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Stem Cell-Derived Cell Therapy for Cancer

Matthew Wilson, Zibai Lyu, Ying Fang, and Yan-Ruide Li

Abstract

The advent of genetic engineering strategies has transformed the landscape of


cancer immunotherapy, leading to the development and adoption of CAR-T cell
therapy. However, the current autologous CAR-T cell platform is hindered by
several factors including limited potency against solid tumors and limited scal-
ability across multiple patients, placing a heavy cost burden on patients. The
development of stem-cell-based technologies is poised to provide an alternative
“off-the-shelf” platform to the current CAR-T model, which can help overcome
these issues. In this review, we examine the current state of stem-cell-based
therapies encompassing potential stem-cell sources, engineering approaches,
clinical implementations, and prevailing challenges facing the field.

Keywords
Allogeneic cancer therapy · Cancer genetic engineering · Cancer
immunotherapy · Chimeric antigen receptor (CAR) · CRISPR-Cas9 ·
Graft-versus-host disease (GvHD) · Natural killer T (NKT) cell · Stem cell

1 Introduction

Cancer poses a significant challenge in contemporary medicine, comprising a diverse


group of diseases with a global impact. Traditional treatments, encompassing surgery,
chemotherapy, and radiation therapy, have made considerable advancements, offering
improved survival rates to patients. However, the complexity of cancer demands

M. Wilson · Z. Lyu · Y. Fang · Y.-R. Li (✉)


Department of Microbiology, Immunology & Molecular Genetics, University of California,
Los Angeles, Los Angeles, CA, USA
e-mail: charlie.li@ucla.edu

# The Author(s), under exclusive license to Springer Nature Switzerland AG 2023


Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2023_196
M. Wilson et al.

innovative strategies to augment existing therapeutic options. One promising avenue


lies in the realm of stem cell-derived cell therapy for cancer.
Stem cells, renowned for their unique ability to self-renew and differentiate into
diverse cell types, have captivated the scientific and clinical communities for their
regenerative potential (Wilson 2009). Stem cell applications have extended to
various medical conditions, ranging from cardiac and neurological disorders to
autoimmune diseases (Wilson 2009). Currently, researchers are exploring the trans-
formative potential of stem cells in revolutionizing cancer treatment strategies.
The emerging field of stem cell-derived cell therapy for cancer holds promise in
overcoming pivotal challenges in oncology (Li et al. 2023). Engineered stem cells
present an opportunity for developing standardized cellular products, eliminating the
need for personalized and patient-specific approaches (Hermanson et al. 2016; Li
et al. 2018, 2021c; Shankar et al. 2020; Zhang et al. 2020; Frank et al. 2020; Euchner
et al. 2021; Zhou et al. 2022). By performing gene engineering or gene editing on a
limited pool of stem cells, the consumption of gene-engineering materials, such as
lentivectors and CRISPR/Cas9/gRNA, could be minimized. This approach enhances
cost-efficiency while maximizing the effectiveness of gene engineering/editing, a
characteristic inherited by subsequent cell divisions and final cell products (Xu et al.
2019; Gerew et al. 2021; Li et al. 2021b). Additionally, the evolution of stem cell-
engineered cellular therapy facilitates the potential for large-scale manufacturing and
stockpiling of products.
This chapter delves into the dynamic field of stem cell-derived cell therapy for
cancer. We explore various stem cell types under investigation, including mesen-
chymal stem cells (MSCs), hematopoietic stem cells (HSCs), and induced pluripo-
tent stem cells (iPSCs), elucidating their therapeutic applications. We evaluate
promising findings from preclinical and clinical studies while addressing imminent
challenges, ranging from safety optimization to enhancing the scalability of these
innovative therapies.

2 Stem Cell Sources for Cell Therapy

The pursuit of innovative cancer therapies and stem cells has emerged as a promising
avenue of exploration. This section delves into the various types of stem cells—
embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal
stem cells (MSCs), and hematopoietic stem cells (HSCs)—as potential cell sources
for advancing cancer treatment (Sagar et al. 2007). Each stem cell type possesses
unique attributes and faces distinct challenges within the context of cancer therapy.
ESCs represent a unique class of pluripotent cells derived from embryos fertilized
in vitro. The process of ESC cultivation involves the development of these embryos
into blastocysts, from which the undifferentiated inner cell mass (ICM) can be
isolated. The hallmark characteristic of ESCs is their pluripotency, enabling them
to self-renew indefinitely and differentiate into all cell types except for placenta
(Hochedlinger and Jaenisch 2003; Wobus and Boheler 2005). This inherent versa-
tility positions ESCs as an attractive candidate for cancer treatment and development
Stem Cell-Derived Cell Therapy for Cancer

of tumor models. ESCs can be programmed into therapeutic cells, particularly T and
natural killer (NK) cells, which can be genetically modified to express tumor-
suppressing proteins, immunostimulatory molecules, and chimeric antigen receptors
(CARs), enabling targeted cancer therapy and immune cell recruitment to tumor sites
(Hochedlinger and Jaenisch 2003; Wobus and Boheler 2005; Zeng et al. 2012).
These customized cells can effectively target cancer cells or recruit other immune
elements to the tumor microenvironment, fostering a multifaceted approach to
cancer treatment. However, the extensive proliferative and differentiating
capabilities of ESCs present potential drawbacks. Their propensity for unlimited
division mirrors cancer behavior, raising concerns about tumorigenic potential,
especially following genetic modifications. Ethical dilemmas also loom over
ESCs, as their generation involves the destruction of in vitro-fertilized embryos,
sparking regulatory variations across countries and affecting ESC research (Tam
et al. 2023; Iltis et al. 2023). Overall, the complex signaling pathways governing
ESC behavior remain incompletely understood, and overcoming immune rejection
and generating safe, heterogeneous cell lines pose ongoing challenges in ESC-based
therapies (Fig. 1).
iPSCs share functional similarities with ESCs while diverging in their origin,
derived through reprogramming adult somatic cells, such as dermal fibroblasts,
peripheral blood cells, or adipose tissue cells. This reprogramming process involves

Fig. 1 Stem cell sources for cell therapy. A diverse array of stem cell sources suitable for cell
therapy is shown, encompassing embryonic stem cells, induced pluripotent stem cells, mesenchy-
mal stem cells, and hematopoietic stem cells, among others.
M. Wilson et al.

the activation of key pluripotency factors like Oct4, Sox2, and Klf4 (Sharkis et al.
2012; Hansen et al. 2018). iPSCs closely mimic ESCs in research settings, providing
an ethical advantage by utilizing cells sourced from consenting adult donors. This
ethical consideration facilitates their transition into clinical trials, where iPSCs
exhibit potential in cancer therapy, particularly in cell-based immunotherapy
(Li et al. 2018; Gutbier et al. 2020; Frank et al. 2020; Iriguchi et al. 2021; Aoki
et al. 2023). They can be reprogrammed into T lymphocytes, retaining T-cell
receptor genes for subsequent differentiation into T cells. These reprogrammed
T cells can be engineered to express CARs and other molecules for targeted cancer
therapy (Li et al. 2018; Allen et al. 2021). iPSCs’ ability to differentiate into various
tissue and cell types offers opportunities for tissue regeneration and disease
modeling, aiding diagnostics, and advancing therapeutics. Nevertheless, the devel-
opment of effective differentiation protocols for desired cell types from iPSCs
remains labor-intensive due to their diverse sources and potential differentiations.
The absence of Good Manufacturing Practice (GMP)-compliant protocols raises
safety concerns during iPSC generation, expansion, and differentiation, emphasizing
the need for standardized procedures to ensure consistency within clinical practice.
Another promising source for cancer therapy resides in MSCs, originating from
bone marrow, adipose tissue, and umbilical cord tissue. MSCs possess the ability
to differentiate into bone, cartilage, and fat tissues, and they are noted for their
regenerative and immunomodulatory properties (Hmadcha et al. 2020). These
attributes render MSCs suitable for clinical trials spanning orthopedic injuries,
autoimmune diseases, and neurological disorders. Beyond their conventional stem-
cell traits, such as self-renewal and robust differentiation capabilities, MSCs exhibit
a unique tumor-homing phenomenon. Driven by tumor tropism, chemotaxis, and the
tumor microenvironment, MSCs are naturally attracted to tumor sites, where they
engage with cancer cells, contributing to the attack against cancerous cells (Shah
2012; Datta et al. 2022). Genetic modifications further enhance their therapeutic
potential by enabling MSCs to express exogenous tumor-targeting or therapeutic
molecules (Shah 2012; Datta et al. 2022; Yan et al. 2023). Additionally, their low
immunogenicity, attributed to minimal MHC-I molecule expression and immuno-
modulatory capabilities, renders MSC allogeneic transplantation well-tolerated. The
duality of MSCs’ interactions with the tumor microenvironment may pose a chal-
lenge. Despite interrupting cancer cell replication to inhibit tumor growth, MSCs can
also differentiate into cancer-associated fibroblasts (CAFs), potentially contributing
to cancer progression and immunosuppression (Mishra et al. 2009; Datta et al.
2022). The outcome of these interactions depends on various factors, including the
tumor model, MSC source, timing, dosage of treatment, delivery methods, and
patient-specific conditions, complicating their application in clinical oncology.
HSCs offer distinct advantages as a potential cell source for cancer therapy,
owing to their natural involvement in blood and immune cell production. Their
integral role in immune cell generation underpins their application in cancer therapy,
notably in HSC transplantation (HSCT). HSCT facilitates reconstruction of a
patient’s immune system, providing a valuable tool for treating hematological
malignancies such as leukemia and lymphoma (Rowe et al. 2016; Ng and Alexander
Stem Cell-Derived Cell Therapy for Cancer

