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10
Considerations for nonclinical
studies conducted to support the
development of cellular therapies
Michael W. Bolt
1
and Padma Kumar Narayanan
2
1
Preclinical Safety Assessment, Vertex, Boston, MA, United States;
2
Preclinical and Clinical
Development Sciences, Wave Life Sciences, Lexington, MA, United States
OUTLINE
Introduction 314
Basic principles based on regulatory
guidance 316
Species selection 319
Study design components 320
Development challenges 321
Challenges associated with stem cell
therapies 321
Tumorigenicity 321
Inappropriate stem cell migration 325
Cell fate 325
Immune rejection 325
Challenges associated with CAR-T cell
therapies 328
CRS and neurotoxicity 329
On-target and off-target, off-tumor
toxicity 332
Graft-versus-host disease (GVHD)
and rejection associated with
allogeneic engineered T cells 335
T-cell receptor cross-reactivity 336
Insertional mutagenesis and clonal
dominance 337
Conclusion 342
References 342
CHAPTER
313
Nonclinical Development of Biologics, Vaccines and
Specialty Biologics, Second Edition
https://doi.org/10.1016/B978-0-443-13344-2.00011-0
© 2025 Elsevier Inc. All rights are reserved, including those for text
and data mining, AI training, and similar technologies.
Introduction
Cell therapies involve the transplantation of human cells to replace or repair damaged tis-
sue or cells, or to enhance cell function. These therapies can consist of a patient’s own cells
(referred to as autologous cells), or cells from a donor (refe rred to allogeneic cells); and typi-
cally use either stem cells or immune cells.
Stem cell therapies (SCT) consists of two main types of stem cells (Fig. 10.1). (1) Tissue-
specific stem cells, or “adult” stem cells, are undifferentiated cells within speci fic tissues,
that can proliferate and differentiate, to replace naturally dying cells within their tissue
and to repair wounds in response to injury. Examples include mesenchymal (a multipotent
stem cell that can be isolated from many tissues such as fat, bone marrow, dental pulp,
placenta and muscle), hematopoietic, neural, corneal, and skin stem cells. (2) Pluripotent
stem cells (PSC), which have the ability to differentiate into all the cells of the adult body,
are further divided into embryonic stem cells (ESC) and inducible pluripotent stem cells
(iPSC). Embryonic stem cells are derive d from the blastocyst of the embryo. Human ESCs
have the ability to differentiate into many different cell types. Human iPSCs are created by
isolating readily accessible and fully differentiated somatic cells, such as the blood, skin, or
urine, and reprogramming them by inducing the overexpression of transcription factors asso-
ciated with pluripotency (such as Oct4, Sox2, cMyc, and Klf4) to allow the differentiated cell
to reverse its condition to an embryonic stage. The resulting cells demonstrate the plasticity of
cell fate, and traits associated with immortalized cell lines. iPSCs can be extensively
FIGURE 10.1 There are two main types of stem cells. Tissue specific and pluripotent stem cells. Pluripotent stem
cells are further divided into embryonic stem cells (ESC) and inducible pluripotent stem cells (iPSCs).
10. Considerations for nonclinical studies conducted to support the development of cellular therapies314
III. Specialty biologics and indications
propagated in vitro and differentiated into a specific cell type, such as cardiomyocytes or neu-
rons (Blau and Daley, 2019).
Stem cell therapies are being investigated as potential treatments for diseases where they
can replace absent, damaged or nonfunctioning cells. For example, pancreatic islet cells to
treat type 1 diabetes or dopaminergic neuronal stem cells to treat Parkinson’s disease. In
2022, there were 48 clinical trials ongoing with hESC derivatives (about half of which
involved hESC-derived ret inal pigment epithelium (RPE) cells to treat patients with macular
degeneration) and 35 clinical trials using iPSC-derived cells to treat a variety of diseases
including age-related macular degeneration, b-thalassemia, heart diseases, neural diseases,
immune disorders, and tumors/cancer (Wang et al., 2022). As described elsewhere (Leven-
thal et al., 2012; Kim and Park, 2017; Gopalarethinam et al., 2023) and summarized in
Table 10.1, there are many advantages to using the different types of stem cells (such as
availability, ease to isolate and expand, and the ability to differentiate into almost any cell
type). However, their use also has risks, which include those for tumorigenicity,
inappropriate stem cell migration, the ability to change into an inappropriate cell type, and
immune rejection.
TABLE 10.1 Advantages and disadvantages of various stem cells used in cell therapies.
Stem cell type Advantages Disadvantages
Embryonic
stem cells (ESC)
• Pluripotent (can differentiate into almost all
types of cells)
• Can maintain in cell culture for >1 year
• Have increased risk for rejection by
immune system after transplantation
• Risk of teratoma formation after
transplantation if residual stem cells
remain after differentiation
• Inefficient process to generate ESC lines
Inducible
pluripotent
stem cells (iPSC)
• Pluripotent (can differentiate into almost all
types of cells)
• Can be derived from abundant somatic cells
• Histocompatibility issues with donor/recipient
transplants can often be avoided
• Risk of genetic instability and teratoma
formation after transplantation if
residual stem cells remain after
differentiation
Mesenchymal
stem cells (MSC)
• Capable of multilineage differentiation
• Can be sourced from various tissues (bone
marrow, adipose tissues, muscle, blood, teeth,
etc.) some of which are easily accessible and
with minimal invasive procedures
• Can be rapidly expanded for large-scale clinical
use
• Can migrate to injured sites in response to
environmental signals
• Can inhibit immune response, promote cell
survival or induce angiogenesis
• Limited capacity for cell proliferation may
reduce risk for tumor formation
• Undesirable differentiation could
obstruct antitumor immune function
• MSCs can only proliferate in vitro for a
limited number of passages before
approaching senescence (which may
limit the ability for cells to proliferate,
differentiate and migrate)
• Underlying patient diseases may
complicate MSC isolation or reduce
efficacy
• Limited cell types can be generated
Introduction 315
III. Specialty biologics and indications
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