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482 Amit Singh
altered to obtain maximum benefit from a combination drug therapy. Lessons from such
clinical trials will aid in rapid and informed decision-making and modulating the course
of the therapy to serve the benefit of the patient.
Multiple challenges need to be overcome to design better immunotherapy and can
benefit from technological advances as well as prioritization. The focus should be on better understanding, evaluating, and interpreting the data from phase I clinical trials so that
challenges of immunotherapy optimizations could be addressed early. This exercise
should be more rigorous with combination studies where the response could be difficult
to interpret and distinct conclusions may not be possible. Besides, in combination therapies, the immunotherapy arm is highly dependent on the target expression and the
immune makes up of the patient and so at times, an overwhelming response could be
interpreted as a combination benefit. A quick look at the challenges with the development of effective immunotherapy relays that they are highly interdependent where
advancement in one can greatly propel significant advancement with the other.
A preclinical animal model that reflects the clinical features of the disease will help in
improved predictive power, better identification and validation of biomarkers, and
organ-specific immune response. Appropriate diagnostic, predictive, and prognostic biomarker identification will facilitate a better understanding of the effects of endogenous vs
synthetic immunity and how these two independent immune responses can be combined
to obtain an improved response. All the clinical trials and preclinical research exploiting
endogenous or synthetic immunity have focused on one of the two approaches with limited overlap and bridging this gap could prove disruptive in cancer immunotherapy. The
field of cancer immunotherapy is highly interdisciplinary and requires a deep understanding of biology, immunology, data/statistical analysis, pharmaceutical, and clinical development and therefore a collaborative initiative across academic, government, and
industry partners is essential. A concerted and focused effort from these partnerships
would lead to significant advancement in the field.
3. Drug development considerations for clinical translation
Clinical translation of cancer immunotherapy involves the development of small
molecules (adjuvants) and biologics, each bringing a different set of challenges with it
and therefore altered the course of development. However, the fundamental principles
of drug development still remain the same with either type of drugs and require the same
rigor and caution. Small molecules form a small subset of this discussion and the major
focus will be on the development of an immunotherapeutic drugs that is biological in
nature such as proteins, gene therapy, or cell therapy. Immunotherapies of such categories can be divided broadly into three types: (1) active immunotherapy (vaccines), (2)
adoptive immunotherapy (transfusion of cells manipulated ex-vivo) and (3) passive immu-
notherapy (antibodies, receptor/ligand). Since these therapies augment immune response
through different mechanisms, they are bound to show nonspecific toxicity including auto-
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immunity. Besides, the development of biologics as a therapeutic drug requires careful
characterization and monitoring to ensure the quality of the product. The Food and Drug
Administration (FDA) is the regulatory body in the United States that is responsible for
monitoring the development, testing, and approval of all drugs and biologics. The following sections will summarize FDA’s approach to ensure the safety and efficacy of cancer
immunotherapies and focus on crucial considerations at different stages of drug development to ascertain successful clinical translation of a preclinical candidate.
3.1 Early-phase considerations
Early on in the preclinical drug development process, one of the most important considerations should be the strategies and plans to manufacture the drug at a scale that supports
the required dose during clinical trials and subsequently as a marketed drug to meet the
demand. FDA has a very strict guideline for the characterization of drug substances and
drug products at different stages of product development. There are several Code of Federal Regulations (CFR) that govern various aspects of the development of the biological
drug product, which will be referred to in the following section, and readers are encouraged to read them independently for detailed understanding. At the early stage of development, the product should be characterized to ensure quality as guided by its
preidentified critical quality attributes (CQA). “CQA is defined as a physical, chemical, bio-
logical or microbiological property or characteristic that should be within an appropriate limit, range or
distribution to ensure desired product quality.” Product characterization can be an arduous task
for complex biological molecules used in cancer immunotherapy due to the inherent variability of biological products and that the early phase of drug development does not
require an extensive characterization of contribution from product components. Drug
characterization is dependent on the stage of clinical development where for phase I,
a preliminary characterization with identified specification should be performed but as
the product moves up in the clinical progress, the quality target product profile specification becomes more defined and stringent. As the product reaches clinical-stage to support marketing approval (phase 3), the product characterization methods and processes
should be finalized, product quality parameters should be well defined with product
acceptance criteria in place and lot release standards built upon historical clinical batches.
Biological product characterization methods are required to ensure the quality based on
identity, purity, safety, and potency.
