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18 Current Regulatory Landscape forGene Therapy Product Development and theRole ofBiomarkers
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products approved by FDA that are designed to modify the human genome
(Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, Carviktyi, Zenteglo, Skysona),
registry studies must be conducted with lengthy LTFU to monitor patients for
delayed adverse events and secondary malignancy. With this LTFU requirement,
recent findings suggest that even with these safer approaches, clonal expansion,
myelodysplastic syndrome (MDS), and in some cases cancers are reported at some
frequency[32]. Therefore, another developing area of biomarker research is insertion site analysis (ISA) and measures of cellular oligoclonality which maybe precursors to cancer.
18.6 Safety Biomarkers for Gene Therapy Products
18.6.1 Immune Toxicities to in vivo gene therapy
Serious treatment‐emergent adverse events (TEAEs), including fatal hepatoxicities, dorsal root ganglia (DRG) toxicity, thrombotic microangiopathies (TMA),
myocarditis, and cytokine release syndrome, have been reported from invivo gene
therapy clinical trials using AAV vectors, which in the worst circumstances, have
resulted in the death of study subjects[33, 34].
Certain pre‐clinical and clinical manifestations of these TEAEs are closely connected to immune toxicities derived from the activation of innate (complement
and Toll‐Like Receptor (TLR) systems) and adaptive immune responses (Antigen‐
presenting, B and T cells) elicited against the delivery vector (viral capsid), the
expression plasmid (ssDNA, ssRNA, bacterial RNA), and/or the expressed TG
protein[35]. The activation of the classical complement pathway has been associated with TMA cases in GT treatment of spinal muscular dystrophy (SMA) and
Duchenne muscular dystrophy (DMD) [33]. Complement activation can occur
byeither direct binding of the C1q protein to the viral capsid or upon activation of
Fc receptors to pre‐existing anti‐AAV antibodies‐viral capsid complexes. Adaptive
immune responses to AAV capsids are evidenced by the signifcant prevalence of
pre-existing anti-AAV antibody (AVA) titers, treatment-boosted AVA titers, and
detection of AAV-specific CD8+ T-cell c responses upon in vivo GTP administration [35, 36, 37]. Also CRS, can occur as a consequence of robust activation of the
Toll‐Like Receptor family (TLR) of receptors. At the molecular level, the presence
of pathogen‐associated molecular patterns (PAMPs) exhibited in the viral capsid
and in the expression plasmids containing the TG can be recognized by members
of the TLR family and initiate MyD88‐mediated expression and secretion of pro‐
inflammatory cytokines such as type I interferons (IFN), IL6, and TNF, [35].
Newly developed AAV products are now engineered to reduce the abundance of
PAMPs with the aim to eliminate activation of TLR‐ mediated pro‐inflammatory
responses. As an example, expression plasmids containing reduced or no CpG
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motifs result in abrogation of TLR9 activation and minimal liver damage when
systemically administered into mice[38, 39]. Although is still not clear what is
minimal threshold of un‐methylated motifs needed to abrogate TLR9‐mediated
responses, product candidates are now engineered to reduce the content of CpG
islands in the oepn reading frames (ORF) of the expression vector[40].
A turning point for in vivo gene therapy came in 2014, when researchers
reported sustained but low‐level expression of Factor IX (FIX) in Hemophilia B
patients[41]. Earlier studies of using systemic AAV vector‐mediated gene therapy
for Hemophilia B resulted in an increase in liver transaminases timed with a loss
of FIX expression, and concomitant AAV capsid‐specific cellular immune res
ponse [42]. This was the first study to suggest that immune suppression may be an
effective mitigation strategy to avoid immune responses and prevent killing of
transduced cells. This hypothesis was later put to the test in a second clinical trial,
again in Hemophilia B, where further observations were made related to increased
alanine transaminase (ALT), loss of TG expression, and detection of T cell
response [43]. A tapering course of glucocorticoid (prednisolone) showed a
decline in ALT levels and stabilization of protein expression. Interestingly, the
obseved AAV capsid‐specific cellular responses were no longer detectable at later
time points [43]. This data suggested that the capsid‐specific immune cellular
response was likely directed against the transduced target tissue (e.g. liver) inducing cellular cytotoxicity and release of liver transaminase, and these two clinical
biomarkers were relevant for elucidating the mechanisms behind the loss of FIX
expression.
