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CD19 CAR THERAPY FOR ALL
FIGURE 1. TCR and CAR Structure
A: Physiological T cell activation is mediated by the heterodimeric T cell receptor (TCR) in
association with the CD3 complex (which comprises the gamma, delta, epsilon, and zeta
chains) and modulated by a multitude of costimulatory receptors, such as CD28. B: In
contrast, CARs possess, in a single molecule, the ability to trigger antigen specific T cell
functions through three critical domains: a single-chain variable fragment (scFv) (at the
top), which mediates antigen recognition; the CD3 zeta chain (green), which initiates T cell
activation; and a costimulatory domain (here CD28, in blue), which is lacking in first
generation CARs and is a hallmark of second generation CARs.
TABLE 1. Outcomes of Patients with ALL Treated with
CD19 CAR Therapy
Publication/Meeting Date Number/Age of Subjects
Complete
Remission Rate
Brentjens, Sci Transl Med 17 5 (adults) 100%
March 21, 2013
Grupp, N Engl J Med 18 2 (children) 100%
April 18, 2013
Davila, Sci Transl Med 19 16 adults 88%
February 19, 2014
Lee, Lancet 20 21 (children) 67%
October 13, 2014
Maude, N Engl J Med 21 30 (25 children, 5 adults) 90%
October 16, 2014
Park, ASCO-2015 33 adults 91%
May 30, 2015
the B cell lineage. Thus, a successful therapy would be expected
to induce a B cell aplasia, which was indeed observed
in murine models 7,8 and later in patients treated with CD19
CAR therapy. Furthermore, we thought that the role of CD19
in B cell development may extend to a role in tumor survival,
which would ensure that CD19 is expressed on most malignant
cells and uncommonly lost. 6,9 We provided the fırst
proof of principle that CAR-modifıed human peripheral
blood T cells targeted to CD19 could eradicate a broad range
of B cell malignancies, including ALL, using immunodefıcient
mice bearing medullary and systemic disease. In these
mice, a single intravenous infusion of CD19 CAR–targeted T
cells could eradicate a tumor and induce long-term remissions.
10 Successful B cell tumor eradication was eventually
obtained with a range of different CD19 CARs, 11-15 paving
the way for several ongoing clinical trials.
KEY POINTS
CAR therapy is an emerging immunotherapy based on
engineering of T cells.
Second generation CARs, which provide costimulatory
support to engineered T cells, have transformed the
prospects of adoptive cell therapy.
CD19 CARs have induced dramatic complete responses in
patients with relapsed, chemorefractory ALL.
The two toxicities of CD19 CAR therapy are B cell aplasia
(destruction of normal cells that express CD19) and sCRS
(which occurs in some patients following in vivo activation
of the infused CAR T cells).
It is reasonable to anticipate that CD19 CAR T cells will
become part of the armamentarium for B-cell ALL and
other B cell malignancies.
CD19 CAR THERAPY FOR ALL
We reported the fırst clinical results obtained with CAR therapy
for patients with ALL more than 2 years ago by utilizing
19–28z, a second generation CAR that we transduced in
autologous peripheral blood T cells collected by apheresis. 16
After enrolling adult patients with relapsed chemorefractory
disease, we treated them with an infusion of 3 million CAR T
cells per kg following a single infusion of cyclophosphamide
(3 g/m 2 ) as chemotherapy conditioning. Four out of four patients
with measurable disease went into molecular remission
within 4 weeks. 17 We and two other groups (from the
Children’s Hospital of the Philadelphia and National Cancer
Institute [NCI]) subsequently published follow-up studies in
adult and pediatric publications, summarized in Table 1. 18-21
Results obtained at the three different centers all reported a
highly remarkable complete remission rate–a rare occurrence
for phase I studies in oncology, especially considering
the dire prognosis of patients with relapsed ALL, particularly
in adults. Although these studies follow the same overall
procedure (apheresis, CAR transduction, T cell infusion following
chemotherapy conditioning), they differ in several
regards, including the CAR design (CD28/CD3-zeta dualsignaling
domain utilized at NCI and Memorial Sloan Kettering
Cancer Center [MSKCC], 4–1BB/CD3 zeta utilized at
the University of Pennsylvania), T cell manufacturing, conditioning
chemotherapy, patient age, tumor burden, tumor
chemotherapy sensitivity, and T cell dosage. 22 Despite these
variances, the comparable outcomes speak to the extraordinary
robustness of CD19 CAR therapy in ALL.
At the 2015 ASCO Annual Meeting (May 29–31, 2015), Dr.
Jae Park will report on 33 adult patients treated at MSKCC, of
which 32 patients are evaluable for response. The median age
was 54 (range, 22 to 74). Twelve patients (36%) had
Philadelphia-positive ALL, 11 patients (33%) had prior allogeneic
stem cell transplant (alloSCT), and 14 patients (42%)
had at least three prior lines of therapy. At the time of the
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