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 in-
stance, 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. ful 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.”
Practical Considerations References
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 clini-
cal 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.”
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 reimburse-
ment, 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 success- 1. U.S. Food and Drug Administration. FDA approval brings first gene therapy to
the United States. Accessed September 4, 2017, from https://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm.
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 http://ir.junotherapeutics.com/
phoenix.zhtml?c=253828&p=irol-newsArticle&ID=2225491.
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
https://www.novartis.com/news/media-releases/novartis-receives-first-ever-
fda-approval-car-t-cell-therapy-kymriahtm-ctl019.
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 re-
ported 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 ●
October 2017
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