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The reason for interest in immunogenicity to safety scientists is that the nature and magni-
tude of the immune reaction to viral vectors not only impacts therapeutic exposure of the
transgene but can, if severe enough, manifest in irreversible cell, tissue, and organ injury.
The most recent example of this was the fatality in a trial, where a patient died within a
week following treatment with a GT containing a Cas-9 nuclease due to a severe immune re-
action resulting in acute respiratory distress syndrome (ARDS) (Lek et al., 2023b; Philippidis,
2023). The precise mechanism underlying this fatality remain unknown, albeit preexisting pa-
tient comorbidities may have contributed.
Innate immunity is the immediate and rapid detection and elimination of viruses and path-
ogens and vectors derived from viruses are not distinguished from their WT counterparts.
The receptors of the immune system are fully encoded in the genome and do not undergo
somatic recombination; therefore, the innate immune response is fixed and nonspecific.
The level of the innate immune response is however, dose-dependent. Innate immune
response mechanisms include pattern recognition such as Toll-like receptor (TLR)-dependent
and myeloid differentiation primary response 88 (MyD88) protein-dependent pathways, that
result in the rapid activation of over 30 different transcription factors (e.g., NF-kB and inter-
feron regulatory factor (IRF)-3), and the release of numerous cytokines and chemokines
(Chaudhary et al., 2023; Dalskov et al., 2023). In addition, innate immunity primes adaptive
immunity against viruses and viral vectors alike. The very presence of viral genomic mate rial
in cells, in most instances rapidly triggers TLR activation so as to clear the viral genome from
the cells and directly signal the adaptive arm of the immune response (Zhu et al., 2009).
Evolutionarily, innate immunity is linked to hemostasis and acts cooperatively as part of
the host defense against pathogens and cellular/tissue injury. The complement system, which
is integral to innate immunity, shares numerous interactions with constituents of the hemo-
static pathway (Ricklin et al., 2016; Kemper et al., 2023; Whyte, 2023). This relationship, which
is encompassed by the term immunothrombosis, is demonstrated by specific downstream ef-
fects of complement activation and cytokine release including thrombocytopenia, dissemi-
nated coagulopathy, thrombotic microangiopathy, and multiorgan vascular injury (Whyte,
2023). All of these clinical sequelae have been associated with immune responses to viral in-
fections and more recently with viral vectors (Ertl, 2022).
Adaptive immunity is oftentimes delayed and variable, based on the strength of the epitope
being presented and the preexisting immunologic memory of the host. The ability of the
adaptive immune system to undergo gene recombination confers enormous diversity and po-
wer in its immunoglobulin (Ig) Ab and T-cell receptor responses. This arm of the immune sys-
tem becomes a challenge for some viral vectors such as AAV, where animal models and
patients who may have had prior exposure to a WT AAV infection and therefore have pre-
existing Abs, can be precluded from the benefit of GT (especially in the context of a drug
product administered syste mically).
Unsurprisingly, this together with the desire to bring GT to a broader patient population
with preexisting Abs, has spurred an enormous scientific effort to understand how to derisk
for immunogenicity (Vandamme et al., 2017; Verdera et al., 2020). In fact, both the Workshop
on Recent Issues in Bioanalysis as well as the IQ consortium drafted excellent and informative
white papers with recommendations of how best to tackle immunogenicity assessments for
GTs (Loo et al., 2022; Yang et al., 2022).
9. Preclinical development of viral vector gene therapies296
III. Specialty biologics and indications
Linking immunity and nonclinical findings
Efforts to mitigate immunogenicity essentially fall into two broad buckets: (1) vector modi-
fication e.g., codon optimization, virion engineering to cloak from innate or adaptive re-
sponses, introduction of immune blocking sequences in the transgene sequence, improved
manufacturing to reduce the number of partial or empty virions and host cell byproducts,
and (2) patient interventions e.g., improved immunosuppression protocols and methods to
deplete anti-vector antibodies (Vandamme et al., 2017; Verdera et al., 2020; Wright, 2020;
Muhuri et al., 2021; Coroadinha, 2023). The field is advancing quickly with multiple ap-
proaches to modify GTs (Mingozzi and High, 2017; Ronzitti et al., 2020). To date, no single
approach has solved the problem of immunogenicity, although each change does abrogate
or delay immunogenicity in model systems. It is not the focus of this chapter to discuss
each approach in detail, however solving this problem will improve patient access and safety
as well as unlock the ability to improve exposure and efficacy in target tissues. Yang et al.
