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Significant growth of the cell and gene therapy (CGT) pipeline in recent years demonstrates the enormous potential of these modalities to treat or even cure otherwise intractable diseases. Several CGT products have been approved for clinical use over the past five years. More than 75 such products have come to the market around the world so far. They include chimeric antigen receptor (CAR) T-cell therapies that involve genetic engineering of patient cells ex vivo as well as in vivo gene therapies that introduce healthy copies of missing or faulty genes to patients through viral vectors.

CGT technology development is advancing rapidly. Efforts are under way to unlock the potential of gene-editing tools such as the Nobel Prize–winning clustered and regularly interspaced short palindromic repeats (CRISPR) technology, to implement nanomaterials for gene delivery (in place of viral vectors), and to develop off-the-shelf allogeneic therapies. As a result, an estimated ~1,200 clinical trials of CGT products are ongoing (1).

Roadblocks Ahead: Those product candidates face a number of obstacles on the road to becoming profitable commercial products. Some difficulties are associated with technological shortcomings. For example, viral vectors are crucial components of many CGTs, but they can cause immune reactions in some patients that undermine both their well-being and the efficacy of treatment (2). Meanwhile, the CGT market faces an increasing threat of shortages in materials (3). As more companies seek to use donor-derived cells for manufacturing allogeneic stem cells or T cells for off-the-shelf treatments, worldwide market fluctuations could follow. The likelihood of many simultaneous market entrants could escalate the need for raw materials.

Regulation of the research, manufacture, and application of CGTs presents another concern. Regulating their production is complicated because of the wide ranging complexity of these advanced therapies, from raw skin grafts (which are relatively simple) to gene-modified cell therapies (which are highly complex products). Many countries lack established regulatory frameworks for producing gene therapy products, especially aggravating the difficulties in commercializing these technologies across geographies. Some countries have set up regulatory schemes for advanced therapies and regenerative-medicine products, but with deepening discrepancies among jurisdiction, the world has failed to deliver an internationally unified framework so far.

The third major roadblock is related to cost. CGT costs average about US$1 million per dose, which makes them inaccessible as treatments for most patients around the world. Without newly designed alternative payment systems that include governments, insurers, and pharmaceutical companies, delivery of CGT cures to those who need them will not be sustainable.

Technical Challenges
Gene therapies face several technical obstacles before they can gain broad clinical application. A major concern is the possibility of an unwanted immune response against viral vectors carrying a therapeutic transgene. It happens when a patient’s immune system recognizes any part of the virus or transgene protein product as a foreign antigen. The resulting immune response can render a treatment ineffective, and it can be dangerous in some patients. Preexisting immunity against adenoassociated viruses (AAVs), one of the most commonly used viral vectors for in vivo gene therapies, has precluded up to 50% of patients from treatment (4). AAV-based treatments often cause a short-term hepatic immune response, which can be dampened with the use of antiinflammatory medications, such as steroids. A number of methods have been proposed to prevent immune detection of gene therapies, including the use of lipid nanoparticles for gene delivery or engineering viral capsids to evade recognition by patients’ antibodies.

Viral vectors also can cause off-target effects. Researchers discovered such an effect in a recent clinical trial, which tested a viral-based gene therapy for the treatment of Leber hereditary optic neuropathy (LHON) disease (5). The condition causes vision loss due to a mutation in a mitochondrial gene. After injecting a gene therapy (AAV carrying a healthy copy of the gene) into one eye and a placebo control into the other eye of the same patients, researchers observed visual improvement in both eyes. Further research suggested that viruses injected into one eye had traveled to the other. Those findings raise questions about the long-term effects of viral movements in patients and potential entrance into unintended cells.

Ex vivo therapies also exploit viruses to deliver genes, but with a much lower risk of off-target effects. The viruses interact only with target cells in a cell culture environment, not in a patient’s body, and only cells that stably express the desired gene are infused back into a patient. Hence, viruses have less chance of “wandering” through the patients’ tissues. A number of CAR T-cell therapies against blood cancers using the same basic paradigm have been approved in recent years. Such therapies involve engineering patients’ T cells to recognize cancer cells and then kill them.

Not all cell types can be isolated and grown in cell culture within a feasible time, however. For now, such treatments are limited to blood sources alone. Applying CGT technology is cumbersome and time-consuming in a clinical setting because it depends on the growth of a patient’s cells in a laboratory/manufacturing environment. And time is precious for most cancer patients. Off-the-shelf therapies that could be used immediately would be a solution to that problem. Donor-derived allogeneic T or natural killer (NK) cells could become options in the near future.

