Received: 15 November 2018 Revised: 17 January 2019 Accepted: 22 January 2019

DOI: 10.1002/ajh.25418

CRITICAL REVIEW

An introduction to chimeric antigen receptor (CAR) T-cell

immunotherapy for human cancer
Steven Feins1,2,3 | Weimin Kong1,2,3 | Erik F. Williams1,2,3 | Michael C. Milone2,3,4,5 |
Joseph A. Fraietta1,2,3,4,5

1
Department of Microbiology, Perelman
School of Medicine, University of Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement in personalized
Pennsylvania, Philadelphia, Pennsylvania cancer treatment. In this strategy, a patient's own T cells are genetically engineered to express a
2
Department of Pathology and Laboratory synthetic receptor that binds a tumor antigen. CAR T cells are then expanded for clinical use
Medicine, Perelman School of Medicine,
and infused back into the patient's body to attack and destroy chemotherapy-resistant cancer.
University of Pennsylvania, Philadelphia,
Pennsylvania Dramatic clinical responses and high rates of complete remission have been observed in the set-
3
Center for Cellular Immunotherapies, ting of CAR T-cell therapy of B-cell malignancies. This resulted in two recent FDA approvals of
University of Pennsylvania, Philadelphia, CAR T cells directed against the CD19 protein for treatment of acute lymphoblastic leukemia
Pennsylvania and diffuse large B-cell lymphoma. Thus, CAR T cells are arguably one of the first successful
4
Abramson Cancer Center, University of examples of synthetic biology and personalized cellular cancer therapy to become commercially
Pennsylvania, Philadelphia, Pennsylvania
5
available. In this review, we introduce the concept of using CAR T cells to break immunological
Parker Institute for Cancer Immunotherapy,
tolerance to tumors, highlight several challenges in the field, discuss the utility of biomarkers in
University of Pennsylvania, Philadelphia,
Pennsylvania the context of predicting clinical responses, and offer prospects for developing next-generation
Correspondence CAR T cell-based approaches that will improve outcome.
Joseph A. Fraietta, South Pavilion Expansion,
Room 9-104, 3400 Civic Center Blvd., Bldg.
421, Philadelphia, PA 19104.
Email: jfrai@upenn.edu
Funding information
Gabrielle's Angel Foundation for Cancer
Research; National Cancer Institute, Grant/
Award Number: P01CA214278-01; Parker
Institute for Cancer Immunotherapy

1 | INTRODUCTION TO ADOPTIVE CELL
THERAPY FOR CANCER
Adoptive transfer is a term coined by Billingham, Brent, and Medawar1,2
to describe allograft rejection, and the phrase “adoptive immuno-
therapy” denotes the infusion of immunocompetent cells for the
treatment of cancer or infectious disease.3 Mitchison and colleagues
first reported specific targeting of tumor grafts through the adoptive
transfer of lymphocytes in murine models over 60 years ago.4 This
strategy has the potential to overcome many of the pitfalls associ-
ated with vaccine-based approaches for treating cancer, such as the
de novo activation and expansion of tumor-specific T cells in vivo,
even in immune compromised patients. Accordingly, adoptive cell
transfer is a robust form of immunotherapy for treatment of estab-
lished tumors.
A major obstacle facing the field of cancer immunotherapy is
breaking tolerance to “self” antigens. Based on the nature of the target,
tumor-specific immune responses are directed against either “self” or
“foreign” antigens.5 Foreign antigens can arise in virally-induced cancers
or from genetic aberrations unique to a particular tumor, such as point
mutations or chromosomal rearrangements that generate epitopes rec-
ognized by T cells and B cells. Immune responses against such foreign
epitopes are likely similar to those elicited against pathogens, and
therefore may not be susceptible to normal pathways that mediate
self-tolerance. In contrast, immune responses mounted against tumor-
associated self-antigens are subject to suppression by central or periph-
eral tolerance mechanisms. One major issue is thymic elimination of
high-affinity T-cell receptors (TCRs), resulting in the predominance of
relatively low-affinity TCRs to self-antigens compared to foreign anti-
gens. In humans, TCRs that recognize self-tumor antigens have a 1.5

Am J Hematol. 2019;94:S3–S9. wileyonlinelibrary.com/journal/ajh © 2019 Wiley Periodicals, Inc. S3

S4
log lower affinity for cognate major histocompatibility complex (MHC):
6
peptide complexes, relative to their virus-specific TCR counterparts.
