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Translating nonclinical data to clinical application
Considerations for dose extrapolation
Justification for proceeding with clinical trials is based on establishment of scientific ratio-
nale, demonstration of POC, and an adequate demonstration of safety in relevant animal
model(s). Unlike pharmaceuticals or biopharmaceuticals, there are no standard algorithms
for extrapolating dose for cell-based therapies. An additional challenge for optimizing doses
in clinical trials is that there are generally data available from fewer cohorts, as well as fewer
subjects within a coho rt, to be used to define an optimal dose. The complexity of animal
models can limit the number of dose levels and, more importantly for cell-based therapies,
often limit the MFD that can be testeddcritical parameters that are normally used to help
inform dose extrapolation. Added to the complexity, investigators must also take into ac-
count factors unique to cell therapies that may impact the dose delivered including: cell con-
centration, injection volume, rate of delivery, location of injection, number of injections, cell
stability, etc. Scaling factors such as body weight, body surface area, blood volume, or target
size (e.g., comparative cross-sectio nal area of spinal cord or volume of a target organ) can be
used to aid in rationalizing the dose selection for patients .
Typically, at least two model species are used to help scale animal doses to humans. This is
a challenge for cell-based therapies as development programs are frequently limited to
toxicity assessment in a single species. Therefore, to improve dose extrapolation, prior pre-
clinical and/or clinical experience from the literature of similar type cell products can be
used to help inform the clinical dose (e.g., clinical experience with administration of cadaveric
human islets can be used to help inform dose of PSC-derived pancreatic progenitors). More-
over, the animal models used will generally be immunocompromised, somewhat confound-
ing the ability to predict how the administered cells will fare when confronted with a
patient’s allo-immunity. The route of administration and the use of any associated immuno-
suppression regimen (to reduce implant rejection) will affect this as well. Lastly, cell products
can have varying degrees of proliferative capacity and/or activity, also potentially related to
route of administration, which may need to be considered in dosing. If an encapsulation de-
vice is used to administer the cells, it could present a physical barrier and set a limit on cell
proliferation/dose expansion after administration. These and other additional safety factors
may need to be considered clinically, based on the specific preclinical findings. Both the
method of scaling and proposed safety factors, if warranted, should be justified to support
the intended Phase 1 dose and dose escalation scheme.
Clinical considerations and endpoints
Many factors need to be considered in the design of early phase PSC-based clinical studies
including: selecting the target patient population, assessing for potential teratomas, deter-
mining the necessity for immunosuppression, and understanding the dosage escalation, de-
livery method, and potential methods for cell tracking. Data from preclinical studies will
guide these decisions. One of the most significant hurdles in the design for clinical studies
for PSC-based products is the selection of clinical endpoints. Many of the initial disease tar-
gets are degenerative diseases that are complicated by rapid progression and lack validated
surrogate markers of disease (Aboody et al., 2011). Early identification of clinically useful
12. Considerations in the development of pluripotent stem cellebased therapies436
III. Specialty biologics and indications
biomarkers for toxicity and efficacy will greatly aid in vivo monitoring of product perfor-
mance. Long-term follow-up of patients receiving PSC-based products will need to be per-
formed with an eye toward assessing safety as well as persistence of cell product.
While informed consent is a routine part of all clinical trials, given the attention surround-
ing PSC-based therapeutics, efforts should be made to ensure that patients are adequately
educated on the risks and realistic potential for benefit, if any, in early-stage clinical trials.
This can be particularly challenging in cases where consent needs to be given in a relatively
short time frame, and in a context whereby the patient was healthy prior to an injury (e.g.,
Geron’s GRNOPC1 trial for acute spinal cord trauma) (Bretzner et al., 2011; Wirth et al., 2011).
Global regulatory guidance
PSC-based cellular therapy products are regulated by the FDA’s Center for Biologics Eval-
uation and Research (CBER). While regulatory guidance often lags behind research in novel
therapies, a significant amount of progress has been made in establishing early guidance for
PSC therapies (Table 12.2); for example, the FDA has published “Guidance for Industry: Pre-
clinical Assessment of Investigational Cellular and Gene Therapy Products” (FDA, 2013). Of
note, the FDA has additional regulatory pathways for development of human cells, tissues
and cellular and tissue-based products (HCT/Ps) intended to repair, replace or supplement
a recipient’s cells or tissues for the same basic functions [21. CFR 1271.10(c)]; PSC-derived
cell therapies are not covered by these regulations and are therefore outside the scope of this
chapter.