Another challenge awaits for companies that depend on allogeneic human materials such as hematopoietic stem cells. With the growing number of CGT companies and their potential simultaneous market entries comes a substantial possibility of mismatch between the demand for donor materials and commercial supply availability by 2025 (6). The problem could be worse for genetically diverse regions, such as in Africa, where the chance of finding matching allogeneic donors is low. Therefore, companies using allogeneic donor materials should consider constructing cell banks as a risk mitigation measure in their commercial readiness strategies.

Regulatory Concerns
CGTs frequently target diseases that afflict only a limited number of people. In fact, rare diseases account for about 70% of the investigational new drug (IND) applications submitted to the US Food and Drug Administration (FDA) for gene therapies. In such cases, clinical development can be complicated by the need to assess clinical safety and efficacy with small and often widely dispersed patient populations. Regulatory guidelines that require large pools of subjects for clinical trials are not relevant to the needs of these products. Their sponsors will require some flexibility in clinical trial design, which can be put into action only after rigorous evaluation by regulatory authorities. So it is best to start working with regulatory agencies early in the development of a CGT, either when designing a clinical trial or before reaching that point — during preclinical development, as is the approach taken by some sponsors. Some guidance documents issued by regulatory bodies can be valuable to product developers in designing clinical trials (see the “Examples” box).

The desire for standardization poses another challenge with CGTs. Their complex production involves many processing steps that involve different biological entities. CGTs can be made from altered cells or tissues, genetic materials, and/or vectors such as plasmids or viruses — with expanded patient cells, engineered organs, viral products, genetically modified cells, and/or innovative gene-editing processes. For example, the manufacturing processes for recently approved CAR T-cell therapies include steps such as isolation, culturing, and expansion of human T cells; production of viral vectors that carry the CAR gene using bacteria to amplify plasmid DNA encoding for viral components; transfection of T cells with viral vectors; and final isolation and formulation of cells for transport and delivery. Successful final products require each operation to perform optimally. Biologics in general are not as well defined as chemical entities. Standardizing approaches to those procedures as much as possible becomes important to minimizing variation across manufacturing lots and facilities.

That demands a significant effort on the part of regulatory decision makers to provide the necessary guidelines to help companies develop and commercialize CGT products. Regulatory agencies should work with industry groups in establishing standards to help developers manage their scale-up processes and the potential evolution of their products throughout the phases of clinical development. Such efforts will be crucial for the long-term safety and effectiveness of CGTs. With the expected wave of clinical trial applications soon to come, those same regulatory agencies are likely to be overwhelmed by the upcoming workload. We believe that they may require additional personnel to deal with these tasks.

Discrepancies among the CGT regulatory frameworks of different countries further complicates matters. Fostering convergence across nations with separate regulatory frameworks, along with reliance and recognition for countries without such frameworks, will be the most prominent means of overcoming obstacles to regulatory inclusion for the CGT market. The European Medicines Agency (EMA) and the FDA are working together to minimize uncertainties in the field. Such collaboration could be extended to relevant institutions in other countries. Working toward global regulatory convergence on CGTs — and the regulatory balance that eventually will result — will benefit patients around the world by improving the accessibility of these potentially revolutionary products. Harmonization will be essential for timely product development and availability, in part because it will enable product developers to submit regulatory applications efficiently and cost effectively across multiple jurisdictions.

To address contemporary regulatory issues for CGT products, foster convergence, and “encourage the Member states to strengthen their regulatory systems,” the World Health Organization (WHO) issued a recent draft document (7). The goal is to make development and access to these innovative medicines easier for patients in all parts of the world. That requires improving patient safety by limiting the exploitation of countries that lack suitable rules for the proper oversight of such innovative medicines.

Financial Issues
High costs are a significant challenge confronting the growth of the CGT market. Astronomic list prices for marketed CGTs hinder equitable access of patients to the drugs. A single dose can cost from a few hundred thousand up to $2.1 million dollars for Novartis’s viral vectored gene-delivery drug Zolgensma (onasemnogene abeparvovec) approved in 2020 to treat patients with the rare genetic disease spinal muscular atrophy (SMA).

Sponsors describe such prices as compensation for their own costs of investing in such a risky business. Research and development (R&D) expenditures into biopharmaceuticals are high, certainly. But another crucial factor driving up the prices of CGTs is their relatively small markets, with most such drugs targeting rare diseases.