Thus, the endogenous T-cell repertoire is often inadequate for control
of human cancer.
2 | BREAKING IMMUNOLOGICAL
T O L E R A N C E T O CA N C E R WI T H CA R T C E L L S
The potential for immunotherapy to treat the most challenging human
cancers has been demonstrated in pre-clinical models and clinical tri-
als. A number of approaches have been taken to circumvent the issue
of tolerance in the setting of cancer immunotherapy, including
infusion of allogeneic T cells, adoptive transfer of expanded tumor
infiltrating lymphocytes (TILs), and inhibition of negative regulators of
immune activation (e.g., cytotoxic T-lymphocyte associated protein
4 [CTLA-4], programmed cell death-1 [PD-1], transforming growth
factor beta [TGFβ], reviewed in Ref. 7). Some therapeutic monoclonal
antibodies (mAbs) are designed to bind a tumor antigen and induce
cell death through various mechanisms or to carry tumoricidal sub-
stances.8 In addition, a newer class of mAbs known as bispecific T-cell
enhancing antibodies has been designed to simultaneously target a
tumor-associated antigen and a T-cell antigen (e.g., CD19 and CD3,
respectively), which results in enhanced co-localization of T cells and
tumors.9 Recently, the use of mAbs to inhibit the aforementioned
negative immune checkpoints (i.e., CTLA-4 and PD-1) has demon-
strated remarkable benefit in the treatment of a variety of cancer
types (reviewed in Ref. 10). Thus, antibody-based immunotherapies
for cancer are now well established in the clinician's armamentarium.
The adoptive transfer of autologous T cells engineered by gene
transfer to express receptors targeting molecules expressed on malig-
nant cells may have greater potential to transform cancer therapeutics
compared to TIL- and antibody-based approaches. Genes encoding
antigen receptors can be introduced into the patient's T cells, which
are then rapidly expanded to derive memory and effector lympho-
cytes capable of proliferating robustly in vivo and eliciting potent anti-
tumor activity. One such strategy to overcome tolerance in cancer is
to genetically redirect and reprogram T cells with chimeric antigen
receptors (CARs). These synthetic receptors combine the effector
functions of T lymphocytes and the ability of antibodies to recognize
pre-defined surface antigens with a high degree of specificity in a
non-MHC restricted manner.
Expression of the first synthetic immunoglobulin/TCR chimeric
molecule with antibody-like specificity was reported over 3 decades
ago.11,12 Shortly following these initial discoveries, Irving and Weiss
determined that a CAR composed of CD8 and the CD3ζ chain could
mediate T-cell activation independently of the endogenous TCR.13
CARs typically encode an extracellular domain for tumor antigen rec-
ognition, linked to one or more intracellular signaling domains that
mediate T-cell activation. The antigen-binding single chain variable
fragment (scFv) portion of a CAR traditionally consists of the variable
heavy (VH) and variable light (VL) chains of an antibody, fused by a
peptide spacer of ~15 residues in length.14 This molecule is joined to
an intracellular signaling molecule comprised of the TCR CD3ζ signal-
ing chain (or the intracellular signaling domain of another immune-
FEINS ET AL.
receptor-tyrosine-based-activation-motif [ITAM]-containing protein),
and optional tandem co-stimulation domains such as the 4-1BB or
CD28 signaling modules. First generation CARs contain CD3ζ alone,
while second generation chimeric receptors also incorporate a co-
stimulatory endodomain (e.g., 4-1BB/CD3ζ). Future studies with third
generation CARs containing multiple co-stimulatory signaling modules
are also underway (reviewed in Ref. 15; see Figure 1). The main
advantage of using CAR-based approaches for cancer immunotherapy
is that the scFv is derived from an antibody with affinities several
orders of magnitude higher than TCRs (reviewed in Ref. 16). Because
scFvs possess the capacity to recognize intact cell surface proteins,
CAR T cell-mediated targeting of tumors is neither restricted and nor
dependent on antigen processing and presentation. CAR T cells are
therefore insensitive to tumor escape mechanisms related to MHC
loss. In addition, CARs can target antigens such as glycolipids, aber-
rantly glycosylated proteins and conformational epitopes that cannot
be easily recognized, if at all, by TCRs. Based on results from clinical
trials conducted at our institution and elsewhere, there is an increas-
ing consensus that CAR T cells have the potential to deliver powerful
anti-tumor effects. These efforts culminated in the recent FDA
approval of CAR T cells directed against the CD19 protein for the
treatment of acute lymphoblastic leukemia (ALL) and diffuse large B-
cell lymphoma (DLBCL).
