CAR-T Cell and Gene Therapy Market: Challenges and Opportunities

Some gene therapies regulate the expression of genes through the delivery of RNA. The predominant technologies include RNA interference (RNAi), which halts production of disease-causing proteins; antisense interference and microRNA modulation (miRNA), which inhibit or enhance translation of mRNA into target proteins; and messenger RNA (mRNA), which generates therapeutic proteins.⁷ RNA therapies can also be administered in vivo or ex vivo. 

CAR-T cell therapies have achieved commercial success more quickly than gene therapies in terms of generating significant revenue and profits, because CAR-T treatments can target diseases affecting larger patient populations (e.g., hematological cancers).

Currently, most gene therapies are licensed in the rare disease field and are administered locally to closed systems, such as the eye or brain, where the viral vector delivery vehicles are protected from attack by the immune system. AAVs are naturally occurring viruses found in the lungs of most humans, and thus there will always be some natural immunity to the AAV vectors used for GT. The closed systems theory limits the number of indications treatable by gene therapy, most of which are rare diseases that affect small patient populations. 

There is hope that gene therapy will work for larger patient populations, such as hemophilia A and B, neurological disorders, and heart disease through systemic delivery. Toxicity issues have been raised about such systemic treatments using current vector delivery systems, highlighting future needs for novel vectors or non-viral delivery systems for treatments of this kind.

For instance, Dr. James Wilson at the University of Pennsylvania, one of the pioneers of gene therapy, publicly expressed grave concern about the safety of using high doses of AAV in gene therapies and, in fact, resigned his position from the Board of Directors of Solid Biosciences in January 2018 for this reason. His resignation was prophetic, because, in March 2018, the FDA placed a hold on Solid Biosciences’ clinical trial to treat Duchenne muscular dystrophy owing to reduced red blood cell and platelet counts in treated patients. A second clinical trial hold was placed on Solid Biosciences in 2019 and lifted in 2020.^15-17

Using more advanced, modified viral vectors or non-viral gene delivery are potential solutions. Non-viral delivery is in its infancy, however, and further advances in nonviral solutions are needed to completely avoid the potential for immune responses. 

The ongoing advances and increasing interest in both AAV-based gene therapies and LV-based CAR-T cell therapies, however, are creating an additional challenge. The most common systems for viral vector production require three to five plasmids as starting materials for transfection of the relevant therapeutic genes into mammalian cell lines. With so many biotech start-ups and big biopharma companies establishing pipelines of gene and gene-modified cell therapies, the demand for GMP plasmid DNA and viral vector manufacture has skyrocketed. So has the need for outsourced viral vector manufacturing services, due to the specialized expertise and production capabilities required.

As a result, there is limited availability of both key raw materials and manufacturing capacity. Most university-based centers used for the production of clinical trial materials have waiting lists of up to two years. ²⁴⁼⁷ Larger-scale production facilities, mostly operated by contract development and manufacturing organizations (CDMOs), are as or even more limited and operate at high capacity-utilization rates. This issue is being addressed to some extent by investments on the part of raw material suppliers, drug developers and CDMOs serving the gene therapy sector (see the full report).

There are numerous factors that must be considered when establishing a manufacturing strategy for gene and gene-modified cell therapies. Many of the key development needs have been addressed in the road map for gene therapy established by the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) with the collaborative input of industry, academic, and government experts.18 First, the disease target, the dose for each patient, the size of the patient population, and the expected market penetration will dictate the quantity of product that must be produced.¹⁹

Whether the product is a gene or gene-modified cell therapy is a key consideration.²⁰ Ex vivo therapies require transfection and cell expansion via cell culture, while in vivo treatments only require vector manufacture. Production processes for autologous therapies must be scaled out, while those for allogeneic treatments can be scaled up. The choices of viral or nonviral delivery and the specific vector type (i.e., lentivirus, recombinant AAV, plasmid DNA) have a direct impact on the optimum upstream and downstream manufacturing platforms — many of which are emerging or still under development — as well as control strategies and analytical requirements.²¹ 

The possible regulatory pathways must also be considered, particularly whether an expedited approval process will be sought, which will affect manufacturing timelines. Equally important is the decision regarding where manufacturing will take place — in house or at a CDMO.²⁷ Either way, access to capacity in appropriately designed facilities leveraging appropriate technologies must be established.²¹ 

Other hurdles include the high cost of gene therapy development, which has led to record high prices for those products that have been approved. Compared with conventional biotherapeutics, process development and manufacturing costs are higher, while clinical development can be less costly, since CGT trials are typically smaller and quicker, albeit often more complex. There is also a need to increase the persistence of gene therapy treatments to ensure that they provide the desired therapeutic effect throughout the lifetime of patients. Technology that enables the development of gene therapies targeting multiple genes is needed in order to treat diseases that are driven by multiple dysfunctional or missing genes, such as Alzheimer’s disease and diabetes.²² 

In the short term, there is a fundamental need to establish robust, reliable, and readily scalable processes for the GMP manufacture of viral vectors and to install more production capacity so approved treatments can reach the market as quickly as possible. During development, most gene therapies have been produced in the lab using small-scale equipment that is operated manually and not practical for larger-volume manufacturing. Manufacturing issues — particularly scale-up challenges — for gene therapies are in fact a top concern for the FDA. ²²

Equipment suppliers have made progress in developing bioreactors and downstream processing systems amenable to vector production (see the full report), but more work needs to be done.²³