(2022) provides an excellent summary table of products, patient related risks and their
impact.
In nonclinical studies, assessment of immunogenicity is complex with regulators often
asking for measures of both cellular (T-cell responses) and humoral responses (total and
neutralizing antibodies (Abs)) to the vector and transgene. Naïve animals, irrespective of spe-
cies, will mount both a response to the virion (like patients), but also to the presence of the
human transgene (which may be unlike patients) (Smith et al., 2022; Eggers et al., 2022).
Translating the relevance of these responses for patient safety is complex as animal models
do not fully represent the human immune system. These two topics are briefly discussed
with respect to the design and translation of immune findings.
Capsid/vector envelope immune responses
Immune reactivity to the presence of the viral vector (capsid or vector envelope) are not
surprising. In fact, most humans and animals have had prior exposure to one or more WT
AAV’s and have immune memory in the form of preexisting Abs (Boutin et al., 2010; Aronson
et al., 2019; Dai et al., 2022; Klamroth et al., 2022). Today most developers prescreen animals,
particularly NHPs, as they often are a natural host for viruses used to develop GT products,
for the presence of neutralizing Abs to the viral vector serotype of interest to help ensure that
the viral vector being tested is not neutralized. Similar approaches are taken in clinical trials
of systemically administered GTs, whereby a threshold for acceptable neutralizing or total Ab
response is determined prior to study enrollmen t. Part of the challenge for developers, is that
screening for prior immunity to a specific vector serotype overlooks the polyclonal nature of
the immune response to cross react to other serotypes that is in part driven by reacting to
conserved regions on the vector capsid or envelope (Tseng and Agbandje-McKenna, 2014).
Transgene immune responses
Immune reactivity to the transgene product, particularly if the human protein is expressed
in animals, is likely to evolve with time. However, evolution of toxicities in animals associ-
ated with immunogenic responses to the transgene may not be driven by the same mecha-
nism of action as found in humans (Eggers et al., 2022; Muhuri et al., 2022). The one
exception might be for patients with true null mutations, e.g., cross-reactive immunological
Lessons learned from clinical trials to guide future development 297
III. Specialty biologics and indications
material (CRIM) negative, who do not express any detectable amount of the transgene pro-
tein. In these patients, introduction of the therapeutic protein e.g., through enzyme replace-
ment, triggers immunogenicity with loss of efficacy and durability over time because of the
repeated administration and stimulation of the immune system (Li et al., 2021). It is difficult
to know if CRIM negative patients receiving GTs will lose efficacy with time or whether this
specific therapeutic modality will lead to the establishment of tolerance (Keeler et al., 2019,
Samelson-Jones and Arruda, 2020). Many of the patient cohorts undergoing GT treatment
represent rare disease patients with small numbers, making it difficult to infer strong statis-
tical correlations between immune responses and changes in transgene expression. Certainly,
there are examples of sustained transgene expression in animals and humans for 10þ years,
but concerns still exist for robust durability of expression (Muhuri et al., 2022). Most notably,
the clinical trial testing of valoctocogene roxaparvovec (Roctavian) showed improved bleed
times (Biomarin, 2023). It is uncertain if this represents a stabilization of transgene expression
or a concern for longevity of expression e only time will tell. It is however exciting, that this
GT was approved for commercial use in the EU and US in January and June 2023,
respectively.