Although CARs were first proposed in the late 1980s, these syn-
thetic antigen receptors were not tested clinically as a cancer therapy
until 2006. The initial results in adult patients were not promising due
to poor persistence of genetically-engineered lymphocytes.17,18 One
study had shown some evidence of anti-tumor effects in 4 of 8 chil-
dren with metastatic neuroblastoma following a single infusion of first
generation CAR T cells containing CD3ζ alone, but the persistence of
these cells was short in most subjects.19 Although CAR T cells were
safe, they continued to show disappointing clinical activity in the
majority of early trials.20 The central issue facing the field was that
CAR T cells did not persist and expand in vivo for more than a few
days. Efforts to overcome this challenge with dose escalation were
not successful, which underscored the need to enhance the persis-
tence and sustain the function of CAR T cells in vivo.
The incorporation of CD28 and 4-1BB signaling modules into
CARs can recapitulate natural co-stimulation and increases the
potency of engineered T cells.21–27 Our pre-clinical work led to the
identification of the 4-1BB (CD137) signaling domain as a critical
determinant of survival and proliferation of CAR T cells in mice with
pre-B ALL and carcinoma.28,29 In these studies, 4-1BB over CD28
co-stimulation or CD3ζ signaling alone in CAR T cells enabled
enhanced survival of tumor-bearing mice.29 We then conducted the
first clinical trial of a second generation CAR signaling through
4-1BB/CD3ζ delivered by lentiviral vector transduction and found
that these CAR T cells are capable of unprecedented on-target clinical
activity in chronic lymphocytic leukemia (CLL).30,31 These findings
served as the springboard to test this approach in other indications,
including ALL32–34 and DLBCL35,36 for which autologous CD19 CAR T
cells are now commercially available. Recent trials of CAR T cells for
the treatment of multiple myeloma have also exhibited promising
results.37–39 Clinical outcomes of patients infused with CAR T cells for
therapy of some of the above indications are summarized in the
FEINS ET AL. S5

FIGURE 1 Schematic of chimeric antigen receptor (CAR) structure. CARs are composed of a single-chain variable fragment (scFv) consisting of
antibody variable heavy (VH) and variable light (VL) chains, fused by a peptide linker. This antigen-binding scFv of a CAR is joined to an
intracellular CD3ζ signaling domain. First generation CARs contain CD3ζ alone, while second generation synthetic antigen receptors incorporate
an addition co-stimulatory endodomain. Third generation CARs include multiple co-stimulatory signaling modules

proceeding reviews found in this special issue of the American Journal
of Hematology.
3 | GENERATION OF S A FE AND
C L I N I C A L L Y E F F E C T I V E C A R T CE L L S
The production of CAR T cells typically involves cell collection from a
patient by leukapheresis, followed by elutriation to remove myeloid
cells, T lymphocyte enrichment, transgene delivery, and ex vivo expan-
sion (see Figure 2). One of the critical cellular manufacturing constraints
is efficient isolation of T cells from leukapheresis samples. Leukapheresis
products from cancer patients consist of a heterogeneous population of
cells, including T cells, myeloid cells (e.g., monocytes, neutrophils, and
dendritic cells), natural killer cells, erythroid cells, and malignant cells.
With certain hematological malignancies such as leukemia, tumor cells
may comprise the bulk of the leukapheresis material. Despite the appli-
cation of positive and negative selection methods, enriched T lympho-
cytes may remain contaminated by inhibitory cell types that can hamper
efficient CAR T cell expansion in culture and subsequently, in vivo. Poor
CAR T cell manufacturing outcome has been attributed to contamina-
tion of autologous peripheral blood mononuclear cells with mono-
cytes.40 Furthermore, we recently reported a rare case in which a single
leukemia cell was inadvertently transduced with the CAR transgene dur-
ing T-cell manufacturing. This resulted in a CAR binding in cis to the
CD19 epitope on the surface of a leukemia clone that had expanded
massively in an ALL patient, masking it from recognition by anti-CD19
CAR T cells.41 Thus, new manufacturing technologies focused on
achieving efficient T-cell purification and tumor cell purging will improve
the safety and potency of cellular products for adoptive transfer
therapies.
