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allogeneic immune responses, in vitro, with mixed lymphocyte reactions by coculturing allo-
geneic CAR T cells with peripheral blood mononuclear cells (PBMCs) from different donors
can be done. Alloreactivity can also be assessed in vivo in immunodeficient NSG mice by
coinfusing allogeneic CAR T cells with PBMCs from HLA-disparate donors, followed by
evaluating the engraftment of CAR T cells.
T-cell receptor cross-react ivity
Adoptive transfer TCR-transduced T cells has shown promising results for cancer treat-
ment, but has also produced severe immunotoxicities caused by on-target as well as off-
target TCR recognition. Off-target toxicities are related to the ability of a single T cell to
cross-recognize and respond to several different peptide-major histocompatibility complex
(pMHC) antigens; a property that is essential for providing broad antigenic coverage despite
aconfined number of unique TCRs in the human body. However, this degeneracy makes it
incredibly difficult to account for the range of targets that any TCR might recognize, and rep-
resents a major challenge for the clinical development of therapeutic TCRs (Amalie and
Hadrup, 2019)(Fig. 10.4). The use of cytotoxic T cells (CTLs) in immunotherapy, specifically
those that are restricted by non-self-major histocompatibility complex (MHC), rather than self
MHC molecules, could be a useful approach in cancer immunotherapy (Stauss, 1999). MHC
molecules are found on the surface of cells and are responsible for presenting antigens to
T cells, which then recognize and respond to these antigens. Since cancer cells often down-
regulate or alter the expression of their MHC molecules, they are less recognizable by the
immune system. By using CTLs that recognize non-self MHC molecules, it may be possible
to overcome this immune evasion strategy and mount an effective antitumor response. Ap-
proaches such as affinity maturation, a process for introducing mutations into the comple-
mentarity determining regions of an antibody that leads to structural alterations that
enhance the strength of the interaction between the antibody and its target, will increase
cross-reactivity and recognition of nontarget-specific peptides. However, they may also in-
crease the occurrence of rare, severe and/or fatal toxicities not observed with T cells engi-
neered to express other therapeutic TCRs within the normal affinity. In particular, two
clinical trials highlight the need to approach the use of TCRs with extreme care (Amalie
and Hadrup, 2019). The first trial applied a high-avidity TCR generated from vaccinated
HLA-A0201 transgenic mice that targeted a melanoma antigen-encoding-A3 (MAGE-A3)-
derived peptide. Of nine enrolled patients, five had objective clinical responses; however,
three experienced neurological toxicity and two eventually died (Morgan et al., 2013). The
toxicities were subsequently explained by the ability of the TCR to cross-recognize a related
peptide, derived from MAGE-A12, which is expressed in the human brain. This peptide only
varies at the position two anchor residue, and might therefore indicate that although natural
TCRs should not target healthy tissue, the strategies applied in adoptive cell therapy might
override peripheral tolerance mechanisms (Amalie and Hadrup, 2019). The second trial
applied a TCR targeting a MAGE-A3-derived peptide that binds HLA-A0101, obtained
from a vaccinated patient, and engineered to obtain higher affinity. Two patients were
treated in this trial, and both developed cardiac arrest and died shortly after T-cell infusion.
Extensive investigations revealed that despite a restricted sequence similarity with the
MAGE-A3 peptide (55% sequence overlap), the TCR had cross-reacted with the protein, titin,
which is expressed in beating cardiomyocytes (Cameron et al., 2013). It was suggested that a
10. Considerations for nonclinical studies conducted to support the development of cellular therapies336
III. Specialty biologics and indications
TCR with optimal on-target (only) affinity may be generated by modifying the TCR in a way
that promotes stronger binding to the peptide part of the TCR recognition motif while
decreasing the overall binding to MHC (Hellman et al., 2019).