2017). HSCs can be genetically engineered to generate specialized immune cells,


including T cells and NK cells, which can express CARs and other tumor-targeting
molecules (Gschweng et al. 2014; Rowe et al. 2016). These modified immune cells
have demonstrated promise in enhancing the patient’s immune response against
cancer cells. However, one of the primary limitations of HSCs is their propensity for
the onset of graft-versus-host disease (GvHD), where HSC-derived immune target
the recipient’s healthy tissues, potentially leading to severe complications. Stringent
donor-recipient matching and immunosuppressive treatments are essential to
mitigate this risk in HSCT or HSC-derived cell therapy, strongly limiting usage
(Montoro et al. 2023). Furthermore, while HSC-based therapies have exhibited
success in certain blood-related cancers, their application in solid tumors is more
nebulous, demanding further research to unlock their full potential in these contexts.
Nevertheless, HSCs remain a valuable asset in cancer therapy, particularly in the
management of hematological malignancies and as a foundation for advancing
innovative immunotherapies.
Beyond the well-explored stem cell types mentioned above, several other cell
sources hold potential for cell therapy applications. One such source is the adipose-
derived stem cells (ASCs), isolated from fat tissue. ASCs exhibit regenerative
properties and have shown promise in tissue repair and regeneration, making them
valuable in treating conditions like skin injuries and degenerative joint diseases.
Another cell type, neural stem cells (NSCs), derived from the nervous system,
possess the ability to differentiate into various neural cell types. These cells hold
potential for addressing neurological disorders and injuries, offering avenues for
neural tissue repair and restoration (Stuckey and Shah 2014). Research into
harnessing the therapeutic potential of ASCs and NSCs continues to expand,
highlighting the dynamic landscape of stem cell-based therapies in diverse medical
fields.

3 Differentiated Cell Types for Therapy

Stem cells possess the potential for genetic modifications and the ability to replicate
in a clonal manner, resulting in the generation of exceptionally pure effector cells.
Advancements in stem cell culture and differentiation techniques have broadened the
spectrum of stem cell-derived cellular candidates. This now encompasses conven-
tional T cells, non-conventional T cells, NK cells, dendritic cells (DCs),
macrophages, and myeloid cells, all of which can be further engineered to acquire
anticancer properties (Fig. 2).
The groundbreaking achievements of immune checkpoint inhibitors and CAR-T
cell therapies, exemplified by the FDA-approved anti-CD19 CAR-T cell therapy for
B-cell malignancies, have underscored the critical role of T cells in immunotherapy
(Sterner and Sterner 2021). Accordingly, conventional αβ T cells have emerged as a
pivotal component of the investigation of stem cell engineering. In alignment with
established T-cell genetic engineering techniques, stem cell-derived αβ T cells can
be modified to express physiological TCRs or synthetic CARs to acquire specificity
M. Wilson et al.

CAR-
CAR-engineering
αβ T iNKT NK

TCR - NK
engineering Differentiation

MAIT γδ T
CD16-engineering CD16-
NK
Stem
cells
CAR-engineering

CAR- TCR/CAR-
CAR-T
iNKT engineering Differentiation Macrophage

DC Myeloid
CAR- CAR-
MAIT γδ T

Fig. 2 Differentiated cell types for therapy. The figure shows various types of differentiated cells
that can be derived from stem cells for cancer therapy and how these differentiated cells can be
engineered to possess anticancer properties. iNKT invariant natural killer T cell, MAIT mucosal-
associated invariant T cell, NK natural killer cell, DC dendritic cell

for tumor antigens (Sadelain et al. 2017). For example, TCR-engineered T cells such
as NY-ESO-1-specific TCR-engineered T cells have propelled advancements in the
treatment for myeloma, lung cancer, melanoma, and sarcoma (Rapoport et al. 2015;
Zhang et al. 2022b). In addition to anti-CD19 CAR-T cell therapy, B-cell maturation
antigen (BCMA) CAR-T cell therapy has also gained approval for the treatment of
multiple myeloma and various B-cell malignancies (Raje et al. 2019; D’Agostino
and Raje 2020; Li et al. 2023). Stem cell-derived αβ T cells can further mitigate the
limitations of current CAR-T cell therapy, particularly cytokine release syndrome
(CRS), owing to their different cytokine patterns (Themeli et al. 2013; Li et al.
2023). Moreover, considering the clinical significance of the CD4+:CD8+ ratio in
therapeutic outcomes, allogeneic αβ T cells derived from induced pluripotent stem
cells (iPSCs) or hematopoietic stem cells (HSCs) can circumvent the challenges
posed by unstable or unfavorable T-cell compositions through precise gene editing
techniques (Themeli et al. 2015; Turtle et al. 2016).
NK cells distinguish target cells through a combination of activating and inhibi-
tory receptors, independently of MHC recognition, thereby mitigating the risk of
GvHD, a concern often associated with conventional CAR-T cell therapy (Ruggeri
et al. 2007; Fang et al. 2017; Rezvani et al. 2017; Abel et al. 2018). Similar to NK
cells derived from other sources ranging from autologous patients to allogeneic
Stem Cell-Derived Cell Therapy for Cancer

donors, stem cell-derived NK cells can be enhanced via multiple approaches


(Hermanson et al. 2016; Li et al. 2018). Promising modifications on NK cells,
validated through preclinical studies, encompass the incorporation of CARs, engi-
neering non-cleavable, high-affinity Fc receptors CD16 to optimize antibody-
dependent cellular cytotoxicity (ADCC), the introduction of IL-15 or IL-2 to aug-
ment NK cell persistence and cytotoxicity, as well as the blockade of inhibitory
receptors such as killer cell immunoglobulin-like receptor (KIR) or NKG2A (Cany
et al. 2015; Rezvani et al. 2017; Mehta and Rezvani 2018; Liu et al. 2018; Li et al.
2018; Zhu et al. 2020a).
Unlike conventional αβ T cells, innate-like T cells such as γδ T cells, invariant
natural killer T (iNKT) cells, and mucosal-associated invariant T (MAIT) cells
employ a distinct recognition mechanism. They identify target cells through a
combination of NK receptors and TCRs without binding to peptide-MHC
complexes, thereby reducing the risk of GvHD (Li et al. 2022a). Remarkably,
these unconventional T-cell populations can also be derived from iPSCs or HSCs
engineered with specific TCRs and exhibit effective cytotoxicity against multiple
myeloma, leukemia, and solid tumors (Wakao and Fujita 2013; Zhu et al. 2019;
Wakao 2020). This progress underscores the potential for additional genetic
modifications on innate-like T cells, such as CAR-iNKT cells or CAR-MAIT
cells, providing a foundation for future off-the-shelf cancer immunotherapy
initiatives (Dogan et al. 2022; Rowan et al. 2023). Besides, preclinical studies
have demonstrated the successful generation of other innate immune cell types
including DCs, macrophages, and myeloid cells from iPSCs (Hansen et al. 2018;
Horton et al. 2020; Zhang et al. 2020). These iPSC-derived innate immune cells are
highly immunostimulatory and therefore can be further modified to enhance cyto-
kine secretion, facilitate phagocytosis of target tumor cells, and develop into an
antitumor state (Horton et al. 2020; Zhang et al. 2020).

4 Mechanisms of Action

Stem cell-derived cell therapies have revolutionized cancer treatment by involving a


wide range of adaptive immune cells and innate immune cells as mentioned in the
previous section, each with unique mechanisms. In this section, major mechanisms
by which these therapies exert their anticancer effects, along with examples of
studies that demonstrate these mechanisms in action, will be elucidated.
Stem cell-derived conventional T cells are often armed with specific TCRs or
CARs designed to recognize corresponding antigens on tumor cell surfaces. When
these engineered stem cell-derived T cells are activated, either through CAR binding
to tumor surface antigens or TCR interaction with peptide-MHC complexes, intra-
cellular signaling pathways that trigger direct cytotoxicity are initiated (Eshhar et al.
1993; Jensen and Riddell 2015; Benmebarek et al. 2019). Consequently, these
activated engineered T cells release perforin and granzyme, launching an attack on
target cells. This process leads to rapid and highly specific T-cell-mediated lysis of
M. Wilson et al.