To achieve durable clinical responses to cell-based gene therapies,
permanent transgene expression is often required. Murine gammare-
troviruses and lentiviruses are two available clinical gene therapy
vector systems that afford long-term CAR transgene expression. Con-
siderable clinical evidence shows that retroviral vectors are safe when
expressed in human T cells. Longitudinal analysis of gammaretroviral
vector-engineered T cells for treatment of human immunodeficiency
virus (HIV) infection revealed the persistence of CAR T cells for over a
decade in patients, without evidence of vector-induced immortaliza-
tion of the engineered lymphocytes.42 However, retroviral vectors
appear to be less safe when used in human stem cells.43,44 In contrast,
lentiviral vectors, especially third generation self-inactivating vectors,
have a lower risk of insertional mutagenesis, which may be attributed
to the absence of strong enhancer elements present in oncogenic
murine gammaretroviruses.45,46 Lentiviral vectors also have substan-
tially higher efficiency for genetically engineering human T cells.47
Nevertheless, we recently reported a case of a CLL patient who had a
clonal expansion of his autologous CAR T cells due in part to lentiviral
disruption of the Tet2 gene.41 Long-term monitoring of patients
receiving CAR T cells engineered with integrating viruses should
therefore continue to be carried out in pharmacovigilance studies. As
“safe harbor” sites in the genome are identified, it may be possible to
develop clinically feasible cellular manufacturing processes based on
S6
FIGURE 2 Depiction of a standard chimeric antigen receptor (CAR) T-cell manufacturing process. Cells are collected from a patient by
leukapheresis, followed by monocyte elutriation and T-cell selection. The selected product is then activated (e.g., using paramagnetic beads
coated with anti-CD3 and anti-CD28 agonistic antibodies) and transduced with a viral vector encoding the CAR transgene. Following gene
delivery, T cells are expanded in culture and subsequently harvested to formulate the final CAR T-cell infusion product
guided integration of antigen receptor transgenes into specific loci
using viral and non-viral methods.48,49
Compositions of CD4+ and CD8+ T cell subsets differ in cancer
patients relative to healthy individuals, and this variability may con-
tribute to the efficacy of CAR T cell infusion products. Stem cell-like
memory T cells (Tscm) were identified by Gattinoni and colleagues to
be a self-renewing pool of lymphocytes with multipotent capacity to
differentiate into central memory (TCM), effector memory (TEM) and
50
effector (TEFF) T cells. When these cells were enriched during CAR
T-cell culture, they demonstrated superior anti-tumor activity com-
pared to other early memory and effector subsets. 50
Clinical studies
are currently being conducted to evaluate the safety and efficacy of
TSCM CAR T cells directed against the B-cell maturation antigen for
the treatment of relapsed/refractory multiple myeloma.51 Similarly,
+ − + is an urgent need for identification of biomarkers to enable clinicians
we recently identified a population of CD27 PD-1 CD8 T cells that
was significantly enriched in CD19 CAR T-cell infusion products from
CLL patients who had complete and durable responses to therapy.41
Low frequencies of this lymphocyte population in CAR T-cell infusion
products are associated with reduced T-cell engraftment and poor
tumor control.41 Other groups have focused on formulating CAR
T cells with defined CD4+:CD8+ compositions and these cellular prod-
ucts have demonstrated robust clinical potency in adult B-cell ALL
patients.52 Synergistic or additive augmentation of CAR T-cell efficacy
could be achieved by infusion of a defined ratio of CAR T cells derived
from early memory (e.g., TSCM and TCM) CD8+ and CD4+ T cells.
In addition, because the presence of antigen-experienced T cells
is known to impair the anti-tumor function of less differentiated
lymphocytes,53 strategies to enrich early memory subsets at the
beginning of CAR T-cell manufacturing or during culture may be
beneficial for increasing the efficacy of the engineered cellular
product. In addition to the aforementioned upfront T-cell purification
approaches, potency enhancement may be achieved by shortening the
54
duration of CAR T-cell culture, limiting replicative lifespan through
prevention of telomere loss,55 metabolic programming,56 use of homeo-
57
static cytokines during lymphocyte expansion and/or epigenetic T-cell
modulation.41,58,59
FEINS ET AL.