483Clinical translation and challenges in cancer immunotherapies
3.1.1 Identity
Identity is the most important property of any biological product and it should be confirmed by validated assays to be labeled and distinguished from any other product (21
CFR 610.14). Assays used for confirming the identity should be specific to the product
and indicate its nature/composition. The type of assay will depend on the nature of the
484 Amit Singh
drug, the assay development for a noncellular immunotherapy drug will be entirely different from those developed for cellular products. Some of the popular assay approaches
for cellular products include surface biomarkers/antigen markers mapping, genetic
expression, polymorphisms, lipid composition, secreted molecule analysis, or peptide
sequencing. Similarly, in the case of tumor antigen as a vaccine, often a peptide or protein
that serves as cancer-specific antigen to help develop an immune response against TAAs is
often conjugated with a carrier immunogenic protein (immunoconjugate) or developed
integrated as a fusion protein. Identity of such products will require understanding its
primary, secondary, and tertiary structure, protein size, and postsynthesis modifications.
All these analyses should also accompany an upper and lower acceptance limit for all identity assays based on rigorous, data-driven identity-function relationships.
3.1.2 Purity
Purity is defined as the relative freedom from extraneous matter in the finished product whether or
not harmful to the recipient or deleterious to the product (21 CFR 610.13). Conceptually, purity
is the absence of impurity and is therefore not measured directly; the measurement of
impurities is used to define the measure of drug purity. There are two approaches to measure purity; the absolute approach where the total amount of the impurities is determined
without detailed knowledge of those impurities or in chromatographic approach includes
detection and determination of the nature of the impurity. Biological products such as
cells or proteins purity would involve knowledge about unintended cell populations,
residual proteins, peptides, and other materials used during the manufacturing process
including growth factors, media components, and metabolic by-products. All the impurities should be characterized for their nature and their quantity and an acceptance criterion should be defined, guided by the batch-to-batch variability in the manufacturing
process.
Testing for pyrogenic/endotoxin content is a major aspect in establishing the purity of
the drug product and there are very strict guidelines for permissible limits based on the
route of administration and exposure in the recipient (21 CFR 610.13b). The concern of
endotoxin contamination levels is even more severe in the case where the biological
product is obtained using bacteria as manufacturing biofactories. The endotoxin levels
can be monitored at different steps of manufacturing to identify the source but from a
regulatory standpoint, the endotoxin level should be analyzed and reported from the final
product. The endotoxin acceptance level for a parenteral drug is at 5 EU/kg body
weight/h or below while for intrathecal administration the limit is set to 0.2 EU/kg body
weight/dose per FDAs recommendation.
3.1.3 Viability
This is a measurement that is specific to cellular therapies where a minimum viability
limit has to be established as a release criterion. Intravenous injections require a cell
viability level of at least 70% per FDA guidance and in c ases that the requirement cannot
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be met, data from different production batches should be collated, analyzed and recommendations for the appropriate levels should be submitted with evidence. In such
cases, the acceptance criteria for the product should be rolled out with information
about the composition, proof of a total number of viable cells, all phenotypically different subcellular populatio ns, and documentation evidence of its safety at the proposed
cell number/dose.
3.1.4 Potency
Potency is defined as the specific ability or capacity of the product, as indicated by appropriate
laboratory tests or by adequately controlled clinical data obtained through the administration of
the product in the manner intended, to effect a given result (21 CFR 600.3). Assays to test
the potency of cellular and gene therapy products has been recommended in a guidance
document by FDA and allows to ensure the quality of the drug product that is going to be
administered at different stages of clinical trial and as commercialized drug postapproval.
Potency assays are chosen from a battery of characterization assays that are developed
through a very thorough and rigorous analysis of the intermediates at different stages
of manufacturing. The characterization could involve molecular, biochemical, immunological, phenotypic, physical, chemical, or biological properties and understand the effect
of these properties on the pharmaceutical activity of the drug product. An ideal potency
assay(s) should be designed for a product with the aim to connect the biological effect of
the drug to the proposed mechanism of action. Biological drug product development is
fairly complex and therefore FDA acknowledges that the potency test may evolve during
the course of process development and that its implementation may be incremental
through different stages of development.
