FEATURE
Entering A New Era of Immunotherapy
The U.S. Food and Drug Administration’s (FDA) approval
of the first chimeric antigen receptor (CAR) T-cell therapy
represents a paradigm shift in the treatment of hematologic
malignancies, but questions remain about its rollout.
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 pedi-
atric 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) transplanta-
tion, 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 Penn-
sylvania’s Perelman School of Medicine in Philadelphia.
ASH Clinical News spoke with Drs. Park and Levine about tis-
agenlecleucel, 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 sup-
pressing 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
4
Focus on Immunotherapy
“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 Prescrip-
tion 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