4 | P R E D I C T I N G R E S P O N S E T O C A R T- C E L L
THERAPY
Despite a number of clinical successes, CAR T cells do not expand or
durably persist in some patients, while in others robust proliferation
and clonal outgrowth of transferred T lymphocytes occur. A certain
level of CAR T-cell expansion and persistence is necessary to induce
meaningful tumor regressions, but the predictive indicators and
mechanism(s) associated with remarkable proliferation, persistence and
favorable clinical responses are largely unknown. Central questions
currently facing the field are how to enhance the potency and sustain
the function of CAR T cells in vivo and how to develop mechanism-
based approaches to increase the resistance of CAR T cells to immuno-
senescence and exhaustion. In consideration of these challenges, there
to determine which patients will respond to CAR T-cell treatment a
priori and so that treatments can be adjusted for maximization of ther-
apeutic effects.
We now have 8 years of experience with using CD19-directed
CAR T cells to treat B-cell malignancies, and our longest involvement
is in treating CLL. In the context of treating CLL with anti-CD19 CAR
T cells, we have not identified patient- or disease-specific features
that forecast which subjects respond best to this treatment or why.
Response (or lack thereof) is not related to patient age, the number of
prior therapies received, p53 mutational status, peripheral or nodal
disease burden, CAR T-cell dose, or other usual risk factors.41,60 How-
ever, in our series of CLL patients, we determined that the majority of
subjects responding to CAR T-cell therapy displayed dramatic in vivo
expansion of CAR T cells in the first 2 weeks following infusion, which
was accompanied by the complete and persistent eradication of
leukemia cells.30,31,60 The degree of CAR T-cell expansion in vivo
strongly and directly correlated with the proliferative capacity of these
cells during ex vivo culture.41,61 In addition, the infused T cells per-
sisted long-term in the responding patients and were polyfunctional
upon CAR-specific stimulation ex vivo. In line with these findings, it
was recently reported that the anti-tumor activity and toxicity of
CD19 CAR T cells in non-Hodgkin's lymphoma (NHL) patients as well
FEINS ET AL.
as overall clinical outcome were associated with the polyfunctional
62
nature of the preinfusion cellular product. Additional predictive
indicators of response to anti-CD19 CAR T-cell therapy include a high
frequency of CD3+CD8+CD27+CD45RO− lymphocytes at the time of
collection, cellular infusion products enriched in transcriptomic signa-
tures of early memory T-cell differentiation (i.e., STAT3-related genes),
and elevated pretreatment serum IL-15 levels.41,62 Given the intensive
manufacturing process, the potential toxicity and possible new alter-
native treatments for some patients, the ability to use biomarkers to
identify which subjects are most likely to respond to CAR T-cell ther-
apy would have a tremendous clinical benefit. Predictive biomarkers
can be utilized by physicians to prescribe CAR T-cell therapy only
to the responding patient population, thus eliminating the unneces-
sary expense and risk of immune-related adverse events for non-
responders. Finally, systematic investigations of the mechanisms that
potentiate the anti-tumor activity of CAR T cells at the cellular and
molecular level may reveal ways to generate potent cell infusion prod-
ucts for many future patients.
5 | OVERCOMING RESISTANCE TO CAR
T - C E L L T H E R A P Y OF H E M A T O P O I E T I C
MALIGNANCIES
A mechanism of CAR T-cell failure in pediatric ALL is loss of the CD19
antigen or epitope, despite otherwise adequate persistence of trans-
ferred cells. Antigen-negative tumor escape variants likely emerge
through selection of sub-clonal leukemia cells that possess a survival
advantage in the face of a powerful antigen-specific assault mediated by
CAR T cells. Unlike other CAR targets, CD19 escape was unexpected
due to its essential role in B-lineage development.63,64 Nevertheless, the
first major mechanism of CD19 escape identified in anti-CD19 CAR
T-cell therapy was alternative splicing, leading to the production of
either a non-membrane bound form of CD19 (Δexon 5-6) or a poorly
expressed variant that lacks an epitope recognized by the CAR scFv
(Δexon 2) on the cell surface. 65
Jacoby and colleagues subsequently
reported that the immune pressure exerted on CD19 by CAR T cells
gives rise to either a rapidly relapsing leukemia lacking the epitope rec-
ognized by CAR, or lineage-switched disease resulting from hematopoi-
etic reprogramming. 66
More recently, Orlando et al. reported that
homozygous or biallelic frameshift mutations in CD19, rather than alter-
native splicing, are the main cause of CD19 loss and acquired resistance
67
to CAR T-cell therapy. Regardless of the escape mechanism, trials
based on administering combinations of CARs against multiple targets
will likely eliminate the emergence of antigen-negative leukemia that
leads to a high degree of relapse in patients.