Ethical and political issues
Because of the controversial nature of ESCs related to legal and political issues that impact
the regulatory process, there are varying degrees of restrictions on the type of work that can
be performed in certain countries. The legal, moral, and ethical status of human embryos is an
emotional issue for many, leading to a significant amount of controversy surrounding ESC
research. Embryos used for the derivation of ESC lines are often donated to research purposes
after donors have completed their families through In Vitro Fertilization (IVF) treatments.
Even though those embryos would otherwise likely be discarded, the controversy centers
around the destruction of the embryo in the creation of the new ESC line. The appeal of
iPSC research is that these cells avoid the ethical issues associated with ESCs as they are
derived from adult cells and not embryos.
Regardless of where one stands on the issue, it is important to understand the dynamic
political landscape in the US and elsewhere. Currently, there are no federal legal restrict ions
on conducting ESC research in the US, and notwithstanding the restriction of NIH funding
from 2001 to 2009, the federal government has had a generally supportive and permissive
policy toward ESCs. However, individual jurisdictions can have specific policies regarding
ESC research and clinical development within their borders. For instance, the State of Califor-
nia provides funding for all forms of ESC research as well as the derivation of new lines. In
contrast, a number of rulings across the United States have imposed restrictions at the state
Global regulatory guidance 437
III. Specialty biologics and indications
level on research with ESC and some private hospitals and clinics have local policies in place
regarding administering ESC-derived therapie s (Matthews and Morali, 2022 ).
Europe is mixed when it comes to ESC research policy, ranging from restrictive to permis-
sive. The UK, Sweden, Denmark, and the Netherlands have the most permissive policies,
allowing both ESC research and the derivation of new ESC lines. Germany and Italy are
considered more restrictivedalthough ESC research is allowed, the derivation of new ESC
lines is not. Worldwide, some governments, such as the UK, Canada, and Aust ralia, regulate
ESC research through the issuance of licenses. Elsewhere, Japan, India, China, South Korea,
and Israel have supportive policies for ESC research, while New Zealand and most of Africa
and South America (with the exceptions of South Africa and Brazil) have restrictive policies
(Matthews and Rowland, 2011).
Clinical studies of PSC-derived therapeutic candidates
Although full descriptions and analyses of clinical investigations of PSC-derived product
candidates are beyond the scope of this book and are covered elsewhere (Kobold et al., 2023;
Temple, 2023; Kim et al., 2022), some reflection on how the preclinical work has translated to
human is instructive. When the first edition of this book was published in 2013, PSC-derived
therapeutics were only beginning to advance into clinical-phase development. Since that
time, when only five clinical studies had launched, the field has grown dramatically, with
approximately 55 trials worldwide as of 2020, and well over 100 cited in 2023 (Table 12.10
(Kobold et al., 2020, 2023)). For the most part, the array of trials launched and underway re-
flects the candidate cell products and indications initially expected to be best addressed with
PSCs (for example, where a discrete well-defined cell type is defective or lost in a relatively
well-understood system, such as beta cells in type 1 diabetes, nigrostriatal dopamine cells in
Parkinson’s Disease, or retinal pigmented epithelial cells in macular degeneration). Yet, at the
same time, some perhaps less expected applications have also emerged, including taking
advantage of the robust propagation capacity of PSCs to generate large numbers of MSCs
for various indications (Dupuis and Oltra, 2021), or CAR-iNK cells for cancer treatment [Cen-
tury Tx] [Fate Tx].