tumor cells, complemented by the activation of the Fas-FasL pathway, which


triggers apoptotic pathways in cancer cells (Kägi et al. 1994; Lowin et al. 1994).
Stem cell-derived NK cells mediate tumor cell killing via two pathways. Upon
interaction between NK cell activating receptors and stress-induced ligands on tumor
cell surface under hypoxia or DNA damage, NK cells initiate direct cell killing
through degranulation (Paul and Lal 2017; Zhou et al. 2022). Moreover, NK cells
can also initiate apoptosis of opsonized cells via Fc receptors through ADCC (Paul
and Lal 2017; Goldenson et al. 2020; Bagheri et al. 2021). It is noteworthy that
preclinical studies have confirmed the robust cytotoxicity exerted by iPSC-derived
NK cells against a wide range of hematologic and solid tumors and their compati-
bility with traditional T cell and immune checkpoint inhibitor therapies (Cichocki
et al. 2020). Multiple off-the-shelf iPSC-derived NK cell products, such as FT576,
that undergo clinical trials have also demonstrated superior cytotoxicity compared to
peripheral blood NK cells, alongside enhanced persistence (Zhou et al. 2022).
Stem cells also serve as an infinite and renewable source for innate-like T cells,
such as MR1-restricted MAIT cells, CD1d-restricted iNKT cells, and γδ T cells,
and their CAR-engineered counterparts. These cells, in addition to utilizing NK
activating receptors for direct cell killing, elicit cytotoxicity through their TCRs
independently of MHC molecules present on tumor cells (Beckman et al. 1994; Dias
et al. 2018). Given the capacity for macrophages to infiltrate solid tumors,
CAR-macrophages (CAR-Ms) have been generated to target both hematologic
malignancies and solid tumors, and iPSC-derived macrophages have further
enlarged the pool for stable and large-scale CAR-Ms production. Human anti-CD19-
and anti-HER2-CAR-Ms, generated by Klichinsky et al., display a pro-inflammatory
(M1) phenotype and accelerate the transition from pro-tumor M2 macrophages into
antitumor M1 macrophages when targeting myelogenous leukemia and ovarian
cancer respectively. They also play a critical role in recruiting and activating
cytotoxic T lymphocytes (CTL), thereby constructing a pro-inflammatory tumor
microenvironment (Klichinsky et al. 2020).
Playing a crucial tool in the initiation of immune responses, DC-based immuno-
therapy can also be enhanced by stem cells considering the extremely low number of
circulating DCs in human peripheral blood (<1.0%) (Oba et al. 2021). Oba et al.
stated that compared with bone marrow-derived DCs, iPSC-derived DCs express
similar levels of surface DC markers and possess comparable antigen-presenting
ability, and these DCs, in combination with traditional radiotherapy, can expedite the
sensitization of tumor-specific CD8+ T cells (Senju et al. 2003, 2009; Oba et al.
2021). Additionally, Cai et al. highlighted the contributions made by iPSC-derived
regulatory DCs (DCregs) with regard to immune modulation. These DCregs can
suppress allograft rejection by facilitating the maturation of alloantigen-specific
regulatory T cells, emphasizing their significance in immune regulation (Cai et al.
2017).
Bridging the innate and adaptive immune systems, iNKT cells have taken a
prominent position in cancer immunotherapy. Although the low quantity of iNKT
cells in human peripheral blood poses a challenge, their large-scale generation can be
augmented through HSCs or iPSCs (Zhu et al. 2019; Li et al. 2021c). Notably,
Stem Cell-Derived Cell Therapy for Cancer

Watarai et al. demonstrated that upon α-GalCer stimulation, iPSC-iNKT cells can
expand in number, facilitate DC maturation, and activate CTLs and NK cells by
releasing IFN-γ (Watarai et al. 2010). In addition to IFN-γ secreted by iPSC-iNKT,
other pro-inflammatory/antitumor cytokines may be supplemented with a diverse
array of stem cell-derived immune cells in cancer immunotherapy. Upon
TCR-dependent activation, γδ T cells possess the capacity to release abundant
pro-inflammatory cytokines including IL-2, IL-12, IL-15, and IL-18, therefore
improving rapid, direct cell killing (Kabelitz et al. 2020). Similarly, MAIT cells,
characterized by their high expression of pro-inflammatory cytokine receptors such
as IL-12R and IL-18R, reciprocally secrete antitumor cytokines including IFN-γ and
TNF-α, which can be further complemented by stem cell-derived MAIT cells (Petley
et al. 2021). Moreover, stem cell-derived immune cells can be genetically modified
to express antitumor cytokines. For instance, Mizuhashi et al. reported that mouse
iPSC-derived proliferating MCs (iPSC-pMCs), genetically engineered to produce
IL-15 and IL-15/Rα, can augment the NK-mediated cytotoxicity in mice, improving
the treatment for mouse melanoma with major histocompatibility complex (MHC)
class I loss (Mizuhashi et al. 2021).

5 Engineering Approaches

Through a multitude of approaches to genetic engineering, the therapeutic persis-


tence, anticancer homing, and tumor-killing efficacy of stem-cell-derived immuno-
therapy are open to further enhancement. The earliest methods of gene editing,
including zinc-finger nucleases (ZFNs) and transcription activation-like effector
nucleases (TALENs), have largely fallen out of favor in lieu of CRISPR-Cas9
mediated editing on account of its greater editing versatility, site specificity, and
reduced off-target binding (Ding et al. 2013; Wright et al. 2014; Ul Ain et al. 2015;
Lanigan et al. 2020; Boti et al. 2023). Editing of the genome alone can enhance
therapeutic cell efficacy and longevity through site-specific knockouts of TCR genes
(e.g., TRAC and TRBC) (Morton et al. 2020; Kagoya et al. 2020; Zhang et al. 2022a;
Ottaviano et al. 2022; Lamothe et al. 2023) to avoid onset of graft vs. host disease
(GvHD) in conventional αβ T-cell therapy, MHC-class genes (e.g., B2M and CIITA)
to reduce host allorejection (Liu and Zhao 2018; Kagoya et al. 2020; Naeem et al.
2023) and immune checkpoint genes (e.g., PD-1, CTLA-4, LAG-3, TIM3)
regulating activation state (Rupp et al. 2017; Dötsch et al. 2023; Zhu et al. 2020b;
Beane et al. 2015; Agarwal et al. 2023; Shi et al. 2017; Zhang et al. 2017). During the
early stages of stem cell culture, engineered expression of transcription factors
driving lineage differentiation may be incorporated to further enhance immune cell
maturity and purity (Ng et al. 2021). Within the clinic, CRISPR-Cas9 modifications
have demonstrated a safe platform for the implementation of a universal, allogeneic
CD19-CAR T-cell therapy that could help reduce individual patient costs following
the current autologous model (Hu et al. 2021; Ottaviano et al. 2022).
In cancer immunotherapy, one of the most well-established methods of enhancing
tumor recognition is through engineered expression of tumor-specific CARs
M. Wilson et al.

recognizing cancer antigens. Expression of synthetic CARs has been most-


extensively adopted and implemented in conventional αβ T cells, with 6 treatments
utilizing CD19- or BCMA-targeting CARs having been FDA-approved for the
treatment of B-cell lymphoma and multiple myeloma (Shohdy et al. 2023; Gordon
et al. 2023; Dhaliwal and Ravi 2023; Awasthi et al. 2023). Currently, broad
applications for CAR-based therapies are being explored against different cancers:
the viability of alternative CAR antigens, such as mesothelin (MSLN) (Ding et al.
2023; Zhu et al. 2023; Yang et al. 2023a), glypican-3 (GPC3) (Shi et al. 2020; Sun
et al. 2022a, b), and CD70 (Sauer et al. 2021; Panowski et al. 2022) for respective
treatment of ovarian cancer, hepatocellular carcinoma, and acute myeloid leukemia
(AML). Furthermore, the potency of arming other immune cells is currently being
explored in innate immune cell types to produce CAR-Ms (Zhang et al. 2020; Chen
et al. 2023; Duan et al. 2023) and CAR-NK cells (Golubovskaya et al. 2023; Yang
et al. 2023a) displaying potent antitumor targeting as well as adjuvant stimulation of
endogenous immune cells. The benefits of both innate and adaptive immune recog-
nition pathways may be harnessed through CAR-engineering of unconventional
innate-like iNKT and MAIT cells for the production of CAR-iNKT and
CAR-MAIT cell therapy. Our group has particularly explored the potential of
allogeneic CAR-iNKT cell therapy on account of their tripartite recognition of
tumor cells and immunosuppressive cells through the CAR domain, lineage-
restricted invariant TCR, and activating NK markers (Zhu et al. 2019; Li et al.
2022b). As an alternative to CAR-T cell therapy, the aforementioned cell types do
not engage with classic MHC-I and MHC-II markers, providing an ideal allogeneic
alternative to traditional CAR-T cell therapy without the risk of inducing GvHD
(Li et al. 2022b; Sadowski et al. 2022). While limited preclinical success has been
observed for non-T cell-based cancer immunotherapies, there still remains a need to
verify safety and success within the clinic.
The engineering of autonomous cytokine expression has also demonstrated the
potential to significantly enhance the efficacy and persistence of therapeutic cells
administered to patients, including IL-15, IL-2, IL-12, and IL-18 (Yeku and
Brentjens 2016). Secretion of IL-15 in particular is vital for supporting NK and
innate-like T cells, enhancing antitumor targeting and in vivo persistence (Liu et al.
2018; Makkouk et al. 2021; Ruixin et al. 2023; Bodden et al. 2023). Furthermore,
IL-15 secretion could potentially aid in the remediation of the tumor environment
through the reprogramming of immunosuppressive cells (Zannikou et al. 2023).
Similar effects have also been observed in vivo on account of recombinant secretion
of IL-2 and IL-12 to enhance CAR-T cell infiltration and proliferation, though they
have been explored to a lesser degree (Becknell and Caligiuri 2005; Yang et al.
2023b; Fang et al. 2023). Recent advances in CAR engineering have seen the
incorporation of such genes encoding IL-2 or IL-15 within the CAR construct itself,
providing continuous cytokine support (Liu et al. 2018). Cytokine stimulation has
been implemented in various forms, including secretion of either soluble or
membrane-bound cytokines or downstream activation (Allen et al. 2021;
Christodoulou et al. 2021).
Stem Cell-Derived Cell Therapy for Cancer