Resistance to CAR therapy has also been attributed to failure of
engraftment and/or expansion and persistence of engineered T cells.
As previously discussed, we and others have demonstrated that T cells
with an early memory phenotype are endowed with superior expansion
potential.41,68,69 In one study, T cells from patients with ALL had higher
absolute numbers of early-lineage lymphocytes than individuals with B
cell Non-Hodgkin lymphoma (NHL), and there was heterogeneity even
among ALL patients, leading us to postulate that in some patients pre-
existing T cell quality may influence the degree of expansion upon in
S7
vivo transfer.69 Successful development of “universal” CAR T cells
derived from healthy, allogeneic donors using precision genome editing
technologies (e.g., transcription activator-like effector nucleases, zinc-
finger nucleases, clustered regularly interspaced short palindromic
repeats [CRISPR]/CRISPR associated protein 9) has the potential to cir-
cumvent issues associated with autologous T-cell defects such as termi-
nal differentiation.
In CLL, we found that CD19-targeted CAR T-cell infusion products
from non-responding patients when compared with those of complete
responders contained significantly higher frequencies of CD4+ and
CD8+ T cells expressing multiple inhibitory receptors (e.g., PD-1, TIM-3,
and LAG-3).41 This finding suggests that in vivo blockade of negative
immune checkpoint molecules with concurrent CAR T-cell therapy rep-
resents a novel treatment strategy for overcoming resistance. Accord-
ingly, administration of a PD-1 blocking antibody therapy to a patient
with refractory diffuse large B-cell lymphoma (DLBCL) that had
relapsed after receiving CAR-modified cells induced re-expansion of
CAR T cells, which was accompanied by a clinically significant anti-
tumor response.70 Future studies are needed to define whether com-
bining in vivo blockade with PD-1 or multiple other inhibitory receptors
after CAR T-cell transfer is beneficial.
6 | CONC LU SION
CAR T cells are changing the paradigm for cancer therapy. This new
era of synthetic biology and medicine has been heralded by the recent
FDA approval of CD19 CAR T cells for the treatment of ALL and
DLBCL. CAR T-cell therapy for multiple other cancers will likely enter
mainstream oncology. The capacity of CAR T cells to overcome toler-
ance, expand as well as traffic to tumor sites, synergize with the
endogenous immune response, and persist long-term in vivo may
allow this living, replicating drug to induce permanent anti-tumor
effects in patients. Engineered T cells could therefore provide signifi-
cant therapeutic and economic advantages over antibody-based treat-
ment regimens and other targeted inhibitors, as these modalities
require prolonged administration and are not generally curative.
Furthermore, administration of CAR T cells could obviate the need for
allogeneic stem cell salvage procedures in the setting of particular hema-
topoietic cancers. Larger studies are currently being conducted to evalu-
ate the safety and reliability of CAR T cells for diseases other than
CD19-positive B-cell malignancies. With the emergence of improved cel-
lular manufacturing techniques, novel cellular engineering approaches,
precision genome editing technologies, and combination therapy strate-
gies, we believe that CAR T cells will soon become an off-the-shelf, cost-
effective, and potentially curative treatment of human cancer.
ACKNOWLEDGMENTS
This work was supported by P01CA214278 (M.C.M. and J.A.F.), the
Parker Institute for Cancer Immunotherapy (M.C.M. and J.A.F.) and
the Gabrielle's Angel Foundation (J.A.F.).
S8
CONF LICT OF IN TE RE ST
M.C.M. and J.A.F. hold patents related to CAR T cell therapy. M.C.M. is
a co-founder and equity holder in Cabaletta Bio. J.A.F. receives research
funding from Novartis Pharmaceuticals Corporation and Tmunity
Therapeutics. The remaining authors declare no competing interests.
ORCID
Joseph A. Fraietta https://orcid.org/0000-0001-7900-8993
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How to cite this article: Feins S, Kong W, Williams EF,
Milone MC, Fraietta JA. An introduction to chimeric antigen
receptor (CAR) T-cell immunotherapy for human cancer. Am
J Hematol. 2019;94:S3–S9. https://doi.org/10.1002/ajh.
25418