One of the biggest challenges that drug developers face is to identify suitable assays
that will be indicative of the potency of a biological drug product. The potency of cellular
therapy for example may not be dependent on one property or characteristic of the cell or
the potency cannot be attributed to one type of cell in a mixed cell population. It is often
advised to develop multiple characterization assays early on in the developmental path so
that as the understanding about the drug characteristic/efficacy grows, most indicative
assays from the pool could be selected to serve as potency assays for that product. In general, the potency of a drug is established through carefully designed and controlled studies
using a quality drug product with defined characteristics and correlated it with the attributes that define the “quality” of the product. Once a drug sponsor is able to establish
attribute(s) of the drug product that affects the efficacy, assays that measure that
attribute(s) can be adopted as potency assays. It is also highly recommended to open a dialogue with the FDA early in the course of drug development to be advised and develop a
framework to design, evaluate and validate potency assays.
485Clinical translation and challenges in cancer immunotherapies
486 Amit Singh
3.2 Late-phase considerations
The majority of late-phase drug development considerations come from large-scale drug
manufacturing challenges where the drug product is produced in large quantities to meet
the demands of large-sized, multisite phase 3 clinical trials. It is important to emphasize
that any changes to the drug production process and testing are easy to implement and
justify before the start of phase 3. Any changes made to the drug product after the completion of phase 3 would require additional justification and studies to ascertain the efficacy and safety to bridge the gap between the product used for clinical studies and that
going to be marketed. A change in the manufacturing facility, equipment or process is all
counted as a significant change and may warrant additional studies to ensure that the
change did not change the identity, purity, safety, and potency profile. Addressing change
in facility or equipment may not have a significant impact on the product quality but a
change in process may lead to change in impurity profile which can have downstream
effects such as toxicity or poor efficacy. It is therefore highly recommended to consult
with FDA prior to any significant change in the process to discuss the merits of the change
and the potential downstream implication of the changes. The following section will discuss some key considerations to factor in during early-stage development and follow up
during late-stage to ensure a smooth regulatory approval of drug products.
3.2.1 Controlling product variability
The most significant challenge with biological drug product development is to control
the variability in the product quality as a function of stages of development and from
batch-to-batch during the manufacturing process. Biological materials have a high inherent variability quotient which could be a function of the biological processes inside the
host that they are produced in (specifically in the case of proteins) as well as the process
that is used for their production. The same protein produced in a bacterial expression
system and mammalian expression system may have the same aminoacid sequence,
but their posttranslational modification (glycosylation, deamidation, methylation, phosphorylation, or acetylation) may be distinct and may influence their safety and efficacy
profile as drugs. A detailed discussion on these aspects has been reviewed elsewhere
and is highly recommended [32]. However, it is pertinent that as the drug is developed
through preclinical to clinical stages, factors that influence the variability of the drug are
identified and controlled in order to control the overall variability of the product.
3.2.2 Controlling quality of raw materials
The quality of the product can be heavily influenced by the quality of the starting materials and reagents that are being used. It is advised that early on in the development process, vendors and their materials/reagent qualification (and relevant assays to implement
it) are built into the quality assurance and quality control program. This is important for
two key reasons; first, if one vendor is unable to supply the starting materials/reagents,
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there are backups to ensure the continuation of the process and second, it helps understand the dependence of the product quality on the quality of the starting material as well
as the robustness of the drug production process with subtle variations. The optimal
approach would be to characterize the starting material with an internally developed assay
(and cross-reference with the certificate of analysis provided by the vendor) and document subtle variations in the quality from the vendor to vendor; run a critical comparative
assessment of the influence of materials from two different vendors on the quality of the
drug product and finally control the process to reduce the variability introduced by the
material.
3.2.3 Controlling assay and reference material quality
The quality of a product is as good as the analytical methods that are used to characterize
the product and assess its quality when compared to reference material. It is therefore
extremely critical that the assays developed are validate d with suitable reference standards to ascertain their sensitivity, accuracy, reproducibility, and repeatability. United
States Pharmacopeia (USP) defines reference standard as “highly characterized specimens of
drug substances, excipients, reportable impurities, degradation products, compendial reagents , and
performance calibrat ors”. FDA works closely with various other local and international
agencies such as the American Society of Testing and Materia ls (ASTM), American
Type Cell Collection (ATCC), and International Co nference on Har monizat ion
(ICH) to develop reference standards and materials. However, with novel drug products, such reference materials may not be available to compare the product quality with
and optimize as needed. In such cases, the reference material for a drug produ ct can be
produced in-house and could be a product from early lots tha t has been ex hausti vely
characterized by validat ed analytical methods. The quality of reference material is absolutely critical for establishing the identity, purity, safety, and potency of product from a
new batch. This problem is more complex with biological reference materials which
can be susceptible t o their storage conditions and handling. It is therefore important to
thoroughly characterize the reference material periodically and smaller quantities of a
product, that matches with that of the original reference material on quality attributes,
should be saved over the course of product development and commercialization for
continued monitoring.
