusion and require intensive care unit (ICU)–level care through the acute phase.

Neurotoxicity, also known by the technical term “CAR-T-cell-related encephalopathy syndrome,” is the second most common AE, and it can occur concurrent with or after CRS.

Tisagenlecleucel was approved with a boxed warning for CRS and neurologic events and, because of the observed risks, a Risk Evaluation and Mitigation Strategy.

Since the early days of CAR T-cell development, when the first cases of CRS threw physicians for a loop, investigators have developed algorithms and protocols to identify patients at greatest risk of AEs and to manage their occurrence. Research has shown, for instance, that if a patient has the cytokine marker interleukin (IL)-6, he or she is more likely to progress to severe CRS; in clinical trials of tisagenlecleucel, administration of the IL-6 receptor-blocking antibody tocilizumab led to complete resolution of CRS in 69 percent of patients. On the same day as tisagenlecleucel’s approval, the FDA expanded the indication for tocilizumab to include treatment of CAR T cell–induced, severe or life-threatening CRS in patients ≥2 years of age.¹

Cerebral edema also remains poorly understood and difficult to manage.

Recently, investigators from multiple institutions and medical disciplines formed the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group to develop a monitoring, grading, and management system for acute toxicities associated with these new therapies.¹²

Although the side effects are not trivial, experienced transplant centers are familiar with managing most of them, Dr. Majhail noted. His hope is that future generations of CAR T-cell products will offer better safety profiles, with clinical trials clarifying the optimal timing of CAR T-cell administration and the therapies to manage toxicities.

“We know the concept – that you can use engineered cells to do specific things in vivo for therapy – is correct,” Dr. Gee affirmed. “Now we just need to know more about for how long and in which patients.”

The Health Economics of CAR T-Cell Therapy

The unprecedented response rates with tisagenlecleucel come at unprecedentedly high costs: Novartis priced tisagenlecleucel at $475,000 for a single infusion. Despite the sticker shock experienced by most, some analysts consider it a reasonable list price for this new line of therapies.

“The price does make your eyes water at first glance, but this product is potentially transformative in the management of this patient population. I think it’s in the right ballpark,” said Stephen Palmer, PhD, professor and deputy director of the Team for Economic Evaluation and Health Technology Assessment at the Centre for Health Economics at the University of York in the United Kingdom. “However, inevitably, there is significant uncertainty regarding whether the modeled long-term value will be realized in clinical practice.”

CAR T-cell products are truly personalized, likely costing more to manufacture per individual patient than any other therapy, Dr. Palmer offered in defense of the price tag. Also, they address an unmet need and offer treatment that is potentially curative.

In support of their pricing, Novartis cited a health technology assessment (HTA) published in February 2017 by the U.K.’s National Institute for Health and Care Excellence (NICE), of which Dr. Palmer was a senior author.¹³ The NICE assessment determined that a cost-effective price for CAR-T therapy would range from $600,000 to $750,000. Based on that analysis, and the current cost of allogeneic hematopoietic cell transplantation (HCT), which Novartis says is between $540,000 and $800,000 for the first year, the company argues that their price is cost effective.

However, Dr. Price explained, it is not a simple “apples-to-apples” comparison. The NICE estimate was taken from an “exploratory analysis and based on hypothetical data, albeit designed to be as realistic as possible in terms of the outcomes we might expect to see with these technologies, according to results reported from early studies.”

Dr. Palmer and colleagues based their assumptions on the early, single-center, pilot data on tisagenlecleucel in the first 30 children and adults treated.¹⁴ That study showed a CR rate of 90 percent, which he noted is better than the 83 percent response rate currently quoted for tisagenlecleucel.

“The company set the price based on value assessments for initial indications, and it can’t necessarily be assumed to provide similar value in subsequent indications,” he added. “Inevitably, differences [in response] would have a marked impact on the cost-effectiveness estimates we generated.”

Thirty-Day Money-Back Guarantee

To mitigate concerns over the drug’s list price, Novartis entered a unique “outcomes-based” payment model with the U.S. Centers for Medicare and Medicaid Services (CMS). The system will not pay for tisagenlecleucel unless the pediatric or young adult patient with ALL who receives it responds to the treatment within 30 days of administration.