6 Preclinical and Clinical Manufacturing

Within the field of cancer treatment, cell-based therapeutics hold great potential, but
are limited by several factors, including high variability, protracted manufacturing,
high sensitivity and low stability, and product heterogeneity (Taefehshokr et al.
2022; Blache et al. 2022). Stringent GMP regulations may abate variability between
batches of cell products by standardizing cell characterization, including testing of
yield, purity, and tumorigenicity (Bedford et al. 2018). Additionally, external aspects
to the manufacturing process itself may impact efficacy in the clinic, including stem
cell origin, administration route, dosing, and combination with other products, to
name a few.
The preclinical applications of these cell products have yielded promising results in
the treatment of a wide range of cancers across various models. Among the most well-
explored preclinically are DCs produced from stem cells as a vaccine to stimulate an
immune response through cancer antigen presentation. Engineering can further facili-
tate DC enhancement either through self-expression of target cancer antigens or
overexpression of presenting molecules (i.e., MHC-I and II, CD1d, MR1, etc.) to
promote stimulation of endogenous lymphocytes (Zeng et al. 2012; Tominaga et al.
2023). Regarding cytotoxic cell types, NK and T cells have been the most extensively
stem cell-derived therapeutic cells. Belonging to opposite arms of innate and adaptive
immunity, both employ unique recognition and killing pathways that may be homed to
tumor cells using CAR engineering (Huang et al. 2022; Klaihmon et al. 2023).
Through innate-like T cells, which simultaneously express NK activating markers
and a lineage-specific TCR, the antitumor potential of both cell types may be
synergized within a single model. In our hands, we have developed a malleable
platform for engineering CAR-iNKT cells against a variety of tumor-specific antigens,
showing strong suppression of cancer growth with limited GvHD onset in mice
(Li et al. 2021c, 2022b). The potency of innate-like T cells has yet to be fully explored
in the preclinical setting, providing potential opportunities to expand upon the
established success of CAR-T cell therapy. Although therapies encompassing other
unconventional T cells, such as MAIT and γδ T cells, have not yet broken through to
clinical trials, they still show great promise within the preclinical setting (Wakao et al.
2013; Watanabe et al. 2018; Zeng et al. 2019). Through a stem cell-based platform,
rare immune cell subtypes such as these may be more easily generated for stockpiling
of “off-the-shelf” therapeutic doses for cancer patients.
Expanding on this preclinical success, several clinical trials have been established
to examine the safety and potency of stem cell-based therapies in cancer patients
(Table 1). While the majority of these studies are still recruiting or remain ongoing,
those that have concluded have shown promising results for patient remission. In
particular, Fate Therapeutics has established several therapeutic CAR-NK cell
products derived from a human clonal master iPSC line, providing both a highly
malleable and controlled platform for generating therapeutic cells. FT500, their
earliest CAR-NK cell product, has demonstrated strong preclinical potency,
engaging in innate cytotoxicity, producing adjuvant stimulation of endogenous
T cells, and augmenting the efficacy of anti-PD-1 combination therapy (Cichocki
Table 1 Current stem cell-derived cell therapies in preclinical or clinical trials
Clinical trial
Cell therapy Phase identifier Description Results
NK Clinical NCT05182073 FT576 in Subjects with Multiple Myeloma Phase I: Recruiting
NCT05336409 CNTY-101 in Participants with CD19+ B-Cell Phase I: Recruiting
Malignancies
NCT04630769 FT516 and IL2 with Enoblituzumab for Ovarian Phase I: Completed—Limited adverse systemic
NCT04551885 Cancer; effects reported in all individuals;
NCT04023071 Solid Tumors; Phase I: Active;
Hematologic Malignancies Phase I: Active
NCT05950334 FT522 With Rituximab in Relapsed B-Cell Phase I: Not Yet Recruiting
Lymphoma
NCT05069935; FT538 in Combination with mAb in Advanced Phase I: Active;
NCT04714372; Solid Tumors; Phase I: Recruiting;
NCT04614636; Acute Myeloid Leukemia; Phase I: Active;
NCT05708924 Advanced Hematologic Malignancies; Phase I: Recruiting
Recurrent Ovarian, Fallopian Tube, Primary
Peritoneal Cancer
NCT05395052 FT536 Monotherapy and Combination with mAb Phase I: Active
in Advanced Solid Tumors
NCT04245722; FT596 as Monotherapy and Combination with anti- Phase I: Active;
NCT04555811 CD20 mAb; Phase I: Active
Combination with Rituximab for Relapse
Prevention in Non-Hodgkin Lymphoma
NCT03841110; FT500 as Monotherapy and Combination with Phase I: Results not yet reported;
NCT04106167 Immune Checkpoint Inhibitors in Solid Tumor; Ongoing
Long-term, Observational Study Post-Treatment
Preclinical iPSC-CD19CAR NK cells show selective targeting of CD19+ hematologic cancers in vitro and elevated NK activation marker
levels post-exposure (Klaihmon et al. 2023; Chang et al. 2023)
iPSC-MCAR NK cells display enhanced cytotoxicity against solid TNBC in vitro and in vivo (Yang et al. 2023a)
M. Wilson et al.
DC Clinical Not Available Therapeutic DC Vaccination with IL-2 as Phase I/II Trial: Autologous HSC-derived DCs
Consolidation Therapy for Ovarian Cancer Patients secrete IL-12, reduce inhibitory CD4+CD25+
T cell subsets, and enhance proportion of CD8+
IFNγ-secreting T cells (Baek et al. 2011)
Preclinical Embryoid bodies form mixed CD11c+ DC populations, which can be enriched for cross-presentation specialized CD141+ DCs
through CD1c+ depletion (Sachamitr et al. 2017)
iPSCs (Horton et al. 2020; Oba et al. 2021; Tominaga et al. 2023), ESCs (Zeng et al. 2012), and CBSCs (Chang et al. 2012) are
viable input for generation of stem-cell-derived DCs, which show strong adjuvant stimulation and cytokine profile
Adjuvant effects can be further enhanced through genetic engineering of tumor antigens expression (e.g., MSLN) (Tominaga
et al. 2023) or overexpression of antigen-presenting markers (e.g., CD1d) (Zeng et al. 2012)
Macrophage Preclinical iPSC-macrophages show proper function and polarization compared to primary macrophages (Gutbier et al. 2020)
iPSC-CD19CAR macrophages display durable suppression of K562 leukemia cells in vitro and in vivo (Zhang et al. 2020)
T Clinical NCT04629729 FT819 in Subjects with B-Cell Malignancies Phase I: Recruiting
Stem Cell-Derived Cell Therapy for Cancer

Preclinical iPSC-T cells display normal differentiation into single-positive lineages (Nishimura and Nakauchi 2019; Iriguchi et al. 2021)
CD8 αβ T cells demonstrate transient ability to suppress H226 hepatocarcinoma growth in vitro and in vivo (Iriguchi et al. 2021)
Anti-EGFRvIII iPSC-CAR T cells demonstrate extravasation across the blood-brain barrier and significantly reduce within
GBM burden in vitro (Huang et al. 2022)
iNKT Clinical jRCT2033200116 Phase I Study of iPS-NKT in Patients with Phase I: Ongoing
Recurrent or Advanced Head and Neck Cancer
Preclinical iPSC-NKT cells display adjuvant effects for endogenous DCs and NK cells (Kitayama et al. 2016; Yamada et al. 2016; Aoki
et al. 2023)
IL-15 stimulation drives phenotypic maturity of iPSC-NKT cells, with Th1-like phenotype bias, that show tumor cell killing
in vitro (Kitayama et al. 2016) and in vivo (Yamada et al. 2016)
MAIT Preclinical iPSC-MAIT cells exhibit appropriate lineage-specific TCR, appropriate chemokine and cytokine response profiles in vitro, and
population of bone marrow, liver, spleen niches in NSG mice (Wakao et al. 2013)
γδ T Preclinical iPSC-derived γδ T cells can be produced from whole blood PBMC input (Watanabe et al. 2018)
Mimetic CD19CAR γδ T cells, expressing Vγ9Vδ2TCR and high level of NK markers, but no/low phenotypic γδ markers,
show broad in vitro tumor killing (Zeng et al. 2019)
M. Wilson et al.

et al. 2020). Within human patients, FT500 administered in weekly doses, both as
monotherapy and in concert with immune checkpoint blockade, has shown tumor
suppression in patients resistant to blockade therapy alone, with limited adverse
reactions (Hong et al. 2020). Furthermore, more elaborately engineered products
such as FT516, a CAR-NK cell line expressing non-cleavable CD16 for enhanced
antibody-dependent cellular cytotoxicity, has shown similar success for combination
therapy against liquid and solid tumors (Strati et al. 2021). These trials underscore
the preliminary efficacy of such therapies against a broad range of cancers, particu-
larly as a course of therapy for patients resistant to first-line interventions. As clinical
trials continue to establish the efficacy of stem cell-derived lymphocytes, the foun-
dation for introducing such therapies into clinical practice draws nearer to becoming
a reality.

7 Challenges and Future Directions

Despite the success achieved through the current autologous model of CAR-T cell
therapy, its clinical utility is limited by its lack of efficacy against solid tumors,
limited scalability for multiple patients, and financial burden placed on cancer
patients. The development of an “off-the-shelf” therapy will reduce the weight of
these expenses by circumventing the need to develop a tailored immunotherapy for
each patient receiving therapy. While other immune cell subtypes, including NK
cells and innate-like T cells, avoid onset of GvHD on account of their intrinsic
recognition mechanisms, necessary steps in isolation, expansion, and genetic engi-
neering present a challenge to maximizing cell product yield. Especially for innate-
like T cells, which represent an extremely low proportion of lymphocytes in
peripheral blood, producing a sufficient number of cells for multiple doses precludes
direct harvest as a cost-effective method.
These barriers to development can be overcome through stem-cell engineering,
which provides a highly scalable and malleable platform that can produce cell
products with limited heterogeneity. The scalability of NK, iNKT, MAIT, and γδ
T cell-based therapies derive from their MHC-independent recognition of tumor
cells, abrogating the onset of GvHD. Among potential sources for stem cell engi-
neering, currently the greatest interest lies in iPSCs due to ease of collection of more
common, terminally differentiated cells for reprogramming. Selecting a lineage
closely related to the desired iPSC-derived lymphocyte can help mitigate functional
variability arising from epigenetic modifications associated with the origin cell type
for iPSCs (Polo et al. 2010; Zhou et al. 2022). Additional variation may arise from
differences in manufacturing protocol, even among products of the same cell
subtype. Additionally, it is necessary to further explore the mechanisms underlying
stem-cell-based therapies. It remains unclear whether there are any discrepancies
between the maturity and cytotoxic capacity of stem cell-derived products versus
their endogenous counterparts. The extensive stem cell manufacturing and engineer-
ing process itself may also lend to differences in therapeutic potency. It is also yet to
be determined if there are any long-term implications associated with the adminis-
tration of stem cell-derived products to patients.
Stem Cell-Derived Cell Therapy for Cancer

Although more comprehensive analysis of stem cell-based therapies is necessary to


fully understand their capabilities, it is undeniable that the platform has already
achieved significant successes in both preclinical and clinical settings. Particularly in
combination with immune checkpoint blockade, these products may provide a durable
alternative for cancer immunotherapy enabling treatment of resistant cancers. As
further advancements in cell engineering continue to progress and become integrated
into the workflow of the stem cell platform, it holds the promise of producing more
ambitious and efficacious cell products for cancer immunotherapy.