To achieve equitable access for all patients who need them, governments and health insurers are expected to pay for these drugs. Considering the potential for upcoming approvals of new CGT products, the burden of those costs could put governments and insurers both under serious financial strain. Alternative payment schemes might relieve some of that.

One option is a value-based payment system in which manufacturers are paid if a treatment proves to be successful. Multiyear payments could be used if long-term effects are uncertain, with payments terminated if a drug ultimately fails to show its intended effects. An example of such an arrangement is the agreement between Spark Therapeutics and health insurance company Harvard Pilgrim Health Care for Luxturna (voretigene neparvovec-rzyl) treatment of patients with an inherited retinal disease (8). Otherwise, a subscription-based payment model, like that of some media streaming services, could provide an answer for other products.

Manufacturing CGTs is expensive. Raw materials such as viral vectors can make up a major portion of the associated cost of goods (CoG). Currently only a few biomanufacturing facilities can produce commercial-grade CGTs, and commercial scales are in thin supply at proportionally high prices. We believe that those costs will decrease as the number of available facilities and competition among contract biomanufacturers grow in the wake of an increasing number of CGT approvals. Advancements in technology also could drive prices down. Development of off-the-shelf allogeneic products such as CAR T-cell therapies and induced pluripotent stem cell (iPSC)–derived products should give rise to more affordable CGT products.

Challenge Accepted
Advancements in technology continue to bring once-futuristic advanced therapies to reality. As leading developers take their product candidates through clinical studies and ultimately to commercialization, particular challenges arise. Some have the potential to halt the progress of upcoming CGTs products and maybe even the industry segment as a whole. It will be better to face them at their roots and come up with proactive solutions now. Technological developments might help the industry to address concerns about undesirable side effects. Regulatory institutions should work with each other and with industry players to delineate principles for designing clinical trials and standardizing approaches to advanced-therapy biomanufacturing. Finally, all stakeholders should discuss and collaborate toward a manageable payment system that can make these therapies accessible to every patient who needs treatment.

References
1 Annual Report 2020: Growth & Resilience in Regenerative Medicine. Alliance for Regenerative Medicine: Washington, DC, 2020; https://alliancerm.org/sector-report/2020-annual-report.

2 Shirley JL, et al. Immune Responses to Viral Gene Therapy Vectors. Mol. Ther. 28(3) March 2020: 709–722; https://doi.org/10.1016/j.ymthe.2020.01.001.

3 Qiu T, et al. The Impact of COVID-19 on the Cell and Gene Therapies Industry: Disruptions, Opportunities, and Future Prospects. Drug Discov. Today 26(10) 2020: 2269–2281; https://doi.org/10.1016%2Fj.drudis.2021.04.020.

4 Bulaklak K, Gersbach CA. The Once and Future Gene Therapy. Nature Commun. 11, 2020: 5820; https://doi.org/10.1038/s41467-020-19505-2.

5 Sahel JA, et al. Gene Therapies for the Treatment of Leber Hereditary Optic Neuropathy. Int. Ophthalmol. Clin. 61(4) 2021: 195–208; https://doi.org/10.1097/iio.0000000000000364.

6 Mooraj H, et al. Cell and Gene Therapies: Delivering Scientific Innovation Requires Operating Model Innovation. Deloitte Insights 2020: https://www2.deloitte.com/content/dam/insights/us/articles/6642-cell-and-gene-therapies/DI_Cell-and-gene-therapies.pdf.

7 WHO Considerations on Regulatory Convergence of Cell and Gene Therapy Products. World Health Organization: Geneva, Switzerland, 16 December 2021; https://cdn.who.int/media/docs/default-source/biologicals/ecbs/who-public-consultation_cgtp-white-paper_16_dec_2021.pdf?sfvrsn=18f6c549_5.

8 Harvard Pilgrim Is First Health Plan to Directly Negotiate Outcomes-Based Agreement for Groundbreaking Gene Therapy. Harvard Pilgrim Health Care: Wellesley, MA, 3 January 2018; https://www.harvardpilgrim.org/public/news-detail?nt=HPH_News_C&nid=1471914707173.

Robert Salcedo is chairman and chief executive officer of OcyonBio, LLC Calle George Sanders, Bo. Camaceyes, Aguadilla, Puerto Rico 00603; https://ocyonbio.com. Corresponding author Will Rosellini, JD, MBS, MS, is cofounder and president of CytoImmune Therapeutics, Inc., 1218 South Fifth Avenue, Monrovia, CA 91016; 1-469-222-2350; https://cytoimmune.com.