Models for cross-reactivity
TCRs may either cross-react with one of the numerous peptides that are presented by
the HLA allele that is used by the TCR to recognize its cognate ligand, or cross-react with
distinct HLA alleles presenting a library of peptides to which the TCR is not tolerant
(Donnadieu et al., 2022). Different strategies are required to assess these two types of
cross-reactivity. HLA alleles not present in the TCR donor can lead to strong T-cell re-
sponses (Fig. 10.4). Allogeneic HLA molecules are highly immunogenic, with 1%e10%
of “naïve” T cells responding to peptide-presenting allogeneic HLA molecules. Therefore,
it is crucial to exclude alloreactivity of therapeutic TCRs. Extensive in vitro screening us-
ing cell lines that express diverse HLA alleles, as well as testing TCR-engineered T lym-
phocytes against the patient’s cells, is necessary before treatment. Careful analysis is
required to assess the potential for cross-reactivity of alternative peptides presented by
the HLA allele presenting the “cognate” peptide. The specificity profile of the therapeutic
TCR can be refined by changing individual residues in the cognate peptide and
measuring which changes result in the loss of T-cell activation. Peptide titration experi-
ments are importan t to assess whether TCR recognition occurs at physiologically low
concentrations or only at high peptide concentrations. To determine whether “natural”
antigen processing and presentation produces the cross-reactive peptide and leads to
T-cell activation, it is essential to assess for the stimulation of TCR-engineered T cells
with cells that endogenously express the corresponding protein. The essential residues
form a peptide motif that can be used to screen human exome databases and identify hu-
man proteins that contain this motif. The corresponding peptides can be synthesized and
tested for recognition by the therapeutic TCR (Donnadieu et al., 2022).
Insertional mutagenesis and clonal dominance
Lentiviral and retro viral vectors are often used to engineer T cells, which has some advan-
tages. CD19-targeting CAR T cells with vector integrations in genes associated with T cell
activation and proliferation exhibited superior clinical outcomes (Nobles et al., 2020). For
example, in patients with B cell acute lymphoblastic leukemia who underwent CD19-
targeted CAR T cell therapy, disruption of the TET2 gene led to increased persistence and
expansion of CAR T cells in vivo, which enhanced therapeutic efficacy and improved clinical
outcomes in patients (Fraietta et al., 2018). Similarly, CAR T cells with CRISPR-edited endog-
enous T cell receptor (TCR) and programmed cell death prote in 1 (PD-1) genes exhibited
improved antitumor activity and persistence in vivo, which led to objective responses in a
subset of patients. Objective response is defined as the percentage of people in a study or
treatment group who have a partial or complete response to the treatment within a certain
period of time (Stadtmauer et al., 2020).
However, there are also disadvantages to engineering T-cells with lentiviral and retroviral
vectors. For example, insertional mutagenesis and clonal dominance associated with the use
of these vectors can lead to cancers such as leukemia. Recchia et al. (2006) reported that retro-
viral vector integration used to express a therapeutic gene in T-cells, could also deregulate
Development challenges 337
III. Specialty biologics and indications
gene expression of neighboring genes; but despite the potentially dangerous interactions with
the T cell genome, retroviral integration had little consequence on the safety and efficacy of
T cell transplantation. In contrast, clonal expansion of CAR T cells harboring lentivector inte-
gration in the Cbl gene, was observed from a patient with acute lymphoblastic leuke mia who
underwent anti-CD22 CAR T-cell therapy. This clonal expansion led to the developmen t of a
relapsed leukemia with a new mutation (Shahet al., 2019). Similarly, a patient developed a
T-cell lymphoma that was derived from a CD19 CAR-T cell, which was likely caused by
insertional mutagenesis in the piggyBac transposon system (Micklethwaite et al., 2021).
Recently, clinical trials with allogeneic CAR T therapies for cancer (AlloCAR T) were placed
on hold by the FDA, because of a chromosomal abnormality found in a bone marrow biopsy
taken from a patient that developed progressive pancytopenia (Allogene press release, 2021).
An investigation is currently underway to further characterize the observed abnormality,
including any clinical relevance, evidence of clonal expansion, or a potential causative
relationship of gene editing using transcription activator-like effector nuclease (TALEN)
technology.
Other researchers (Bushman, 2020; Papayannakos and Daniel, 2013) have described the
potential risks and benefits of using retroviral and lentiviral vectors in cell and gene therapy,
and they highlight the importance of careful des ign and monitoring of these therapies to
minimize the risk of adverse events associated with insertional mutagenesis (such as leuke-
mia). This includes the use of insulators, the targeting of safe genomic loci, and the selective
engineering of lentiviral vectors to improve their safety profile.