On the use of immunosuppressants in nonclinical studies
Traditionally, toxicology studies are conducted in healthy animals without the use of im-
munosuppressants, specifically so that developers can evaluate the int erplay of the immune
system following treatment. In some instances, pharmacologists and toxicologists have lever-
aged immunosuppressive protocols in their studies in order to circumvent strong immuno-
genic reactions to GT vectors as well as the transgene product. However,
immunosuppressants present challenges and should be carefully considered before employ-
ing, if at all, in toxicology studies. Firstly, they cannot fully overco me xenogenic hurdles and
with time animals will break tolerance, so duration of immunosuppression is limited. Sec-
ondly, in applying immunosuppressants it is difficult to interpret local and systemic tolerance
to a GT, particularly if using conventional immunosuppressants such as cyclosporine and
dexamethasone that have broad activity and will mask immunogenicity. Developers need
to consider the translational utility of immunogenicity assessments in nonclinical species
and how to set an NOAEL if the top GT dose evaluated in animals drives a toxicity that is
in part related to immunogenicity. Lastly, use of immunosuppressants for extended periods
of time can lead to the emergence of secondary infections, complicating any safety interpre-
tations of GT’s.
In clinical trials, management of immunogenicity now typically involves prophylactic and
protracted treatment with a cocktail of immunosuppressive drugs that are weaned some
weeks or months following initial vector dosing. This approach, while helpful in the manage-
ment of immune-mediated toxicities such as hepatoxicity, neurotoxicity, and cardiac toxicity,
is not the solution. Decreasing or eliminating immune recognition and neutralization of viral
vectors whether by innate sensors (PRR’s, etc.), preexisting Abs, complement opsonization, or
cellular engulfment (either by professional or nonprofessional cells), would mean more of the
administered dose reaches the intended target tissue. Improving target exposure by mini-
mizing imm unogenicity, can result in decreased doses with improved safety.
The challenge ahead is to find the right combination of immune modifications to the vec-
tor, transgene, its manufact uring, and patient management, that improves patient safety. The
9. Preclinical development of viral vector gene therapies298
III. Specialty biologics and indications
complexity of immunogenicity is a salient reminder that the mammalian immune system has
a long history of evolving alongside viruses, developing new and efficient ways to recognize,
target, and destroy.
Insertional mutagenesis
Viral vectors leverage the machinery of the virus to deliver genetic material to cells of the
body. This ability raises concerns for oncogenesis stemming from a direct consequence of
insertion into the host genome or driving genomic instability that may drive clonal selection.
The potential risk for this directly correlates with the specific viral vector. Integrating viral
vectors such as LV, in spite of advances in their design, carry a perceived risk for insertional
mutagenesis and oncogenic transformation, more than any other vector platform. This is
attributed to the inherent nature of the virus to integrate its DNA into regions of open chro-
matin and insertion within transcriptional units (Milone and O’Doherty, 2018). To date, the
most common application of LV vectors has been in the ex-vivo manufacturing of CAR-T
cells for oncology and hematopoietic stem cells (HSCs) for hemoglobinopathies. Two prod-
ucts using LV vectors in an ex-vivo application of HSCs both from bluebird bio, Beti-cel (Zyn-
teglo) for the treatment of b-Thalassemia and sickle cell disease (SCD), and Eli-cel (Skysona)
for the treatment of CALD, recently raised concerns for insertional mutagenesis. Both prod-
ucts experienced clinical holds in 2021: Zynteglo, when four patients showed emergence of
acute myeloid leukemia (AML) and Skysona, when three patients developed myelodysplastic
syndrome (MDS). These holds sparked fears that the field might be revisiting the ghosts of
the past. Dedicated investigations of these incidents by the sponsor showed that at least
two of the three cases of myelodysplastic syndrome may have been related to insertion
into a proto-oncogene called MECOM. Despite this risk, Skysona has been approved because
the benefits far outweigh the risks to these critically ill patients. This approval was granted
with the agreement to continue long-term monitoring of CALD patients receiving the GT
and inclusion of a Black Box warning on the product label for the risk of hematological ma-
lignancy (FDA, 2022g; Patel, 2022). Of concern, genomic analysis of the remaining treated
boys also show insertion into MECOM, with evidence of an emerging clone, and in at least
four patients the presence of bone marrow dysplasia as noted in the summary basis of
approval (SBA). In the case of AML, the investigations showed that it was very unlikely
that it was triggered by the LV vector, as integration site analyses showed that the most
frequent gene of insertion was around the VAMP4 gene. VAMP4 has no known association
with the development of AML nor with processes such as cellular proliferation or genome
stability. These cases reinforce that, with the use of integrating vectors there is a need to pro-
vide data to support an understanding for the risk of insertional mutagenesis.
