Bright Future for Gene Therapy in Hematologic Malignancies

Christina Loguidice
Published: Tuesday, Feb 27, 2018
Michael Pulsipher, MD
Michael Pulsipher, MD
Chimeric antigen receptor (CAR) T-cell therapy has been named the Advance of the Year in the American Society of Clinical Oncology’s (ASCO’s) Clinical Cancer Advances 2018. 1 It’s not hard to understand why. CAR T-cell therapy is unique among treatments because it simultaneously serves as a cell therapy, gene therapy, and immunotherapy. Typically, T cells are extracted from the patient, genetically modified to express a CAR, expanded in vivo, and then reinfused, enabling a patient’s immune cells to fight the cancer. Thus far, remarkable results have been observed in young patients with acute lymphoblastic leukemia (ALL) and adults with lymphoma and multiple myeloma.

During an OncLive Peer Exchange® moderated by Krishna V. Komanduri, MD, a panel of experts discussed the current state of CAR T-cell therapies and shed light on the future directions of this exciting new therapeutic approach, which is currently being investigated in more than 400 clinical trials.2

Where We Currently Stand

So far, 2 CAR T-cell therapies have been approved by the FDA: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta).3,4 Tisagenlecleucel was approved in late August 2017 for patients 25 years and younger with B-cell precursor ALL that is refractory to treatment or in its second or later relapse.3 Approval was based on the results of the ELIANA trial, which showed a 3-month complete remission rate of 83% and a 6-month probability of survival of 89%.5

Although these results are impressive, the panelists noted that there is not a great need for CAR T-cell therapy in pediatric ALL.

Most of these patients are effectively treated with standard chemotherapy, with cure rates of 80% to 90%, said Michael Pulsipher, MD. That leaves only a small population of patients with refractory disease who might benefit from CAR T-cell therapy. However, the benefits can be significant for this small subset. “By treating these same patients whom we would have put in hospice previously, we now have 75% of them alive at 1 year and more than 60% of them cured—we think—over the long term,” he said.

Pulsipher lamented that tisagenlecleucel must be used off-label in adults older than 25 years. “We desperately need new clinical trials in the adult population to keep going forward, because there’s no doubt this is an active treatment. I have a 72-year-old who’s in remission for ALL with this,” he said.

In mid-January 2018, about a month after this Peer Exchange discussion, the FDA granted priority review for tisagenlecleucel as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for or who have relapsed after autologous stem cell transplant.6 The designation was based on results of the phase II JULIET study.

FDA approval of axi-cel came in October 2017.4 It is approved for adult patients with relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapy. The treatment can be used for 4 lymphoma subtypes: DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.4

Approval was based on findings from the ZUMA-1 study, which showed an overall response rate of 82% and a complete response rate of 54% after a single infusion of therapy.7 Although these rates were lower than those observed in the pediatric population, they were outcomes for patients who had no other options for potentially curative treatment, the panelists noted.

“You have to remember these patients were not even eligible for an autotransplant, or they had already failed, so this is a population that had a significant unmet need, and these are tremendously exciting results,” said David Maloney, MD, PhD. “There is nothing else that would give this kind of remission in this population,” he added. Furthermore, follow up at 15.4 months indicated that responses were durable, with 42% of patients remaining in complete remission.8

Current Treatment Challenges

A key challenge with CAR T-cell therapy is the adverse event (AE) profile, with cytokine release syndrome (CRS) and neurological toxicity being common, particularly among adults. In the longer term ZUMA-1 data, the incidence of grade ≥3 AEs was 12% for CRS and 31% for neurological toxicity among 101 patients.8 “Almost half of the patients required some type of intervention with either an IL-6 receptor antibody blocker or steroids,” Maloney said.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Rapid Reviews in Oncology®: Practice-Changing Data in Acute Myeloid Leukemia: A Rapid Update From Atlanta OnlineDec 21, 20182.0
Year in Review™: Reflecting on Recent Evidence for the Treatment of Hematologic MalignanciesFeb 28, 20192.0
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