Pioneers in translating to human trials
The first FDA-approved trial using a PSC-based product was for the treatment of spinal
cord injury with an ESC-derived oligodendrocyte progenitor cell product, GRNOPC1, spon-
sored by Geron Corporation (Menlo Park, CA, USA). Oligodendrocytes are cells that support
and insulate axons in the CNS. Geron initially received FDA approval in January 2009 to
commence clinical trials; however, the trial was put on hold shortly thereafter with subse-
quent re-approval in June 2010. The Phase 1 study was open to patients with a neurologically
complete (ASIA Impairment Scale A) traumatic spinal cord injury to the thoracic region be-
tween T3 and T11. GRNOPC1 was administered once to patients in the subacute phase be-
tween 7 and 14 days after the injury (Lineage Cell Therapeutics, 2010). Additional clinical
studies with the cell product (now known as LCTOPC1) were conducted by Asterias Bio-
therapeutics, which acquired the asset in 2013, and subsequently Lineage Cell Therapeutics,
12. Considerations in the development of pluripotent stem cellebased therapies438
III. Specialty biologics and indications
to examine dose escalation and administration to patients who suffered a cervical spinal cord
injury, up to 42 days postinjury (Fessler et al., 2022). In the preclinical work leading up to the
Geron trial, a low incidence of small cystic structures was observed within the cell grafts;
however, the company further develop ed the quality control, and there has been no evidence
of neoplasm or signs of tumorigenic risk in the clinical patients. To date, as long as 10 years
postadministration, it appears that the procedure and product candidate are relatively safe
and well-tolerated, with some indications of initial efficacy (McKenna et al., 2022; Fessler
et al., 2022).
Advanced Cell Technology, Inc. (ACT; Marlborough, MA, USA) was the second company
to receive FDA approval to com mence clinical trials using an ESC-derived product. In
November 2010, the company received FDA approval to initiate a Phase 1/2 multicenter clin-
ical trial with MA09-hRPE, consisting of PSC-derived retinal pigmented epithelium (RPE)
cells that were injected subretinally to treat patients with Stargardt’s macular dystrophy
(SMD), a genetic form of juvenile macular degeneration (ACT). Soon after, in January 2011,
ACT received approval to initiate a Phase 1/2 multicenter clinical trial to treat patients
with dry age-related macular degeneration (AMD), the most common form of macular
degeneration (ACT). In September 2011, ACT received approval to initiate a Phase 1/2 trial
in the UK for the treatment of SMD; this marked the first-ever European approval for a clin-
ical trial using an ESC-derived product. In addition, preliminary results show measurable im-
provements in vision in two patients treated with ACT’s MA09-hRPE (Schwartz et al., 2012 ).
Indeed, PSC-based therapeutics have been most extensively tested in retinal and ocular
conditions, with 32 trials comprising 410 patients now completed or underwa y [Airtable,
adapted from Treefrog]. While most of these trials have used ESC as starting material for
the investigational product, in 2013 the first trial in the world using iPSC was launched,
led by Dr. Masayo Takahashi at Riken in Japan (Mandai et al., 2017). This was also the first
test of an autologous PSC-derived therapeutic. That specific trial has progressed slowly
TABLE 12.10 Number of clinical trials for pluripotent stem cell-based products over time.
Therapeutic area 2013 2020 2023
Ocular/eye 4 25 34
Neuro 0 6 10
Endocrine 0 6 11
Cancer 0 4 18
Cardiac/circulatory 0 7 16
Injury/musculoskeletal 1 4 7
Blood disorders 0 2 4
COVID/infectious disease 0 0 4
Other 0 0 5
Total 5 55 109
From: www.clinicaltrials.gov, Kobold et al. (2020, 2023), and https://airtable.com/shrzzoHVEguIGmry6/tblpmrrUOKnKXeeId
Clinical studies of PSC-derived therapeutic candidates 439
III. Specialty biologics and indications
because theoretical safety concerns were raised regarding a genomic mutation identified in
one of the patient’s iPSC lines, but this area has been especially fruitful, in part because
the cells can be more directly monitored than most conditions, by way of intraocular
exam, and optical coherence tomography (OCT). Initially, subretinal delivery trials injected
cells alone, but in 2016 a trial was launched by Regenerative Patch Technologies (RPT) in
which the cells are administered as a combination product, attached to a custom paralene
membrane, using a cleverly designed custom delivery tool (Kashani et al., 2018). Initial re-
ports appear to reflect and extend the observations of the pioneers such as ACT (Schwartz
et al., 2012), that the RPE-based product candidates may well provide significant efficacy
in vision (Kashani et al., 2022). We look forward to further trials and characterization of
such benefits of this approach.