8 Discussion

Stem cells, including MSCs, HSCs, ESCs, and iPSCs, represent compelling
candidates for cancer immunotherapy. The current body of research and early-stage
clinical trials provide substantiated evidence supporting the feasibility of engineered
stem cells as a means to generate potent effector cells and bolster antitumor immune
responses for the eradication of cancer. Stem cell engineering and differentiation
confer not only an inexhaustible supply of therapeutic cellular products but also
establish a versatile and adaptable platform for further modifications aimed at enhanc-
ing the antitumor efficacy of resultant cellular products.
The realization of whether stem cell-engineered approaches manifest additional
efficacy in comparison to those employing mature human periphery blood mononu-
clear cell (PBMC)-derived immune cells as therapeutic targets hinges upon clinical
trials. It is conceivable that the two approaches may, in some instances, complement
each other. Ongoing development of clinical trials is poised to provide preliminary
insights.
Given the intricate nature of diseases like cancer, it is probable that the attainment
of enduring therapeutic benefits will necessitate combination therapies. Engineered
stem cell products, characterized by their “off-the-shelf” availability, hold promise
as constituents of treatment regimens that encompass established cancer therapies,
such as surgery, radiation, chemotherapy, and targeted interventions, as well as
emerging cancer immunotherapies, including immune checkpoint inhibitors,
oncolytic viruses, cancer vaccines, and adoptive cellular therapies (Depil et al.
2020; Li et al. 2021a). The adaptability of engineered stem cell products, their
suitability for customization, and scalability to cater to specific cancer types render
them a promising addition to the oncological arsenal, poised to enhance treatment
outcomes and ameliorate patients’ quality of life (Li et al. 2023). As the field
continues to evolve, a methodical and prudent approach is imperative to ensure the
safe and efficient translation of stem cell-based therapies into clinical settings.

Acknowledgments We thank Dr. Lili Yang from the University of California, Los Angeles
(UCLA) for her insightful discussion. Y.-R.L. is supported by a UCLA MIMG M. John Pickett
Post-Doctoral Fellow Award, and a CIRM-BSCRC Postdoctoral Fellowship.

Declaration of Interests The authors declare no competing interests.


M. Wilson et al.

References
Abel AM, Yang C, Thakar MS, Malarkannan S (2018) Natural killer cells: development, matura-
tion, and clinical utilization. Front Immunol 9:1869
Agarwal S, Aznar MA, Rech AJ et al (2023) Deletion of the inhibitory co-receptor CTLA4
enhances and invigorates chimeric antigen receptor T cells. Immunity S1074-7613(23):
00407–00407. https://doi.org/10.1016/j.immuni.2023.09.001
Allen AG, Pattali R, Izzo KM et al (2021) A bicistronic vector expressing CD16 and a membrane
bound IL-15 construct in iPSC derived NK cells increased cytotoxicity and persistence. Blood
138:4809. https://doi.org/10.1182/blood-2021-153258
Aoki T, Motohashi S, Koseki H (2023) Regeneration of invariant natural killer T (iNKT) cells:
application of iPSC technology for iNKT cell-targeted tumor immunotherapy. Inflamm Regen
43:27. https://doi.org/10.1186/s41232-023-00275-5
Awasthi R, Maier HJ, Zhang J, Lim S (2023) Kymriah® (tisagenlecleucel)—an overview of the
clinical development journey of the first approved CAR-T therapy. Hum Vaccines Immunother
19:2210046. https://doi.org/10.1080/21645515.2023.2210046
Baek S, Kim C-S, Kim S-B et al (2011) Combination therapy of renal cell carcinoma or breast
cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial. J Transl Med
9:178. https://doi.org/10.1186/1479-5876-9-178
Bagheri Y, Barati A, Aghebati-Maleki A et al (2021) Current progress in cancer immunotherapy
based on natural killer cells. Cell Biol Int 45:2–17. https://doi.org/10.1002/cbin.11465
Beane JD, Lee G, Zheng Z et al (2015) Clinical scale zinc finger nuclease-mediated gene editing of
PD-1 in tumor infiltrating lymphocytes for the treatment of metastatic melanoma. Mol Ther J
Am Soc Gene Ther 23:1380–1390. https://doi.org/10.1038/mt.2015.71
Beckman EM, Porcelli SA, Morita CT et al (1994) Recognition of a lipid antigen by CD1-restricted
αβ+ T cells. Nature 372:691–694. https://doi.org/10.1038/372691a0
Becknell B, Caligiuri MA (2005) Interleukin-2, interleukin-15, and their roles in human natural
killer cells. Adv Immunol 86:209–239. https://doi.org/10.1016/S0065-2776(04)86006-1
Bedford P, Jy J, Collins L, Keizer S (2018) Considering cell therapy product “good manufacturing
practice” status. Front Med 5:118. https://doi.org/10.3389/fmed.2018.00118
Benmebarek M-R, Karches CH, Cadilha BL et al (2019) Killing mechanisms of chimeric antigen
receptor (CAR) T cells. Int J Mol Sci 20:1283. https://doi.org/10.3390/ijms20061283
Blache U, Popp G, Dünkel A et al (2022) Potential solutions for manufacture of CAR T cells in
cancer immunotherapy. Nat Commun 13:5225. https://doi.org/10.1038/s41467-022-32866-0
Bodden M, Häcker A, Röder J et al (2023) Co-expression of an IL-15 superagonist facilitates self-
enrichment of GD2-Targeted CAR-NK cells and mediates potent cell killing in the absence of
IL-2. Cancer 15:4310. https://doi.org/10.3390/cancers15174310
Boti MA, Athanasopoulou K, Adamopoulos PG et al (2023) Recent advances in genome-
engineering strategies. Genes 14:129. https://doi.org/10.3390/genes14010129
Cai S, Hou J, Fujino M et al (2017) iPSC-derived regulatory dendritic cells inhibit allograft rejection
by generating alloantigen-specific regulatory T cells. Stem Cell Rep 8:1174–1189. https://doi.
org/10.1016/j.stemcr.2017.03.020
Cany J, van der Waart AB, Spanholtz J et al (2015) Combined IL-15 and IL-12 drives the
generation of CD34+-derived natural killer cells with superior maturation and alloreactivity
potential following adoptive transfer. Onco Targets Ther 4:e1017701. https://doi.org/10.1080/
2162402X.2015.1017701
Chang M-C, Lee C-N, Chen Y-L et al (2012) Cord blood stem-cell-derived dendritic cells generate
potent antigen-specific immune responses and anti-tumour effects. Clin Sci Lond Engl 1979
123:347–360. https://doi.org/10.1042/CS20110272
Chang Y, Jin G, Luo W et al (2023) Engineered human pluripotent stem cell-derived natural killer
cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy.
Bioact Mater 27:168–180. https://doi.org/10.1016/j.bioactmat.2023.03.018
Stem Cell-Derived Cell Therapy for Cancer