Models for genotoxicity including CRISPR and TALEN
Models for assessing genomic integration of a given vector mainly include cell-based as-
says that were largely derived to evaluate the leukemias observed in HSC-based gene ther-
apy (Fig. 10.4). T-cell culture assays were designed to model the recurrent activating vector
insertions in the Lmo2 locus noted in early human SCID gene therapy trials. For instance,
a murine thymocyte culture assay can reproduce the insertions in Lmo2 as well as other
T-cell proto- oncogenes (including Mef2c) that functionally associate with developmental ar-
rest and possible transformation. A second assay, termed the in vitro immortalization assay,
reports the induction of replating activity in primary murine hematopoietic cells as a result of
insertional activation of proto-oncogenes such as Evi1. A third assay uses an immortalized
murine cell line (BAF3) to measure the frequency of IL-3-independent mutants that arise
because of vector-induced insertional mutagenesis, and is probably the most common assay
to assess for transformation of engineered T cells by testing for antigen-independent and IL-2
independent proliferation (Donnadieu et al., 2022).
With the advent of site-specific genomic modifications, either with CRISPR/Cas system or
piggyBac transposons, gene editing is associated with potential side effects stemming from
off-target cleavage of the genome, which can be hard to predict. Off-target effects include
insertions/deletions (indels) of genomic information at unwanted sites and can lead to chro-
mosomal translocations between on-target and off-target sites or between different off-target
sites. There is a battery of in silico, in vitro, and ex vivo methods available for genome-wide
assessment of off-target cleavage sites, including the bioinformatics tools MIT CRISPR
Design Tool or E-CRISP, GUIDE-seq, Digenome-seq, CIRCLE-seq117 and SITE-seq, and
CAST-seq, which have recently been established to assess chromosomal translocations in
10. Considerations for nonclinical studies conducted to support the development of cellular therapies338
III. Specialty biologics and indications
edited cells. Cumulatively, these methods indicate that (1) the number of off-target sites and
the efficiency with which they are modified strongly depend on the individual gRNAs; (2)
in silico methods can fail to predict experimentally determined off-target sites (false nega-
tives); and (3) in vitro methods may report false positives and hence lack sufficient
specificity.
In summary, we have discussed the various toxicities that patients receiving engineered T
lymphocyte infusions may experience. These toxicities can range from mild and easily
managed to severe and life-threatening. While there have been some advancements in our
understanding of these adverse events, there is still much to learn about the mechanisms
that underlie them. Current preclinical models, which mainly consist of in vitro coculture
systems and standard xenograft models in immunocompromised mice, have not been suc-
cessful in predicting these toxicities. Nevertheless, Donnadieu et al. (2022) have introduced
new tools and models (Table 10.3) that can more accurately reproduce the toxicities seen in
patients.
TABLE 10.3 Methods and tools used for toxicity assessment of engineered T cells, their advantages, limita-
tions, and potential improvements.
Toxicity
assessment Methods and tools Advantages Limitations
Required
improvements
CRS and
neurotoxicity
Ex vivo coculture
models with CAR T
(including tumor cells
and macrophages)
• Easy to implement
• Offers mechanistic
insights
• Not always
correlated with
in vivo CRS
• Not representative
of in vivo
complexity
• Development of
human 3D models
(organoids,
organotypical,
organ-on-a-chip)
that will integrate
other cells
Serum biomarkers from
treated patients
• Good correlation for
predicting severe
CRS and
neurotoxicity
• Not fit-for-purpose
biomarkers
• Unbiased
multiparametric
assessments
(longitudinal,
spatial, single cells)
Syngeneic models • Mimics crosstalk
between CAR
T cells and innate
immune cells
• Use of mouse CAR
constructs
• Differences between
mouse and human
T cells (poor
persistence of
murine T cells)
• Improvement of
CAR engineering in
murine T cells
Immunocompromised
SCID-beige mice
• Partly functional
innate immune cells
• Partially correlated
with patient CRS
• Species-specific
barriers requiring
high amount of
human CAR T cells
and tumor cells
• Model set-up with
different tumor
types
(Continued)
Development challenges 339
III. Specialty biologics and indications
TABLE 10.3 Methods and tools used for toxicity assessment of engineered T cells, their advantages, limita-
tions, and potential improvements.dcont’d
Toxicity
assessment Methods and tools Advantages Limitations
Required
improvements
Humanized NSG/
SGM3 mice
(reconstituted with
human PBMCs or
CD34þ cells)
• Recapitulates patient
CRS and
neurotoxicity
• Complicated,
variability in human
reconstitution, high
costs, long
engraftment times,
time-consuming
• Model simplification
and standardization
• Model set-up with
different tumor
types
• Improved
characterization of
neurotoxicity
Primates • Recapitulates patient
CRS and
neurotoxicity
• High predictive
value due to similar
physiology between
human and
nonhuman primate
cells
• Ethical
considerations
• High costs
• Limited cohorts
• Non-tumor-bearing
• Increased
accessibility and
dedicated personnel
On-target and
off-target off-
tumor
NSG mice • Valuable when the
expression of the
target antigen is
similar between
human and murine
cells
Syngeneic models • Effective when the
expression of the
target antigen is
similar between
human and murine
cells.