ViaCyte and its academic collaborators led the way on delivery of PSC-derived products for
type 1 diabe tes, and like RPT, codeveloped a custom delivery device specifically to ensure
proper administration, and in some versions, immune protection of the cells. The device also
affords the opportunity for removability of the cells, which appears to be unique to the ViaCyte
paradigm (Brandon et al., 2020). Virtually all other PSC-derived product candidates under
investigation may not be removed following administration without concomitant removal of
endogenous tissue, again raising the risk:benefit equation significantly above tradition al
drug trials where the investigational agent can generally be withdrawn if adverse events arise.
Relative to preclinical development, ViaCyte saw some success in the clinic, with the first
demonstration of human insulin production from a PSC-derived product in implanted subjects
(Shapiro et al., 2021); yet at the same time had challenges, including substantial fibrotic reac-
tions to the cell-containing delivery device, which appear to be benign but hinder realization
of the full therapeutic capacity of the investigational product. Of note, such fibrotic reactions
were not observed in preclinical animal studies, highlighting the fact that some results substan-
tially affecting product development may never be known until the clinical investigations get
underway. On the other side of the coin, ViaCyte also observed phenomena in animal studies,
which had no counterpart in human clinical testing. Common to all preclinical studies utilizing
immune compromised rodents, there is a certain amount of subject attrition due to spontaneous
tumors such as thymomas as the animals age (Prochazka et al., 1992; Kato et al., 2009; Yasuda
et al., 2017), but also, in the case of the ViaCyte subcutaneous cell delivery in a semirigid device,
a phenomenon arose preclinically of foreign body sarcoma or solid sta te tumorigenesis, also
known as the Oppenheimer effect in medical device development (Oppenheimer et al., 1955;
Vince et al., 1991). Fortunately, the field and FDA had already determined by the 1980s that
this phenomenon was not observed with, or pertine nt to human delivery devices; indeed
ISO10993 recommends testing medical devices in nonrodent species, but this was not an option
for ViaCyte’s combination product where (as discussed above) immunocompromised animals
(rodents being the only option) were necessary to avoid xeno-rejection (Brandon et al., 2020).
Along with ACT (since acquired by Astellas), ViaCyte (since acquired by Vertex) had one of
the longest histories, and a substantial body of work in clinical testing of PSC-derive products.
Indeed, the two workhorse cell lines of these two companies, MA09, and CyT49, have likely
been administered to far more human subjects than any other lines. Finally of note, in 2022 it
was reported that ViaCyte had administered the first PSC-derived cells engineered to be
hypo-immune to a human subject, in a combination product called VCTX-210, codeveloped
with CRISPR Therapeutics (Kobold et al., 2023).
12. Considerations in the development of pluripotent stem cellebased therapies440
III. Specialty biologics and indications
Reflection on clinical investigations to date and looking forward
Over 100 clinical trials with PSC-derived therapies are now completed or underway (see
Table 12.10, Kobold et al., 2023, and well summarized in a sortable online database curated
by Treefrog [Airtable, adapted]). Virtually all are Phase 1/2 trials, with no Phase 3 trials yet
announced publicly. Approximately 40 trials are completed, comprising approximately 540
participants, with another 60 ongoing/recruiting, comprising approximately 3400 partici-
pants [six of those are long-term follow-up (LTFU) trials from other completed Phase 1/2 tri-
als]. Regenerative medicine approaches may include LTFU as long as 15 years
postadministration depending upon the indication and perceived risk of the candidate prod-
uct. Based on risk-benefit analysis, and unlike typical drug trials, all trials and first-in-human
exposure of PSC-derived products have been in patients rather than normal healthy volun-
teers. While inclusion of placebo/sham controls has been rarely encountered in early trials,
potential requirement for their inclusion should be discussed with the appropriate regulatory
agencies.