Chen Y, Zhu X, Liu H et al (2023) The application of HER2 and CD47 CAR-macrophage in
ovarian cancer. J Transl Med 21:654. https://doi.org/10.1186/s12967-023-04479-8
Christodoulou I, Koldobskiy M, Ho WJ et al (2021) Engineered interleukin-15 autocrine signaling
invigorates anti-CD123 CAR-NK cells. Blood 138:2806. https://doi.org/10.1182/blood-
2021-146609
Cichocki F, Bjordahl R, Gaidarova S et al (2020) iPSC-derived NK cells maintain high cytotoxicity
and enhance in vivo tumor control in concert with T cells and anti–PD-1 therapy. Sci Transl
Med 12:eaaz5618. https://doi.org/10.1126/scitranslmed.aaz5618
D’Agostino M, Raje N (2020) Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do
better? Leukemia 34:21–34. https://doi.org/10.1038/s41375-019-0669-4
Datta J, Dai X, Bianchi A et al (2022) Combined MEK and STAT3 inhibition uncovers stromal
plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like
features to overcome immunotherapy resistance in pancreatic cancer. Gastroenterology 163:
1593–1612. https://doi.org/10.1053/j.gastro.2022.07.076
Depil S, Duchateau P, Grupp SA et al (2020) “Off-the-shelf” allogeneic CAR T cells: development
and challenges. Nat Rev Drug Discov 19:185–199. https://doi.org/10.1038/s41573-019-0051-2
Dhaliwal A, Ravi S (2023) Myelodysplastic syndrome after anti-CD19 chimeric antigen receptor
T-cell therapy: a case series. Cureus 15:e44677. https://doi.org/10.7759/cureus.44677
Dias J, Boulouis C, Gorin J-B et al (2018) The CD4-CD8- MAIT cell subpopulation is a
functionally distinct subset developmentally related to the main CD8+ MAIT cell pool. Proc
Natl Acad Sci 115:E11513–E11522. https://doi.org/10.1073/pnas.1812273115
Ding Q, Regan SN, Xia Y et al (2013) Enhanced efficiency of human pluripotent stem cell genome
editing through replacing TALENs with CRISPRs. Cell Stem Cell 12:393–394. https://doi.org/
10.1016/j.stem.2013.03.006
Ding J, Guyette S, Schrand B et al (2023) Mesothelin-targeting T cells bearing a novel T cell
receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors. Onco
Targets Ther 12:2182058. https://doi.org/10.1080/2162402X.2023.2182058
Dogan M, Karhan E, Kozhaya L et al (2022) Engineering human MAIT cells with chimeric antigen
receptors for cancer immunotherapy. J Immunol 209:1523–1531. https://doi.org/10.4049/
jimmunol.2100856
Dötsch S, Svec M, Schober K et al (2023) Long-term persistence and functionality of adoptively
transferred antigen-specific T cells with genetically ablated PD-1 expression. Proc Natl Acad Sci
U S A 120:e2200626120. https://doi.org/10.1073/pnas.2200626120
Duan Z, Li Z, Wang Z et al (2023) Chimeric antigen receptor macrophages activated through TLR4
or IFN-γ receptors suppress breast cancer growth by targeting VEGFR2. Cancer Immunol
Immunother 72:3243–3257. https://doi.org/10.1007/s00262-023-03490-8
Eshhar Z, Waks T, Gross G, Schindler DG (1993) Specific activation and targeting of cytotoxic
lymphocytes through chimeric single chains consisting of antibody-binding domains and the
gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci 90:
720–724. https://doi.org/10.1073/pnas.90.2.720
Euchner J, Sprissler J, Cathomen T et al (2021) Natural killer cells generated from human induced
pluripotent stem cells mature to CD56(bright)CD16(+)NKp80(+/-) in-vitro and express
KIR2DL2/DL3 and KIR3DL1. Front Immunol 12:640672. https://doi.org/10.3389/fimmu.
2021.640672
Fang F, Xiao W, Tian Z (2017) NK cell-based immunotherapy for cancer. Semin Immunol 31:37–
54. https://doi.org/10.1016/j.smim.2017.07.009
Fang L, Yuan S, Wang M et al (2023) Recombinant oncolytic adenovirus armed with CCL5, IL-12,
and IFN-γ promotes CAR-T infiltration and proliferation in vivo to eradicate local and distal
tumors. Cell Death Dis 9:328. https://doi.org/10.1038/s41420-023-01626-4
Frank C, Ryan B, Svetlana G et al (2020) iPSC-derived NK cells maintain high cytotoxicity and
enhance in vivo tumor control in concert with T cells and anti–PD-1 therapy. Sci Transl Med 12:
eaaz5618. https://doi.org/10.1126/scitranslmed.aaz5618
M. Wilson et al.

Gerew A, Sexton S, Wasko KM et al (2021) Deletion of CISH and TGFβR2 in iPSC-derived NK


cells promotes high cytotoxicity and enhances in vivo tumor killing. Blood 138:2780. https://
doi.org/10.1182/blood-2021-150731
Goldenson BH, Zhu H, Wang YM et al (2020) Umbilical cord blood and iPSC-derived natural killer
cells demonstrate key differences in cytotoxic activity and KIR profiles. Front Immunol 11
Golubovskaya V, Sienkiewicz J, Sun J et al (2023) CAR-NK cells generated with mRNA-LNPs kill
tumor target cells in vitro and in vivo. Int J Mol Sci 24:13364. https://doi.org/10.3390/
ijms241713364
Gordon LI, Liu FF, Braverman J et al (2023) Lisocabtagene maraleucel for second-line relapsed or
refractory large B-cell lymphoma: patient-reported outcomes from the PILOT study.
Haematologica. https://doi.org/10.3324/haematol.2023.283162
Gschweng E, De Oliveira S, Kohn DB (2014) Hematopoietic stem cells for cancer immunotherapy.
Immunol Rev 257:237–249. https://doi.org/10.1111/imr.12128
Gutbier S, Wanke F, Dahm N et al (2020) Large-scale production of human iPSC-derived
macrophages for drug screening. Int J Mol Sci 21:4808. https://doi.org/10.3390/ijms21134808
Hansen M, Varga E, Aarts C et al (2018) Efficient production of erythroid, megakaryocytic and
myeloid cells, using single cell-derived iPSC colony differentiation. Stem Cell Res 29:232–244.
https://doi.org/10.1016/j.scr.2018.04.016
Hermanson DL, Bendzick L, Pribyl L et al (2016) Induced pluripotent stem cell-derived natural
killer cells for treatment of ovarian cancer. Stem Cells 34:93–101. https://doi.org/10.1002/stem.
2230
Hmadcha A, Martin-Montalvo A, Gauthier BR et al (2020) Therapeutic potential of mesenchymal
stem cells for cancer therapy. Front Bioeng Biotechnol 8:43. https://doi.org/10.3389/fbioe.2020.
00043
Hochedlinger K, Jaenisch R (2003) Nuclear transplantation, embryonic stem cells, and the potential
for cell therapy. N Engl J Med 349:275–286. https://doi.org/10.1056/NEJMra035397
Hong D, Patel S, Patel M et al (2020) 380 Preliminary results of an ongoing phase I trial of FT500, a
first-in-class, off-the-shelf, induced pluripotent stem cell (iPSC) derived natural killer (NK) cell
therapy in advanced solid tumors. J Immunother Cancer 8. https://doi.org/10.1136/jitc-2020-
SITC2020.0380
Horton C, Davies TJ, Lahiri P et al (2020) Induced pluripotent stem cells reprogrammed from
primary dendritic cells provide an abundant source of immunostimulatory dendritic cells for use
in immunotherapy. Stem Cells Dayt Ohio 38:67–79. https://doi.org/10.1002/stem.3095
Hu Y, Zhou Y, Zhang M et al (2021) CRISPR/Cas9-engineered universal CD19/CD22 dual-
targeted CAR-T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Clin
Cancer Res 27:2764–2772. https://doi.org/10.1158/1078-0432.CCR-20-3863
Huang J, Li YB, Charlebois C et al (2022) Application of blood brain barrier models in pre-clinical
assessment of glioblastoma-targeting CAR-T based immunotherapies. Fluids Barriers CNS 19:
38. https://doi.org/10.1186/s12987-022-00342-y
Iltis AS, Koster G, Reeves E, Matthews KRW (2023) Ethical, legal, regulatory, and policy issues
concerning embryoids: a systematic review of the literature. Stem Cell Res Ther 14:209. https://
doi.org/10.1186/s13287-023-03448-8
Iriguchi S, Yasui Y, Kawai Y et al (2021) A clinically applicable and scalable method to regenerate
T-cells from iPSCs for off-the-shelf T-cell immunotherapy. Nat Commun 12:430. https://doi.
org/10.1038/s41467-020-20658-3
Jensen MC, Riddell SR (2015) Designing chimeric antigen receptors to effectively and safely target
tumors. Curr Opin Immunol 33:9–15. https://doi.org/10.1016/j.coi.2015.01.002
Kabelitz D, Serrano R, Kouakanou L et al (2020) Cancer immunotherapy with γδ T cells: many
paths ahead of us. Cell Mol Immunol 17:925–939. https://doi.org/10.1038/s41423-020-0504-x
Kägi D, Vignaux F, Ledermann B et al (1994) Fas and perforin pathways as major mechanisms of
T cell-mediated cytotoxicity. Science 265:528–530. https://doi.org/10.1126/science.7518614
Stem Cell-Derived Cell Therapy for Cancer

Kagoya Y, Guo T, Yeung B et al (2020) Genetic ablation of HLA class I, class II, and the T-cell
receptor enables allogeneic T cells to be used for adoptive T-cell therapy. Cancer Immunol Res
8:926–936. https://doi.org/10.1158/2326-6066.CIR-18-0508
Kitayama S, Zhang R, Liu T-Y et al (2016) Cellular adjuvant properties, direct cytotoxicity of
re-differentiated Vα24 invariant NKT-like cells from human induced pluripotent stem cells.
Stem Cell Rep 6:213–227. https://doi.org/10.1016/j.stemcr.2016.01.005
Klaihmon P, Kang X, Issaragrisil S, Luanpitpong S (2023) Generation and functional characteriza-
tion of anti-CD19 chimeric antigen receptor-natural killer cells from human induced pluripotent
stem cells. Int J Mol Sci 24:10508. https://doi.org/10.3390/ijms241310508
Klichinsky M, Ruella M, Shestova O et al (2020) Human chimeric antigen receptor macrophages
for cancer immunotherapy. Nat Biotechnol 38:947–953. https://doi.org/10.1038/s41587-020-
0462-y
Lamothe RC, Storlie MD, Espinosa DA et al (2023) Novel CRISPR-associated gene-editing
systems discovered in metagenomic samples enable efficient and specific genome engineering.
CRISPR J 6:243–260. https://doi.org/10.1089/crispr.2022.0089
Lanigan TM, Kopera HC, Saunders TL (2020) Principles of genetic engineering. Genes 11:291.
https://doi.org/10.3390/genes11030291
Li Y, Hermanson DL, Moriarity BS, Kaufman DS (2018) Human iPSC-derived natural killer cells
engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23:181–
192.e5. https://doi.org/10.1016/j.stem.2018.06.002
Li Y-R, Dunn ZS, Zhou Y et al (2021a) Development of stem cell-derived immune cells for off-the-
shelf cancer immunotherapies. Cell 10. https://doi.org/10.3390/cells10123497
Li Y-R, Zhou Y, Kim YJ et al (2021b) Development of allogeneic HSC-engineered iNKT cells for
off-the-shelf cancer immunotherapy. Cell Rep Med 2:100449. https://doi.org/10.1016/j.xcrm.
2021.100449
Li Y-R, Zhou Y, Kramer A, Yang L (2021c) Engineering stem cells for cancer immunotherapy.
Trends Cancer. https://doi.org/10.1016/j.trecan.2021.08.004
Li Y-R, Dunn ZS, Garcia G et al (2022a) Development of off-the-shelf hematopoietic stem cell-
engineered invariant natural killer T cells for COVID-19 therapeutic intervention. Stem Cell Res
Ther 13:112. https://doi.org/10.1186/s13287-022-02787-2
Li Y-R, Zeng S, Dunn ZS et al (2022b) Off-the-shelf third-party HSC-engineered iNKT cells for
ameliorating GvHD while preserving GvL effect in the treatment of blood cancers. iScience 25:
104859. https://doi.org/10.1016/j.isci.2022.104859
Li Y-R, Dunn ZS, Yu Y et al (2023) Advancing cell-based cancer immunotherapy through stem cell
engineering. Cell Stem Cell. https://doi.org/10.1016/j.stem.2023.02.009
Liu X, Zhao Y (2018) CRISPR/Cas9 genome editing: fueling the revolution in cancer immunother-
apy. Curr Res Transl Med 66:39–42. https://doi.org/10.1016/j.retram.2018.04.003
Liu E, Tong Y, Dotti G et al (2018) Cord blood NK cells engineered to express IL-15 and a CD19-
targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32:520–531.
https://doi.org/10.1038/leu.2017.226
Lowin B, Hahne M, Mattmann C, Tschopp J (1994) Cytolytic T-cell cytotoxicity is mediated
through perforin and Fas lytic pathways. Nature 370:650–652. https://doi.org/10.1038/
370650a0
Makkouk A, Yang XC, Barca T et al (2021) Off-the-shelf Vδ1 gamma delta T cells engineered with
glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust
antitumor efficacy against hepatocellular carcinoma. J Immunother Cancer 9:e003441. https://
doi.org/10.1136/jitc-2021-003441
Mehta RS, Rezvani K (2018) Chimeric antigen receptor expressing natural killer cells for the
immunotherapy of cancer. Front Immunol 9
Mishra PJ, Mishra PJ, Glod JW, Banerjee D (2009) Mesenchymal stem cells: flip side of the coin.
Cancer Res 69:1255–1258. https://doi.org/10.1158/0008-5472.CAN-08-3562
M. Wilson et al.