This model means that “there is a mechanism in place to ensure that value is more closely aligned to patient outcome,” Dr. Palmer explained. If the drug is approved for additional indications such as non-Hodgkin lymphoma (NHL), in which response rates have only reached 39 percent, “essentially, you will only pay for the 39 percent of patients with NHL who respond, rather than the 83 percent of patients with ALL who respond.”

“Innovations like this reinforce our belief that current health-care payment systems need to be modernized … to ensure access to new high-cost therapies, including therapies that have the potential to cure the sickest patients,” said CMS Administrator Seema Verma in a press release.¹⁵

“Generally, it is a positive development that companies are relating their pricing decisions to value assessments in the U.S.,” said Dr. Palmer, “ensuring that the price we pay is more closely linked to the value we think the product delivers to the patient and the efficiency of the health-care system.”

However, there are limitations to this innovative approach. Dr. Majhail noted that 30-day response might not be the optimal measure of efficacy, with most patients achieving remission at this timepoint with conventional therapies. “We may observe some tumor shrinkage at one month in certain patients, but this early response doesn’t always translate into a long-term response,” he explained. “The therapy may still stop working, and the cancer may come back.”

To further mitigate longer-term financial toxicity risk, Dr. Palmer envisions another innovative payment model. Similar to a leasing arrangement, the payer would remit an annual payment of, say, 25 percent of the purchase price every year for four years, with the payment contingent on survival each year. “This would further reduce the uncertainties about long-term efficacy and more closely align the payment to the actual value being achieved,” he said.

Even if proven cost-effective in terms of survival, the price tag does not account for the management of side effects of CAR T-cell therapy, including CRS and B-cell aplasia. Dr. Majhail considers the Novartis price a “bit misleading,” because it doesn’t include any of the attendant costs of administering CAR T-cell therapy or managing its associated complications.

“If the therapy doesn’t work, you may not have to pay that $475,000, but you do have to pay for everything else that’s going on,” said Dr. Majhail. This includes “the scans and tests needed to determine if the patient is a candidate for CAR T-cell therapy, staging the patient, performing lung function testing, collecting the cells by apheresis, processing cells in the lab, treating patients with firstline chemotherapy, and the in-patient hospital stay.” If and when AEs occur, that could expand to include a stay in the ICU and the administration of tocilizumab.

Dr. Majhail estimates the total bill will equal or exceed the costs associated with HCT. His worry is that while only a few hundred HCTs are performed each year, should CAR T-cell therapies live up to the hype and prove effective in more common cancers, the numbers may increase exponentially. “If we develop CAR-T cell therapies for a larger variety of diseases, at some point we may have to step back and ask, ‘How sustainable is this?’”—By Debra L. Beck

References

1. U.S. Food and Drug Administration news release, August 20, 2017. Accessed September 29, 2017, from https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm.
2. U.S. Food and Drug Administration. “Transcript for the July 12, 2017, meeting of the Oncologic Drugs Advisory Committee (ODAC) (PM Session).” Accessed September 29, 2017, from https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM573721.pdf.
3. American Society of Hematology press release, August 30, 2017. Accessed September 29, 2017, from http://www.hematology.org/Newsroom/Press-Releases/2017/7704.aspx.
4. U.S. Food and Drug Administration news release, October 18, 2017. Accessed October 18, 2017, from https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm.
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7. Schuster SJ, Bishop MR, Waller EK, et al. Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)—an interim analysis. Abstract #007. Presented at the 14th International Conference on Malignant Lymphoma, June 14, 2017; Lugano, Switzerland.
8. Maus MV, Nikiforow S. The why, what, and how of the new FACT standards for immune effector cells. J Immunother Cancer. 2017;5:36.
9. Novartis press release, August 30, 2017. Accessed September 28, 2017, from https://www.novartis.com/news/media-releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapy-kymriahtm-ctl019.
10. Bersenev A. “Failure in CAR T-cell products manufacturing.” Accessed October 3, 2017, from http://stemcellassays.com/2016/03/failures-cart-manufacturing/.
11. Cellectis press release, September 4, 2017. Accessed October 2, 2017, from http://www.cellectis.com/en/press/cellectis-reports-clinical-hold-of-ucart123-studies.
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14. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507-17.
15. CMS. “CMS: Innovative treatments call for innovative payment models and arrangements.” Accessed October 1, 2017, from https://www.cms.gov/Newsroom/MediaReleaseDatabase/Press-releases/2017-Press-releases-items/2017-08-30-2.html.