Anti‐TG cellular responses have also been documented in the recent analysis of
myocarditis in multiple Duchenne Muscular Dystrophy (DMD) trials[44]. Several
DMD patients receiving a single intravenous dose of an AAV vector carrying a gene
to correct the expression of mini‐dystropin developed symptoms of myocarditis
around a month following dosing [45]. These patients experienced significantly
increased muscle weakness and myocarditis, that improved upon various rounds of
immunosuppresive treatments. A combined effort between researchers and developers, demonstrated that those DMD patients carrying exon deletions affecting the
N‐terminal region of the dystrophin gene were the ones suffering from loss of efficacy and myocarditis. The most plausible explanation is that the immune system of
these patients lacks tolerance to the corrected version of the mini‐dystrophin protein introduced by the GT. Hence, the TG is recognized as a neo‐antigen by the
immune system which, in turn, mounted an anti‐TG‐specific cellular response (TG‐
specific CD8+ T cells) responsible for the observed tissue damage. It is not clear
why all patients with an apparent at‐risk genotype did not develop symptoms, but
biomarker assays to detect transgene reactive T‐cell responses may be relevant to
monitor in patients with null mutations or large deletions of the protein the GT
intends to repair.
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Although activation of cellular immune response to AAV vectors (both capsid and
transgene) can trigger cellular toxicity, it does not appear to be the only mechanism by
which AAV gene therapies mediate cellular damage. Selecting a high dose AAV
(10e13 to 10e14 vector genomes (vg) per kilogram (kg) of body weight) has been associated with an increased number in renal and hepatic toxicities in clinical studies[46].
One mechanism contributing to cytotoxicity is endoplasmic reticulum (ER) stress
response and unfolded protein response, where cells are overwhelmed and cannot
handle the translational demands imposed by gene therapy treatment. Hordeaux and
colleagues demonstrated that reducing transgene expression in DRG neurons by
including a specific microRNA target sequence prevented neuronal degeneration and
axonopathy following CNS administration of the vector[47]. The authors, as well as
several other published studies, reported that modulation of inflammatory responses
through coadministration of immunosuppressives was ineffective in reducing the
severity and incidence of the AAV‐mediated pathology suggesting a toxic effect mediated by the TG level of expression eliminating the potential for confounding immune
responses[48, 49, 50]. For neurotoxicity, serum neurofilament light chain has been
identified as a promising biomarker for neuronal damage in nonclinical toxicology
studies, and this may help clinical research programs design mitigation measures for
potential neurotoxocity in clinical studies[51].
As mentioned at the beginning of this section, cytotoxicity and tissue damage
may also be caused secondary to arteriole and capillary endothelial pathology and
microvascular thrombosis caused by thrombotic microangiopathy (TMA) [52].
Although the exact mechanisms for TMA are not fully understood, complement
activation is thought to be involved in this process[53]. This is why activation of
the classical complement pathway may be used as exploratory safety biomarker in
early studies seeking to understand the contribution of pre‐existing AVA to potential immune toxicities.
Current regulatory expectations are founded in the pre‐clinical and clinical findings described earlier. FDA and EMA acknowledge that because immune responses
can pose serious safety risks, measuring cellular and humoral immune responses to
both the vector and the TG‐encoded protein, or to the gene‐editing components, are
acceptable approaches to address clinical safety outcomes [8, 24, 26, 54]. Other
monitoring strategies may include periodic clinical, laboratory testing (i.e. pro‐
inflammatory cytokines), and imaging assessments [55]. Some of the principles
enunciated for the evaluation of immunogenicity of therapeutic proteins can be
applied to predict, evaluate, and mitigate the immunogenicity risks of GTP. For
example, the immunoassays developed and validated to monitor AVA and anti‐TG
antibody responses can be validated according to recommendations described in the
2019 FDA Guidance on Immunogenicity Testing of Therapeutic Protein
Products–Developing and Validating Assays for Anti‐Drug Antibody Detection[56].
Similarly, using immunogenicity risk assessment principles can help define a
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fit‐for‐purpose bioanalytical strategy and implementation of therapeutic interventions to reduce robust immune responses. The co‐development of in vitrodiagnostics
(IVD) has been discussed in another chapter of this book. Yet, the utility of using IVD
to determine pre‐existing AVA titers as exclusion criteria for patient enrolment and/or
treatment remains unclear. Reducing the incidence of immune‐related adverse
events in single dose treatments may still be mitigated through rational drug design
and concurrent implementation of therapeutic interventions specially for those
patients for which gene therapy is the only available course of action[57].