Who is performing these trials? Most of the product candidates require special handling
and delivery systems, and extensive and intensive monitoring of the trial participants, well
beyond that of a typical drug or even a biological clinical trial, so specialized facilities and
personnel are required. Of the approximately 100e110 trials currently shown in public da-
tabases, approximately 60% have industry sponsors, with the other 40% from academic in-
stitutions or government sponsors. Fourteen countries currently have clinical testing
underway. While the first trials were launched in the US and UK in the early 2010s,
several other countries including China, Japan, Australia, and Korea were soon also well
represented with a number of trials each, and Sweden, Iran, and Germany have also
approved clinical trials in recent years (Kobold et al., 2023), Treefrog [Airtable, adapted].
While obviously most trials utilized ESC at first, by 2018, the trend was turning, and
now most use iPSC. Of the total trials to date, approximately 50% have used ESC and
50% iPSC. The ESC lines deployed are generally well described in the literature and public
databases, in contrast to the iPSC for which there has been less transparency (Kobold et al.,
2023).
What can we say about how clinical results have reflected preclinical work? Importantly,
out of the hundreds of patients that have been treated worldwide by these commercial spon-
sors, no teratomas or tumorigenic events have been publicly reported. The lack of teratomas
or tumors is an incredible achievement for the field, given the complexity and diversity of
manufacturing protocols and starting cell lines, and is a testament to the thorough nonclinical
assessments each sponsor has performed. These programs are complex, expensive, labor-
intensive, and time consuming. But with the continued rigorous attention to quality and
safety, progress toward the tremendous promise of the platform continues on a positive
trajectory.
Summary
Production of PSC-based products is a long and complex process that starts with donor
tissues and ends with preparation of product for patient administration. There are many
Summary 441
III. Specialty biologics and indications
points along the novel manufacturing processes where elements that pose potential risks for
adverse events can be introduced. Therefore, stringent safety assessments are necessary and
include evaluation for contamination by infectious disease agents, use of animal products,
genomic instability of cell cultures over time, and potential tumorigenicity (Aboody et al.,
2011). See Table 12.11 for a summary of current challenges in the development of PSC-
based the rapeutics.
Pluripotency, the most important characteristic distinguishing PSCs from adult stem cells
(such as MSCs), gives rise to their greatest advantagedthe ability to form virtually any cell
typedand yet also their most significant riskdthe ability to form teratomas. As research ad-
vances, methods fo r minimizing risks will be developed and implemented. Knowledge
gained from clinical studies will feed back to improve product development and enhance
our understanding of the underlying biology at work. The unique and diverse biological
characteristics of each PSC-based product, which dictate the type and extent of preclinical
testing required, combined with the rapidly evolving state of research, pose challenges for
regulatory review. However, early engagement with regulatory agencies will facilitate the
process by providing dialog on preclinical study design, intended disease target, and clinical
plan. While investigators are still in the early stages of defining safety for PSC-based prod-
ucts, resu lts thus far have been promising. Data from early clinical trials are anticipated
with great optimism.
TABLE 12.11 Current challenges in the development of pluripotent stem cell-based therapies.
Selecting appropriate cell line
Determining appropriate cell type and stage of development (progenitor/terminally differentiated) required to
obtain desired clinical effect
Understanding regulation and control of cell cycle
Product characterization
Ensuring quality, consistency, and availability of manufacturing reagents
Developing robust, consistent, reproducible manufacturing protocols
Minimizing/eliminating undifferentiated stem cells in final product
Manufacturing for scalability
Optimizing manufacturing process while being mindful of current regulatory constraints
Ensuring long-term genomic stability
Choosing appropriate animal model for pharmacology, toxicity, and other in vivo studies
Developing best method for cell preparation immediately prior to transplantation
Developing methods for tracking cells and assessing activity following transplantation
Determining best method for cell delivery
Ensuring long-term graft retention, survival, and activity
Selecting appropriate biomarkers for clinical study
Determining timing of therapeutic intervention in disease course, i.e., the pathophysiologic status of the
microenvironment
Determining first-in-human dose and establishing human effective dose
Selecting appropriate patient population
Operating within ethical and political constraints
12. Considerations in the development of pluripotent stem cellebased therapies442
III. Specialty biologics and indications
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