NcXHF

SADELAIN ET AL
CD19 CAR Therapy for Acute Lymphoblastic Leukemia
Michel Sadelain, MD, PhD, Renier Brentjens, MD, PhD, Isabelle Rivière, PhD, and Jae Park, MD
OVERVIEW
Chimeric antigen receptor (CAR) therapy is an emerging immunotherapy that shows great promise for cancer, in particular acute lymphoblastic
leukemia (ALL). CARs are recombinant receptors for antigen, which, in a single molecule, redirect the specificity and function of T lymphocytes.
Following their genetic transfer to patient T cells, the latter acquire the ability to recognize leukemia cells and destroy them. Several years
ago, we identified CD19 as an attractive target for CAR therapy for most B cell malignancies, including ALL. We and others have reported
remarkable clinical outcomes in adults and children with ALL, achieving a high complete remission rate irrespective of age, prior treatments,
or other prognostic markers. Severe cytokine release may develop in patients with high tumor burdens. Several interventions are available
to curb the cytokine release syndrome when it occurs. Based on the impressive results obtained with CD19 CAR therapy for ALL, it is realistic
to expect that CD19 CARs will become part of the armamentarium for B cell-ALL and other B cell malignancies.
Chimeric antigen receptors (CARs) are recombinant receptors
for antigens, which in a single molecule, redirect
the specifıcity and function of T lymphocytes. A general
premise for their use in cancer immunotherapy is to rapidly
generate tumor-targeted T cells, bypassing the barriers to and
incremental kinetics of active immunization. 1 Second generation
CARs not only redirect cytotoxicity, but also reprogram
T cell function and longevity, thus conferring supraphysiological
properties on T cells, which then become “living
drugs” that exert both immediate and sustained therapeutic
effects. 2
T cells normally recognize their target antigen through the
T cell receptor (TCR), which binds to human leukocyte antigen
(HLA)-peptide complexes displayed on the surface of
target cells. The TCR does not itself signal, but it does determine,
based on its affınity for the HLA-peptide complex, the
strength of the activation signals the T cell generates on contacting
the tumor. The strength of these signals is further
modifıed by costimulatory receptors, which may be either activating
(such as CD28 and 4–1BB) or inhibitory (such as
CTLA-4 and PD-1). 3 The ligands for these receptors are not
ubiquitously expressed, and therefore place costimulation
under the control of the target cell engaged by the T cell.
Thus, professional antigen presenting cells, such as B cells
and dendritic cells, may express powerful ligands for CD28
and 4–1BB, but tumors typically do not, as is the case for
ALL. The concept underlying second generation CARs is to
provide costimulatory support to T cells irrespective of the
presence of a ligand on tumor cells (Fig. 1). In this context, T
cells that engage the tumor through the CAR are given a costimulatory
signal within the tumor microenvironment itself,
resulting in a pharmacologic boost that we thought
would radically alter the functional profıle of T cells. 4 The
CARs that have recently shown impressive clinical outcomes
in patients with B cell malignancies, especially ALL, are indeed
second generation CARs.
CAR TARGETS AND THE CD19 PARADIGM
Unlike the physiological TCR, which engages HLA-peptide
complexes, CARs are able to engage native cell surface molecules
and do not require any processing or HLA expression
to be recognized. CARs therefore can recognize target antigens
on any HLA background, in contrast to TCRs, which
need to be matched to the patient’s HLA haplotype. Furthermore,
CARs can target tumor cells that have downregulated
HLA expression or proteasomal antigen processing, two mechanisms
that contribute to tumor escape from TCR-mediated
immunity. 5 Another attractive feature of CAR-mediated T cell
responses is that they are not limited to proteins and may target
carbohydrate and glycolipid structures. The target must, however,
be found on the tumor cell surface.
Identifying appropriate CAR targets is important to
achieving complete tumor eradication, as is avoiding damage
to normal tissues that express the same target antigen (“ontarget,
off-tumor effect”). Two decades ago, we selected
CD19 as the prime target for developing our CAR technology.
CD19 is a cell-surface antigen found on most B lineage
lymphomas and leukemias. 6 We chose CD19 not only because
it is highly expressed in these tumors, but also for its
highly restricted expression in normal tissues. CD19 is indeed
known to be only expressed among normal tissues in
From the Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Michel Sadelain, MD, PhD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: m-sadelain@ski.mskcc.org.
© 2015 by American Society of Clinical Oncology.
e360
2015 ASCO EDUCATIONAL BOOK | asco.org/edbook