Mizuhashi S, Kubo Y, Fukushima S et al (2021) Immune cell therapy against disseminated


melanoma by utilizing induced pluripotent stem cell-derived myeloid cell lines producing
interferon-beta or interleukin-15/interleukin-15 receptor alpha. J Dermatol Sci 102:133–136.
https://doi.org/10.1016/j.jdermsci.2021.03.005
Montoro J, Balaguer-Roselló A, Sanz J (2023) Recent advances in allogeneic transplantation for
acute myeloid leukemia. Curr Opin Oncol 35:564–573. https://doi.org/10.1097/CCO.
0000000000000992
Morton LT, Reijmers RM, Wouters AK et al (2020) Simultaneous deletion of endogenous TCRαβ
for TCR gene therapy creates an improved and safe cellular therapeutic. Mol Ther J Am Soc
Gene Ther 28:64–74. https://doi.org/10.1016/j.ymthe.2019.10.001
Naeem M, Hazafa A, Bano N et al (2023) Explorations of CRISPR/Cas9 for improving the long-
term efficacy of universal CAR-T cells in tumor immunotherapy. Life Sci 316:121409. https://
doi.org/10.1016/j.lfs.2023.121409
Ng AP, Alexander WS (2017) Haematopoietic stem cells: past, present and future. Cell Death Dis 3:
17002. https://doi.org/10.1038/cddiscovery.2017.2
Ng AHM, Khoshakhlagh P, Arias JER et al (2021) A comprehensive library of human transcription
factors for cell fate engineering. Nat Biotechnol 39:510–519. https://doi.org/10.1038/s41587-
020-0742-6
Nishimura T, Nakauchi H (2019) Generation of Antigen-Specific T Cells from Human Induced
Pluripotent Stem Cells. Methods Mol Biol Clifton NJ 1899:25–40. https://doi.org/10.1007/978-
1-4939-8938-6_3
Oba T, Makino K, Kajihara R et al (2021) In situ delivery of iPSC-derived dendritic cells with local
radiotherapy generates systemic antitumor immunity and potentiates PD-L1 blockade in pre-
clinical poorly immunogenic tumor models. J Immunother Cancer 9:e002432. https://doi.org/
10.1136/jitc-2021-002432
Ottaviano G, Georgiadis C, Gkazi SA et al (2022) Phase 1 clinical trial of CRISPR-engineered
CAR19 universal T cells for treatment of children with refractory B cell leukemia. Sci Transl
Med 14:eabq3010. https://doi.org/10.1126/scitranslmed.abq3010
Panowski SH, Srinivasan S, Tan N et al (2022) Preclinical development and evaluation of alloge-
neic CAR T cells targeting CD70 for the treatment of renal cell carcinoma. Cancer Res 82:2610–
2624. https://doi.org/10.1158/0008-5472.CAN-21-2931
Paul S, Lal G (2017) The molecular mechanism of natural killer cells function and its importance in
cancer immunotherapy. Front Immunol 8
Petley EV, Koay H-F, Henderson MA et al (2021) MAIT cells regulate NK cell-mediated tumor
immunity. Nat Commun 12:4746. https://doi.org/10.1038/s41467-021-25009-4
Polo JM, Liu S, Figueroa ME et al (2010) Cell type of origin influences the molecular and
functional properties of mouse induced pluripotent stem cells. Nat Biotechnol 28:848–855.
https://doi.org/10.1038/nbt.1667
Raje N, Berdeja J, Lin Y et al (2019) Anti-BCMA CAR T-cell therapy bb2121 in relapsed or
refractory multiple myeloma. N Engl J Med 380:1726–1737. https://doi.org/10.1056/
NEJMoa1817226
Rapoport AP, Stadtmauer EA, Binder-Scholl GK et al (2015) NY-ESO-1–specific TCR–engineered
T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 21:914–921.
https://doi.org/10.1038/nm.3910
Rezvani K, Rouce R, Liu E, Shpall E (2017) Engineering natural killer cells for cancer immuno-
therapy. Mol Ther 25:1769–1781. https://doi.org/10.1016/j.ymthe.2017.06.012
Rowan AG, Ponnusamy K, Ren H et al (2023) CAR-iNKT cells targeting clonal TCRVβ chains as a
precise strategy to treat T cell lymphoma. Front Immunol 14
Rowe RG, Mandelbaum J, Zon LI, Daley GQ (2016) Engineering hematopoietic stem cells: lessons
from development. Cell Stem Cell 18:707–720. https://doi.org/10.1016/j.stem.2016.05.016
Ruggeri L, Mancusi A, Capanni M et al (2007) Donor natural killer cell allorecognition of missing
self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its
predictive value. Blood 110:433–440. https://doi.org/10.1182/blood-2006-07-038687
Stem Cell-Derived Cell Therapy for Cancer

Ruixin S, Yifan L, Chuanlong W et al (2023) Expressing IL-15/IL-18 and CXCR2 improve


infiltration and survival of EGFRvIII-targeting CAR-T cells in breast cancer. Biochem
Pharmacol 212:115536. https://doi.org/10.1016/j.bcp.2023.115536
Rupp LJ, Schumann K, Roybal KT et al (2017) CRISPR/Cas9-mediated PD-1 disruption enhances
anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep 7:737. https://doi.org/
10.1038/s41598-017-00462-8
Sachamitr P, Leishman AJ, Davies TJ, Fairchild PJ (2017) Directed differentiation of human
induced pluripotent stem cells into dendritic cells displaying tolerogenic properties and resem-
bling the CD141+ subset. Front Immunol 8:1935. https://doi.org/10.3389/fimmu.2017.01935
Sadelain M, Rivière I, Riddell S (2017) Therapeutic T cell engineering. Nature 545:423–431.
https://doi.org/10.1038/nature22395
Sadowski K, Olejarz W, Basak G (2022) Modern advances in CARs therapy and creating a new
approach to future treatment. Int J Mol Sci 23:15006. https://doi.org/10.3390/ijms232315006
Sagar J, Chaib B, Sales K et al (2007) Role of stem cells in cancer therapy and cancer stem cells: a
review. Cancer Cell Int 7:9. https://doi.org/10.1186/1475-2867-7-9
Sauer T, Parikh K, Sharma S et al (2021) CD70-specific CAR T cells have potent activity against
acute myeloid leukemia without HSC toxicity. Blood 138:318–330. https://doi.org/10.1182/
blood.2020008221
Senju S, Hirata S, Matsuyoshi H et al (2003) Generation and genetic modification of dendritic cells
derived from mouse embryonic stem cells. Blood 101:3501–3508. https://doi.org/10.1182/
blood-2002-07-2254
Senju S, Haruta M, Matsunaga Y et al (2009) Characterization of dendritic cells and macrophages
generated by directed differentiation from mouse induced pluripotent stem cells. Stem Cells 27:
1021–1031. https://doi.org/10.1002/stem.33
Shah K (2012) Mesenchymal stem cells engineered for cancer therapy. Adv Drug Deliv Rev 64:
739–748. https://doi.org/10.1016/j.addr.2011.06.010
Shankar K, Capitini CM, Saha K (2020) Genome engineering of induced pluripotent stem cells to
manufacture natural killer cell therapies. Stem Cell Res Ther 11:234. https://doi.org/10.1186/
s13287-020-01741-4
Sharkis SJ, Jones RJ, Civin C, Jang Y-Y (2012) Pluripotent stem cell-based cancer therapy: promise
and challenges. Sci Transl Med 4:127ps9. https://doi.org/10.1126/scitranslmed.3003920
Shi L, Meng T, Zhao Z et al (2017) CRISPR knock out CTLA-4 enhances the anti-tumor activity of
cytotoxic T lymphocytes. Gene 636:36–41. https://doi.org/10.1016/j.gene.2017.09.010
Shi D, Shi Y, Kaseb AO et al (2020) Chimeric antigen receptor-glypican-3 T-cell therapy for
advanced hepatocellular carcinoma: results of phase I trials. Clin Cancer Res 26:3979–3989.
https://doi.org/10.1158/1078-0432.CCR-19-3259
Shohdy KS, Pillai M, Guest R et al (2023) Evidence of clinical efficacy of a first generation CD19
CAR T cell in B cell malignancies. EJHaem 4:882–885. https://doi.org/10.1002/jha2.731
Sterner RC, Sterner RM (2021) CAR-T cell therapy: current limitations and potential strategies.
Blood Cancer J 11:1–11. https://doi.org/10.1038/s41408-021-00459-7
Strati P, Bachanova V, Goodman A et al (2021) Preliminary results of a phase I trial of FT516, an
off-the-shelf natural killer (NK) cell therapy derived from a clonal master induced pluripotent
stem cell (iPSC) line expressing high-affinity, non-cleavable CD16 (hnCD16), in patients (pts)
with relapsed/refractory (R/R) B-cell lymphoma (BCL). J Clin Oncol 39:7541–7541. https://doi.
org/10.1200/JCO.2021.39.15_suppl.7541
Stuckey DW, Shah K (2014) Stem cell-based therapies for cancer treatment: separating hope from
hype. Nat Rev Cancer 14:683–691. https://doi.org/10.1038/nrc3798
Sun H, Xing C, Jiang S et al (2022a) Long term complete response of advanced hepatocellular
carcinoma to glypican-3 specific chimeric antigen receptor T-cells plus sorafenib, a case report.
Front Immunol 13:963031. https://doi.org/10.3389/fimmu.2022.963031
Sun Y, Dong Y, Sun R et al (2022b) Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with
IL7 co-expression for the treatment of solid tumors. Mol Ther Oncolytics 25:160–173. https://
doi.org/10.1016/j.omto.2022.04.003
M. Wilson et al.