Despite these challenges, venture capitalists are eager to pump billions of dollars into both gene and cell therapy companies. A rapid return on investment (ROI) — along with the potential for these therapies to target the root genetic causes of disease and be truly curative — is the allure, with candidates moving from clinical trials to commercial approval in 4–5 years. Indeed, venture capital and large and mid-sized pharma companies are actively funding start-ups and more established firms focused on developing novel gene therapies, as well as investing in their own programs.⁷

In 2020, the regenerative medicine sector attracted $15.9 billion in financing through just the first three quarters of the year, shattering the previous record of $13.3 billion for all of 2018, despite the COVID-19 pandemic.⁵ Public financing continued to drive the sector through the end of Q3 2020, through both IPOs ($2.8 billion) and follow-on financing ($5.7 billion). Venture capital financing at $4.1 billion through the first three quarters of 2020 was also on track to surpass the previous record of $4.3 billion set in 2019. Gene therapy financing totaled $3.5 billion in Q3 2020 alone and $12 billion through the end of Q3, up 178% and 114% from 2019 levels, respectively.

1. “FAQs about Rare Diseases.” National Institutes of Health. Accessed 6 Feb. 2021. 
2. The Alliance for Regenerative Medicine Announces Record Sector Financing in 2020. The Alliance for Regenerative Medicine. 19 Nov. 2020. 
3. Finkel, Elizabeth. “The gene therapy revolution is here. Medicine is scrambling to keep pace.” The Conversation. 4 Jun. 2019. 
4. Q2 2019 Quarterly Regenerative Medicine Global Data Report. Alliance for Regenerative Medicine. 2019. 
5. ARM’s Q3 2020 Trend Talk. Alliance for Regenerative Medicine, 2020. 
6. Curran, Kevin. “The gene therapy sector is experiencing an acceleration.” Rising Tide Biology. 10 Jun. 2019. 
7. Sullivan, L.S. and J. Bergin. “Genetic Modification Therapies – Clinical Applications & Technology Platforms.” Drug Development & Delivery. Nov./Dec. 2018. 
8. Global Cell and Gene Therapy Market to Surpass US$ 35.4 Billion by 2026. Coherent Market Insights. 5 Feb. 2019.  
9. Gene Therapy Market Size, Share & Trends Analysis Report By Vector (Lentivirus, RetroVirus & Gamma RetroVirus), By Indication (Beta-Thalassemia Major/SCD, ALL, Large B-cell Lymphoma), And Segment Forecasts, 2019 – 2026. Rep. Grand View Research. Apr. 2019. h
10. Gene Therapy Market Size Worth $5.55 Billion By 2026 | CAGR: 33.9%. Grand View Research,. Apr. 2019. 
11. Global $1.01 Billion Cell and Gene Therapy Market 2019-2025: Steady Investment and Consolidation in the Market. Research and Markets. 7 Aug. 2019.  
12. Gene Therapy Market by Vector Type (Viral Vector and Non-viral Vector), Gene Type (Antigen, Cytokine, Tumor Suppressor, Suicide, Deficiency, Growth Factors, Receptors, and Others), and Applications (Oncological Disorders, Rare Diseases, Cardiovascular Diseases, Neurological Disorders, Infectious Disease, and Other Diseases) - Global Opportunity Analysis and Industry Forecast, 2017-2023. Rep. Allied Market Research. Feb. 2018. 
13. Gene Therapy Market (Product - Yescarta, Kymriah, Luxturna, Strimvelis, Gendicine; Application - Ophthalmology, Oncology, Adenosine Deaminase Deficient Severe Combined Immunodeficiency (ADA-SCID)) - Global Industry Analysis, Size, Share, Growth, Trends, and Forecast 2018 – 2026. Rep. Transparency Market Research. Oct. 2018. 
14. Liu, Cynthia. “Gene and cell therapy: The R&D and market insights you need to get a competitive edge.” Chemical Abstract Service Blog. 12 Apr. 2019. 
15. Walters, Jennie. “James Wilson resigns from Solid Biosciences’ Board.” Biocentury. 17 Jan. 2018. 
16. Linnane, Ciara. “Gene therapy stocks slammed after scientist reveals safety concerns.” Market Watch. 30 Jan. 2018. 
17. Vinluan, Frank. “FDA Lifts Solid Bio Clinical Hold, Duchenne Study Cleared to Resume.” Xconomy. 1 Oct. 2020. 
18. Carbonell, Ruben, Arpan Mukherjee, Jonathan Dordick and Christopher J. Roberts, “A Technology Roadmap For Today's Gene Therapy Manufacturing Challenges.” Cell & Gene. 18 Apr. 2019. 
19. Snyder, Richard O., Clive Glover, Rajiv Vaidya and Matt Niloff. “Accelerating The Development of Viral Vector Manufacturing Processes.” Pharma’s Almanac. 24 May 2019. 
20. Sargent, Brandy, Clive Glover, Pratik Jaluria, John Madsen, Alan Moore and Tracy TreDenick. “Key Considerations for Gene Therapy Commercialization.” The Cell Culture Dish. 2018.  
21. Heidaran, Mo. “Establishing Manufacturing Controls: A Hurdle for the Cell and Gene Therapy Industry,” Regulatory Affairs Professionals Society. 25 Apr. 2019. 
22. Dunn, Andrew. “The gene therapy era has arrived. So have the challenges.” BioPharma Dive. 7 Jun. 2019. 
23. Challener, Cynthia A.  “Cell and Gene Therapies Face Manufacturing Challenges.” BioPharm International. 30:20–25 (2017). 
24. “Gene Therapy: A Paradigm Shift in Medicine,” Informa White Paper. Nov. 2018.