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Entering A New Era of Immunotherapy

December 30, 2021

On August 30, 2017, the FDA approved the first gene therapy in the United States: Tisagenlecleucel (Kymriah, Novartis) is a CD19-directed CAR T-cell therapy approved for certain pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphocytic leukemia (ALL).1

"These are patients who have tried at least one or two prior therapies, sometimes including bone marrow (BM) transplantation, and none of these therapies are working," explained Jae Park, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, who is investigating CD19-directed CAR T-cell therapies in B-cell malignancies. "In this setting, CAR T cells can induce complete responses (CRs) in the range of about 80 percent, which is quite remarkable and higher than anything we have seen in this setting."

With tisagenlecleucel, the high remission rates were achieved within three months of a one-time infusion.2

Like many of the other "hot" cancer therapies, CAR T-cell therapy is an immunotherapy. However, unlike immune checkpoint inhibitors, CAR T-cell therapies harness the power of each patient's individual immune system, making it the "ultimate in personalized therapy," according to Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy at the University of Pennsylvania's Perelman School of Medicine in Philadelphia.

ASH Clinical News spoke with Drs. Park and Levine about tisagenlecleucel, how CAR T-cell therapies work, and the challenges of putting them into practice.

The CAR Pipeline

"In patients with cancer, immune T cells are not successfully suppressing cancer cells," Dr. Park said, offering a simple explanation of how and why CAR T-cell therapy works. "With CAR T-cell therapy, we take T cells from the patient and modify them to express a new artificial receptor engineered to recognize cancer cells. We then infuse those cells back into the patient, where they are better able to recognize and start killing off cancer cells."

Tisagenlecleucel, like most other CAR therapies furthest in the pipeline, modifies T cells to target cells that have the CD19 antigen on their surface. It is approved for patients with ALL, but CAR T-cell therapies are being investigated in other hematologic malignancies, including chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).

The FDA accepted another CD19-directed candidate, axicabtagene ciloleucel, for priority review on May 26, 2017. Submission of the biologics license application was supported by data from the phase II ZUMA-1 trial of patients with refractory, aggressive NHL. After a median follow-up of 8.7 months, the objective response rate after a single infusion of axicabtagene ciloleucel was 82 percent, including a CR rate of 39 percent.3

"This therapy is being looked at specifically in patients with diffuse large B-cell lymphoma (DLBCL), which is more common than ALL," said Dr. Park, adding that the FDA has set a Prescription Drug User Fee Act target action date of November 29, 2017.

Juno Therapeutics also has several CAR T-cell therapies under investigation, but early safety results from those trials highlighted concerns. In late 2016, a trial of JCAR015 in adult patients with relapsed or refractory B-cell ALL was halted following reports of two patient deaths due to cerebral edema.4 However, updated results of a second therapy, JCAR017, have been more positive to date. Data from the phase I TRANSCEND study presented earlier this year showed an objective response rate of 86 percent and a CR rate of 59 percent in patients with relapsed or refractory DLBCL.5

This list represents only the tip of the CAR T-cell therapy iceberg, according to Dr. Levine, who estimated that approximately 40 companies are now conducting preclinical studies of CAR T-cell or engineered T-cell products. Trials of CD19-targeting and other CAR therapies are being conducted in patients with MM, glioblastoma, pancreatic cancer, ovarian cancer, mesothelioma, breast cancer, prostate cancer, and melanoma, to name a few.

Curbing Adverse Events

Dr. Levine noticed the public excitement over CAR T-cell therapy in 2011, after he and a group of colleagues published a brief report in the New England Journal of Medicine detailing an early success with CAR T-cell therapy targeting CD19 in a patient with CLL.6

"After we published that paper, we had several thousand inquires that came into the university from patients or families asking for access to the clinical trial, not only in CLL, but for many other cancers," Dr. Levine recalled. "There is intense interest in this type of therapy, and patients feel empowered by [the prospect of] using their own immune system to fight back against their cancer."

Although clinical trials of CAR T-cell therapies are seeing positive results across multiple hematologic malignancies, the agents' unfamiliar safety profiles give some researchers and regulators pause.


There is intense interest in this type of therapy, and patients feel empowered by [the prospect of] using their own immune system to fight back against their cancer.

As opposed to traditional treatments like hematopoietic cell transplantation and high-dose chemotherapies, with which the associated adverse events (AEs) are well known and can be managed, the AEs commonly associated with CAR T-cell therapy (tumor lysis syndrome [TLS], neurotoxicity, and cytokine release syndrome [CRS]) are not well understood.

"A subset of patients is not only hospitalized, but moved to the intensive care unit, because of these AEs," Dr. Levine said. Fortunately, he added, researchers are already determining how to best predict who those patients will be and how to manage them.

"These near-term effects correlate with patients' leukemia burden at the time of infusion, so we can use that information to identify patients at a higher risk of developing TLS or CRS," he said. "The University of Pennsylvania and the Children's Hospital of Philadelphia and colleagues at the National Cancer Institute, Seattle Children's, and Texas Children's have published a CRS management algorithm and, more recently, a set of early-detection biomarkers for severe CRS."7 In a small study of patients with B-cell ALL treated with anti-CD19 CAR T-cell therapy, researchers at Memorial Sloan Kettering Cancer Center also identified serum C-reactive protein levels as reliable indicators of the risk of developing severe CRS.8

If a patient has the cytokine marker interleukin (IL)-6, for instance, he or she is more likely to progress to severe CRS. Patients who have this marker can receive an IL-6 receptor-blocking antibody as an early antidote.