• Generation of
transgenic mice
expressing the target
antigen
• Intrinsic species-
specific differences
in target expression
• Generation of
transgenic mice for
multiple antigens is
laborious
• Improvement of
CAR engineering in
murine T cells
Humanized NSG/
SGM3 mice
(Reconstituted with
human PBMCs or
CD34þ cells)
• Informative when
expression of target
antigen is restricted
to hematopoietic
system
• Laborious
• High costs
• Long engraftment
times.
• Time-consuming
• Simplify and
standardize model
with different tumor
types
Primate models • High predictive
value due to
species-specific
similarities
• Ethical
considerations
• High costs
• Non-tumor-bearing
• Limited cohorts
• Increased
availability and
trained personnel
10. Considerations for nonclinical studies conducted to support the development of cellular therapies340
III. Specialty biologics and indications
TABLE 10.3 Methods and tools used for toxicity assessment of engineered T cells, their advantages, limita-
tions, and potential improvements.dcont’d
Toxicity
assessment Methods and tools Advantages Limitations
Required
improvements
Off-target
Screening with human
cell
Microarray platform
• Evaluate off-target
binding of human
CAR T-cell therapy
products (whole
cells or scFv
formats)
• High cost
• Increase protein
coverage
• Extension of the
technology within
the plasma
membrane proteome
and the secretome
GVHD/rejection MHC-disparate
Allogeneic mouse
Models
• Impossible to test
human T-cell
products
NSG mice • Xeno reactions can
be used as a
surrogate for GVHD
with human CAR-T
cells.
• Coadministration of
CAR T cells and
HLA mismatched
PBMCs can be used
to determine
alloreactivity.
• Not relevant to
evaluate the
rejection of infused
CAR T cells
• Limited utility with
PBMCs derived
from individuals
with several HLA
types (classes I and
II and minor HLAs)
Mixed lymphocyte
reaction
• Ease of
implementation
• Limited guidance on
what HLA types
(major and minor)
on donor PBMCs
must be tested in
the assay
TCR cross-
reactivity
In vitro screening of
TCR T-cell
Responses against
human cell lines
Expressing diverse
HLA alleles
• Ease of
implementation
In vitro screening of
TCR T-cell
Responses against
mutated cognate
Peptides
(Positional scanning
peptide libraries)
• Predicts the peptide
residues that are
essential for TCR
binding well
(Continued)
Development challenges 341
III. Specialty biologics and indications
Conclusion
Stem cell transplantation and CAR-T therapies have shown remarkable clinical responses.
To support clinical trials and registration, nonclinical studies with cellular therapies are con-
ducted to assess their efficacy, safety, and potential toxicity. The design of these studies
should be tailored to each specific therapy and consider factors such as the properties of
the therapy, clinical indication, and patient population. Key elements to consider include
the type of cell therapy (e.g., stem cells vs. CAR T cells), source of cells used (autologous
or allogeneic), and modifications made to the cells (such as the addition of a suicide gene
or gene editing), as they can impact nonclinical studies.
In addition to efficacy, these nonclinical studies can help to identify and potentially mini-
mize the risk for tumorigenicity, inappropriate migration, unstable fate, immune rejection,
GVHD, cross-reactivity, on-target/off-tumor or off-target toxicity or severe toxicities that
arise from the interaction between activated CAR-T cells and macrophages, and lead to
CRS and neurotoxicity.
Although significant progress has been made in unders tanding the toxicities associated
with stem and CAR-T cell therapies, there is still a need for improved nonclinical models
to predict and potentially mitigate these adverse events. Furthermore, the identification of
predictive biomarkers can aid in early detection and intervention in the clinical setting. These
advancements could ultimately lead to more cell therapies available to patients, that are safe
and effective.
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