487Clinical translation and challenges in cancer immunotherapies
4. Conclusion
Developing immunotherapeutic products is a highly challenging task that has
gained increased momentum in the past 10 years with breakthrough clinical results. Cellular therapy, cancer vaccines, monoclonal antibodies, therapeutic proteins, and
488 Amit Singh
antibody-drug conjugates are generally categorized under the umbrella of immunotherapy and are quickly becoming the standard option for the treatment of cancer. There are
significant challenges that still need to be addressed but the great advancement that has
been made especially in the past 5 years should be celebrated. Importantly, the regulatory
agencies have realized and acknowledged the developmental and regulatory challenges in
bringing these complex products to the market and are working aggressively to streamline and harmonize the process. FDA has been organizing workshops with international
regulatory agencies, published guidance documents to integrate the requirements for
such products, and formed advisory committees to discuss and address the scientific challenges and issues associated with the development of immunotherapeutic products. The
majority of the approved cancer immunotherapies have shown benefits in a smaller subset
of the larger patient population, primarily due to the complex underlying biological processes that result in the anticancer activity. However, as our understanding of cancer biology and its interaction with the human immune system grows, the outreach and benefits
of immunotherapy will also broaden within the patient populations.
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Index
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Note: Page numbers followed by f indicate figures and t indicate tables.
A
Acellular component, of TME, 136
Adipocytes/adipose tissue-associated fibroblasts,
252–253
Adoptive T cell therapy (ACT), 410–411, 475
Advanced malignancies, 331–332
ADXS-HPV, 48t
Agarose, 68–69t
AIM2- like receptors, 36t
Akoya Biosciences CODEX, 304–305
Albumin-binding vaccine, 212
Albumin-hitchhiking strategy, 231
Alginate, 68–69t
Alginate-based cryogel scaffolds, 78–80
Allogenic cell transfers, 411–412
Analytical validity, 361
AND gate, CAR-T cells with, 14f,15–16
Angiogenesis, 162–165, 255
Anti-CD326 antibody, 107
Antigen presentation, 246–247
Antigen-presenting cells (APCs), 231
Anti-PD-1, 103
Anti-PDL1/PDL1 imaging agents, 434, 436f
APS001F, 48t
Aptamer-based panels, 377–378
Attenuated Salmonella,49
AuNRs. See Gold nanorods (AuNRs)
Autoinducers, 40
Auxotrophies, 44
Axicabtagene ciloleucel, 5, 25
B
Bacillus Calmette–Guerin (BCG), 34, 242
Bacterial
therapeutics, 54–55
Bacteroides,42
bacTRL-IL-12, 48t,53
Barcode-based multiplexing, 304–305
β-cyclodextrin-based NPs, 232
Bicistronic CAR, 14f,15
Bifidobacterium longum,42–43
Biomaterials, 98–99, 98f
Bioprinting, 159
Biostable polymers, 70
Bispecific T-cell engagers (BiTEs), 12–13, 454
Bonemarrow-derived mesenchymal stem cells
(BMSC), 252–253
Bortezomib, 162–164, 163f
Branched DNA (bDNA), 305–306
Bulky electroporation, 176
C
Cancer, 63
Cancer-associated fibroblasts (CAFs)
engineered nanovaccine against stromal antigens
DCs vaccines, 278
fibroblast activation protein (FAP) expression,
277–278
multivalent vaccines, 278–279
heterogeneity
of origin, 252–253
phenotype, 253
hypoxic TME, 254
manifestations, 252
regulation by ECM remodeling, 254
regulation by tumor angiogenesis, 255
regulation via paracrine pathway,
253–254
regulatory effects on adaptive immune cells
T cells, 260–261
Tregs, 261
regulatory effects on innate immune cells, 256f
dendritic cells (DCs), 259–260
myeloid-derived suppressor cells (MDSCs),
259
natural killer (NK) cells, 258–259
tumor-associated macrophages (TAM),
255–258
reprogramming to immunosupportive state
fraxinellone into nanoemulsion (nanoPue),
277
genotoxic chemicals, 276–277
puerarin into nanoemulsion (nanoPue), 277
resting fibroblasts, 252
491
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