A review of the most common forms of retroviral vector derived insertional mutagenesis
classifies four mechanisms by which these typically occur: (1) enhancer insertion: gene activa-
tion by integration of an enhancer sequence, (2) promoter insertion: gene activation by integra-
tion of a promoter sequence, (3) disruptive insertions: gene inactivation by insertional
disruption, and (4) substitutional insertions: gene activation by mRNA 3
0
end substitution
(Bushman, 2020). Examples of each type of genetic insertion have now been documented
in patients and were associated with an increased risk for clonal expansion. An excellent
Lessons learned from clinical trials to guide future development 299
III. Specialty biologics and indications
review is provided by Bushman (2020). Based on the science today, clear plans to understand
risk for insertional mutagenesis as well as long-term follow up will likely be an ongoing ask
for sponsors using integrating viral vector platforms.
While AAV has not been historically associated with genomic integration, nor with any
oncogenic transformation in the vast number of treated patients to date, emergence of low
levels of integration and hepatocellular carcinoma (HCC) in neonatal mice have raised
concern for regulatory authorities (Russell, 2007; Chandler et al., 2015). Further investigation
has demonstrated that these tumors resulted from integration of sequences in the Rian locus,
a genomic locus only found in mice thereby questioning their translational relevance (Bolt
et al., 2021). In addition, an AAV5 clinical trial for the treatment of phenylketonuria (PKU)
was placed on clinical hold in 2021 due to nonclinical pharmacology study data sh owing
emergence of liver tumors in mice in the high dose group at week 52 (Terry, 2021). No further
information has emerged as to whether this issue has been resolved. Importantly, similar
findings have not emerged in humans or any of the longest AAV dog studies to date (Elver-
man et al., 2017; Batty et al., 2022; Retson et al., 2023). Only one study has hypothesized that
clonal expansion associated with vector integrations occurs in the liver of dogs following sys-
temic AAV, but without associated evidence of liver enzyme changes or hepatic injury
(Nguyen et al., 2021). In this light, it is difficult to determine if the integrations identified
within the clonal population would be asso ciated with a diagnostic outcome of hepatocarci-
noma. In fact, a more recent follow up to this work suggests that despite the presence of inte-
gration there was no evidence for tumorigenesis (Batty et al., 2024). An in-depth review of the
state of the science for AAV integration was held in 2021 at the American Society of Gene and
Cell Therapy, and the outcomes of that panel concurred that the risk of AAV-mediated onco-
genesis in humans was considered theoretical (Sabatino et al., 2022). It is clear however, that
safety data from research and pharmacological studies are taken seriously by regulators and
that safety signals are not the exclusive realm of GLP toxicology work.
In summary, investigators should consult with the regulators to ascertain if a genotoxicity
plan is warranted for GT programs to avoid unnecessary program delays and costly mistakes
irrespective of the platform used.
Conclusions
The promise of GT, once just a dream more than 6 decades ago, is now realizing the prom-
ise of ‘cure’ not just treatment for patients with rare diseases but also chronic diseases such as
hemophilia and sickle cell disease (Friedmann, 1992). The recent patient deaths in clinical tri-
als with some GTs is sobering and reminds us that these are novel medicines about which we
still have much to learn. The pace at which the field has moved over the last 2 decades, from a
world-wide moratorium on all GTs to the successful treatment of a growing number of pa-
tients, is testament to the enormous efforts of dedicated scientists and clinicians. Ten years
ago, the first edition of this book saw the field still struggling with manufacturing sufficient
quantity of vectors to treat a single patient with an adequate systemic dose. In the next
10 years it will be exciting to see how the field has evolved. In the words of Joseph Chamber-
lain (and not a curse), “I think that you will all agree that we are living in most interesting times”.
9. Preclinical development of viral vector gene therapies300
III. Specialty biologics and indications
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