In fact, the recent FDA approval of tisagenlecleucel included an expanded indication for the anti-IL-6 receptor antibody tocilizumab to treat CAR T-cell–induced severe or life-threatening CRS in patients two years or older.1 In clinical trials, 69 percent of patients had complete resolution of CRS within two weeks after one or two doses of tocilizumab.

Though the AEs are significant, Dr. Levine said that many patients are attracted to the idea of receiving one-time treatment, rather than prolonged treatment with a long list of side effects. "When one compares the potential for a one-time treatment with some short-term side effects, albeit severe, to the side effects that go along with high-dose chemotherapy, the patients I have talked to are very interested in pursuing CAR T-cell therapy," he noted.

As seen in the clinical trials of JCAR015, neurotoxicity is another potentially fatal AE of CAR T-cell therapies – and one of the less well-understood side effects. Such events can range from mild to severe aphasia, confusion, delirium, seizures, and cerebral edema. "We don't yet quite understand the mechanisms of this neurotoxicity and are monitoring patients carefully," Dr. Park said.

Practical Considerations

The need for careful monitoring of the specific side effects of CAR T-cell therapy is just one of the reasons why, for now, administration of this therapy is limited to clinical trials, and why the FDA is requiring that hospitals and affiliated clinics that plan to dispense tisagenlecleucel be specially certified.

Other challenges to integrating CAR T-cell therapy into clinical practice are the logistics of manufacturing and administering the treatment, according to Dr. Park.

"Some patients might not be able to make it through the first step of this therapy because the optimal collection of T cells occurs when the disease is somewhat stable," Dr. Park said. "The challenge then becomes finding the right time to collect T cells in patients who may have rapidly progressive disease, determining the best time to admit patients to start therapy, and figuring out what to do in the interim while the T cells are produced."

Some patients might not be able to make it through the first step of this therapy because the optimal collection of T cells occurs when the disease is somewhat stable.

Another aspect to iron out is reimbursement for this new gene therapy. Novartis, the manufacturer of tisagenlecleucel, is collaborating with the Centers for Medicare and Medicaid Services to create an outcomes-based approach to reimbursement, allowing for payment only when pediatric and young adult ALL patients respond to tisagenlecleucel within the first month after infusion.9

However, it remains to be seen how quickly institutions administering the therapy will be reimbursed, how much successful therapy will cost, and how much of that cost patients will bear.

"It will likely be a lot of money, but it will likely be cheaper than the cost of a BM transplant," Dr. Park predicted. "Even though it is expensive, it will be a good option and hope for patients who otherwise don't have many options."

Continued Research

As trials of CAR T-cell therapies continue, researchers hope to increase their understanding of this highly personalized therapy.

First will be determining how safe and efficacious these products are in the long term. So far, the clinical trials have reported limited follow-up – generally less than 12 months. Initial protocols have called for one- or two-year follow-up, but FDA guidance for gene therapy requires extended patient follow-up of 15 years, Dr. Levine said.

Researchers also want to better understand why responses to CAR-T therapy vary from one type of malignancy to another.

"In patients with ALL, the response rate is 80 percent, but CR rates are much lower – 30 to 40 percent – in NHL and CLL," Dr. Park said. "These are still remarkable outcomes, compared with other standard therapies available for these patients, but they aren't as high. Why is there this difference when using the same CAR T cells?"

And, as with most therapies developed as "last resorts" for patients whose disease has relapsed or not responded to multiple prior lines of therapy, there will be interest in moving CAR T-cell therapy into a secondline spot, Dr. Levine said.

"That will definitely be a strategic consideration by Novartis, Kite, and others that are in the advanced stages of clinical trials," he said.—By Leah Lawrence  â—


  1. U.S. Food and Drug Administration. FDA approval brings first gene therapy to the United States. Accessed September 4, 2017, from
  2. Buechner J, Grupp SA, Maude SL, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): update to the interim analysis. Abstract S476. Presented at the 2017 European Hematology Association Annual Meeting, June 24, 2017; Madrid, Spain.
  3. Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). CT019. Presented at the 2017 American Association for Cancer Research Annual Meeting, April 5, 2017; Washington, DC.
  4. Juno Therapeutics. Juno Therapeutics places JCAR015 phase II ROCKET trial on clinical hold. Accessed September 4, 2017, from
  5. Abramson JS, Palomba ML, Gordon LI, et al. High CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001). Abstract 128. Presented at the 14th International Conference on Malignant Lymphoma, June 17, 2017; Lugano, Switzerland.
  6. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-33.
  7. Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664-79.
  8. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra25.
  9. Novartis. Novartis receives first ever FDA approval for a CAR-T cell therapy, Kymriah (TM) (CTL019), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice. Accessed September 5, 2017, from

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