Taefehshokr S, Parhizkar A, Hayati S et al (2022) Cancer immunotherapy: challenges and


limitations. Pathol Res Pract 229:153723. https://doi.org/10.1016/j.prp.2021.153723
Tam TTKK, Xu S, Liu P, De Los Angeles A (2023) Dawn of development: exploring early human
embryogenesis using stem cells. Cell Stem Cell 30:1006–1007. https://doi.org/10.1016/j.stem.
2023.07.009
Themeli M, Kloss CC, Ciriello G et al (2013) Generation of tumor-targeted human T lymphocytes
from induced pluripotent stem cells for cancer therapy. Nat Biotechnol 31:928–933. https://doi.
org/10.1038/nbt.2678
Themeli M, Rivière I, Sadelain M (2015) New cell sources for T cell engineering and adoptive
immunotherapy. Cell Stem Cell 16:357–366. https://doi.org/10.1016/j.stem.2015.03.011
Tominaga S, Ojima T, Miyazawa M et al (2023) Induced pluripotent stem cell-derived dendritic cell
vaccine therapy genetically modified on the ubiquitin-proteasome system. Gene Ther 30:552–
559. https://doi.org/10.1038/s41434-023-00388-z
Turtle CJ, Hanafi L-A, Berger C et al (2016) CD19 CAR–T cells of defined CD4+: CD8+
composition in adult B cell ALL patients. J Clin Invest 126:2123–2138. https://doi.org/10.
1172/JCI85309
Ul Ain Q, Chung JY, Kim Y-H (2015) Current and future delivery systems for engineered
nucleases: ZFN, TALEN and RGEN. J Control Release 205:120–127. https://doi.org/10.1016/
j.jconrel.2014.12.036
Wakao H (2020) Reprogramming of MAIT cells to pluripotency and redifferentiation. In: Kaipe H,
Magalhaes I (eds) MAIT cells: methods and protocols. Springer, New York, pp 237–257
Wakao H, Fujita H (2013) Toward the realization of cell therapy. Cell Cycle 12:2341–2342. https://
doi.org/10.4161/cc.25706
Wakao H, Yoshikiyo K, Koshimizu U et al (2013) Expansion of functional human mucosal-
associated invariant T cells via reprogramming to pluripotency and redifferentiation. Cell
Stem Cell 12:546–558. https://doi.org/10.1016/j.stem.2013.03.001
Watanabe D, Koyanagi-Aoi M, Taniguchi-Ikeda M et al (2018) The generation of human γδT cell-
derived induced pluripotent stem cells from whole peripheral blood mononuclear cell culture.
Stem Cells Transl Med 7:34–44. https://doi.org/10.1002/sctm.17-0021
Watarai H, Fujii S, Koseki H, Taniguchi M (2010) P84. Murine induced pluripotent stem cells can
be derived from and differentiate into natural killer T cells. Differentiation 80:S45. https://doi.
org/10.1016/j.diff.2010.09.090
Wilson JM (2009) A history lesson for stem cells. Science 324:727–728. https://doi.org/10.1126/
science.1174935
Wobus AM, Boheler KR (2005) Embryonic stem cells: prospects for developmental biology and
cell therapy. Physiol Rev 85:635–678. https://doi.org/10.1152/physrev.00054.2003
Wright DA, Li T, Yang B, Spalding MH (2014) TALEN-mediated genome editing: prospects and
perspectives. Biochem J 462:15–24. https://doi.org/10.1042/BJ20140295
Xu H, Wang B, Ono M et al (2019) Targeted disruption of HLA genes via CRISPR-Cas9 generates
iPSCs with enhanced immune compatibility. Cell Stem Cell 24:566–578.e7. https://doi.org/10.
1016/j.stem.2019.02.005
Yamada D, Iyoda T, Vizcardo R et al (2016) Efficient regeneration of human Vα24+ invariant
natural killer T cells and their anti-tumor activity in vivo. Stem Cells Dayt Ohio 34:2852–2860.
https://doi.org/10.1002/stem.2465
Yan L, Li J, Zhang C (2023) The role of MSCs and CAR-MSCs in cellular immunotherapy. Cell
Commun Signal 21:187. https://doi.org/10.1186/s12964-023-01191-4
Yang M, Guan T, Chen C-F et al (2023a) Mesothelin-targeted CAR-NK cells derived from induced
pluripotent stem cells have a high efficacy in killing triple-negative breast cancer cells as shown
in several preclinical models. J Immunother Hagerstown Md 1997 46:285–294. https://doi.org/
10.1097/CJI.0000000000000483
Yang Y, Yang H, Alcaina Y et al (2023b) Inducible expression of interleukin-12 augments the
efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models. Nat
Commun 14:2068. https://doi.org/10.1038/s41467-023-37646-y
Stem Cell-Derived Cell Therapy for Cancer

Yeku OO, Brentjens RJ (2016) Armored CAR T-cells: utilizing cytokines and pro-inflammatory
ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans 44:412–418. https://
doi.org/10.1042/BST20150291
Zannikou M, Duffy JT, Levine RN et al (2023) IL15 modification enables CAR T cells to act as a
dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM.
J Immunother Cancer 11:e006239. https://doi.org/10.1136/jitc-2022-006239
Zeng J, Shahbazi M, Wu C et al (2012) Enhancing immunostimulatory function of human
embryonic stem cell-derived dendritic cells by CD1d overexpression. J Immunol Baltim Md
1950 188:4297–4304. https://doi.org/10.4049/jimmunol.1102343
Zeng J, Tang SY, Wang S (2019) Derivation of mimetic γδ T cells endowed with cancer recognition
receptors from reprogrammed γδ T cell. PLoS One 14:e0216815. https://doi.org/10.1371/
journal.pone.0216815
Zhang Y, Zhang X, Cheng C et al (2017) CRISPR-Cas9 mediated LAG-3 disruption in CAR-T
cells. Front Med 11:554–562. https://doi.org/10.1007/s11684-017-0543-6
Zhang L, Tian L, Dai X et al (2020) Pluripotent stem cell-derived CAR-macrophage cells with
antigen-dependent anti-cancer cell functions. J Hematol Oncol 13:153. https://doi.org/10.1186/
s13045-020-00983-2
Zhang Q, Yang J, Manoharan ENEA et al (2022a) CRISPR/Cas9-mediated gene knockout followed
by negative selection leads to a complete TCR depletion in ortho CAR19 T cells. Bio-Protocol
12:e4485. https://doi.org/10.21769/BioProtoc.4485
Zhang Y, Liu Z, Wei W, Li Y (2022b) TCR engineered T cells for solid tumor immunotherapy. Exp
Hematol Oncol 11:38. https://doi.org/10.1186/s40164-022-00291-0
Zhou Y, Li M, Zhou K et al (2022) Engineering induced pluripotent stem cells for cancer
immunotherapy. Cancer 14:2266. https://doi.org/10.3390/cancers14092266
Zhu Y, Smith DJ, Zhou Y et al (2019) Development of hematopoietic stem cell-engineered
invariant natural killer T cell therapy for cancer. Cell Stem Cell 25:542–557.e9. https://doi.
org/10.1016/j.stem.2019.08.004
Zhu H, Blum RH, Bjordahl R et al (2020a) Pluripotent stem cell–derived NK cells with high-affinity
noncleavable CD16a mediate improved antitumor activity. Blood 135:399–410. https://doi.org/
10.1182/blood.2019000621
Zhu H, You Y, Shen Z, Shi L (2020b) EGFRvIII-CAR-T cells with PD-1 knockout have improved
anti-glioma activity. Pathol Oncol Res 26:2135–2141. https://doi.org/10.1007/s12253-019-
00759-1
Zhu Y, Zuo D, Wang K et al (2023) Mesothelin-targeted CAR-T therapy combined with irinotecan
for the treatment of solid cancer. J Cancer Res Clin Oncol. https://doi.org/10.1007/s00432-023-
05279-9

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