As per the duration of LTFU studies, health authorities recommend that a risk‐
based approach is followed, with a clear identification of delayed adverse events
risk factors[8]. For instance, for gene therapy, besides the validation of anti‐AVA
and anti‐TG antibody assays, it may be pertinent to apply a risk‐based approach to
identify patient and product‐related immunogenicity factors and define the final
bioanalytical strategy[58]. As evidenced by the myocarditis events observed in the
DMD population treated with an in vivo GTP, the evaluation of adaptive immune
responses to the TG product may be advisable for a patient population with null
mutations where central tolerance to the native protein may be absent. Similar
to what has been implemented for rare disease patients receiving enzyme‐
replacement therapy (ERT) products[59], a pre‐dose immune‐suppressive conditioning regimen (i.e. glucocorticoids) followed by a post‐dosing treatment with a
combination of immuno‐suppressants (i.e. rituximab, rapamycin), and provisions
for early administration of IL‐6 and complement system inhibitors (i.e. tocilizumab, eculizumab), can considerably reduce unwanted immune responses and
improve the efficacy of the treatment.
New‐generation AAV GT candidates are been developed using gene editing and
codon optimization technologies to select candidates with reduced immunogenicity risk, improved gene expression levels, and lower off‐target toxicity [40, 60].
This new generation of products is likely to redefine regulatory recommendations
but for the moment and until further clinical data are collected, requirements for
the validation of safety biomarkers should be discussed in advance with the pertinent health authority.
18.6.2 Immune Toxicities to Ex Vivo GT
Ex vivo gene therapy products were generally able to overcome the immuntoxicity
of invivo gene delivery mostly because lentiviral vectors LV have been used ex vivo
to transduce human cells and thereforeavoid oncogenicity concerns. Autologous
exvivo gene therapy products are by definition “self.” The components used for
genetic modification (e.g. viral vector) can be washed away during manufacturing
and prior to final product infusion. In addition, many exvivo modified cell therapy
treatments include a lymphodepleting (or ablating) conditioning regimen that is
18 Current Regulatory Landscape forGene Therapy Product Development and theRole ofBiomarkers
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administered to the patient to “make space” and allow engraftment of the transferred cells, considerably reducing the magnitude of otherwise robust immune
responses [61, 62, 63].
Nonetheless, early studies documented immunogenicity to autologous exvivo
genetically modified cells and postulated that this immune response negatively
impacted efficacy[27]. It is plausible that residual virus or manufacturing components and transgenes (non‐self, truncated, or misfolded proteins) trigger unwanted
immune reactions that may limit a gene therapy application. Xenogeneic respon
ses to chimeric antigen receptor (CAR) T cells have been documented in a number
of studies. In a CAR T‐cell product for colorectal cancer, the development of an
anti‐CAR antibody response coincided with rapid clearance of subsequent CAR
T‐cell infusions[64]. For another CAR T‐cell product directed against CD19, early
CAR clearance was described to be related with relapses[65]. Anti‐CAR antibodies against repeatedly dosed, transiently transduced CAR T cells directed against
mesothelin were shown to lead to anaphylaxis in at least one case[66]. Immune
responses to CAR T have been linked to the presence of non‐human sequences
present in the CAR construct and the cases where immunological responses to
CAR T products have been reported employed a murine derived single chain variable fragment (scFv)[67, 68]. New CAR T constructs are fully humanized molecules and carry a reduced risk for inducing anti‐CAR T antibodies. The
development of “off‐the‐shelf” CAR T therapy products is bound to replace the
use of autologous cells and the consequent risk of graft‐versus‐host disease risk
disease leading to poor engraftment of the product. This risk should be explore in
this new modality of CAR T products.
-
18.6.3 Long-Term Risks
Long‐term risks associated with genetic modification have always been a consideration in the development of gene therapy products. This has led to the development of safer LVV and AAV vectors. But even with these vectors, genetic and
immune toxicities remain of concern and need to be further elucidated [32].
Although the described toxicities have only precluded development of some GTP,
additional data should be collected to examine if biomarkers for tracking genetically modified cells, their clonal predominance, immune toxicities and possible
treatment options will be of greater importance in the future.
18.7 Concluding Remarks
The future for GT remains promising as we are better able to design and select
safer and more effective treatments based on the evaluation of key biological
References 443
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processes or biomarkers. As the field gains more experience, additional biomarker
development may shed light into the development of new GT products with
improved safety and efficacy. These new biomarkers may include those linked to
immune activation and toxicity and will eventually help improve the safety and
efficacy of new GT treatments.
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