Confronting Challenges in Developing Cell and Gene Therapies

Cell and gene therapies cover a broad spectrum, from immunotherapies to gene editing. If one word describes the market for these therapies, it would be: growing. Estimates vary, but by 2030 the cell and gene therapy market should reach $40 billion¹, and maybe more than twice that.² But this market expansion depends on solving some challenges in the field: difficulty in delivering therapies to the patients and into the intended target within their bodies; ensuring the quality and consistency of these complex products; and streamlining the process of CAR-T cell therapies.

The “ability to offer cell therapies to broader patient groups” is one major challenge in delivering cell and gene therapies, says Christopher Jewell, PhD, chief scientific officer at Cartesian Therapeutics. “For example, in cancer, approved therapies for lymphomas apply only to small fractions of patients, and progress in applying these technologies to solid tumors has been extremely challenging.” In addition, Jewell notes, “While cell and gene therapies offer amazing opportunities and selectivity, development for their use in other areas, such as autoimmunity, remains essentially untapped.”

Jewell also notes what he calls practical challenges. One is the need for an efficient regulatory process for these therapies. That’s problematic, because as these treatments quickly evolve, so must the regulations. In addition, he points to a need for higher throughput and improved reproducibility of these therapies.

Creating consistency

Like all treatments, cell and gene therapies must be reliable. “The manufacturing of cell and gene therapies faces significant challenges related to ensuring product quality and consistency,” says Sergey Vlasenko, PhD, associate vice president of the pharma/biopharma segment at Agilent Technologies. “These challenges can be compounded by the complexity of the products and the patient-specific variability of autologous cell therapies.”

With these therapies, small changes in manufacturing can create major changes in a therapy’s quality and efficacy. That makes it “critically important to employ in-process controls and analytics to monitor critical quality attributes—CQAs—throughout the manufacturing process,” Vlasenko explains. “At present, these challenges pose significant obstacles to the delivery of effective and sustainable cell-based therapies.”

To address that challenge, Agilent and Lonza are collaborating to enhance Lonza’s Cocoon Platform, which is an automated method of manufacturing cell therapies. “The collaboration aims to define the ideal CQAs for cell therapies and to build improved analysis packages that enable the manufacturing of higher quality therapeutic products with greater consistency,” Vlasenko says. “By integrating Agilent’s analytical technologies within the Cocoon Platform automated manufacturing workflows, manufacturers will be able to ensure that in-process controls and analytics can be employed on-demand to deliver a more consistent drug product.”

Such advances could improve the therapies delivered to a patient and increase the number of patients who could be treated, because automated manufacturing should reduce the sometimes-prohibitive costs of these treatments.

Attacking autoimmune diseases

Another way to increase the number of patients treated would be to expand the indications that can be addressed with cell or gene therapies. One candidate area is autoimmune diseases. As an example, Jewell and his colleagues developed a T-cell therapy for generalized myasthenia gravis, which involves rogue antibodies and can cause limb weakness, trouble with speech, and other taxing symptoms. That therapy, Descartes-08 (DC-08), entails extracting T cells from a sample of a patient’s own blood and engineering them with mRNA. After the cells are intravenously returned to the patient, they kill B cells involved in myasthenia gravis.

Based on the results of a Phase IIa trial, Jewell says, “The engineered RNA cell therapy appears safe and well tolerated, with a dramatic clinical improvement.” He adds, “It’s been very exciting to hear from patients about some of their incredible experiences.” Further clinical research is underway to “rigorously test the efficacy of DC-08, and also collect samples that could shed new light on the mechanism of action of myasthenia gravis and other B cell-mediated autoimmune diseases,” Jewell explains.

Cartesian aims at even wider goals. As Jewell says, “A broad goal is to help the field gain confidence in RNA-based cell engineering as safe and transformative technologies, and to lead the way in advancing these therapies for autoimmune disease.”

Expanding delivery mechanisms

Traditional delivery strategies for gene therapies include adenoviruses, adeno-associated viruses, and lentiviruses. Due to immune-related clearance or toxicity, viral-delivery modalities can only be dosed once, limiting their application to one-and-done therapies.

“Non-viral platforms—like the technology we are developing based on extracellular vesicles, or EVs—do not activate the immune response as much or at all, opening the door for repeat or even chronic dosing strategies and their application to a broader set of genetic diseases,” says Jonathan Thon, PhD, the CEO of STRM.BIO.

Other scientists also see potential value in using EVs. Kevin Morris, PhD, a professor at Griffith University’s Menzies Health Institute Queensland in Australia, and his colleagues wrote: “Extracellular vesicles (EVs) are esteemed as a promising delivery vehicle for various genetic therapeutics.”³ As Morris and his colleagues noted, EVs come with several benefits: “They are relatively inert, non-immunogenic, biodegradable, and biocompatible.” The idea is to put a protein, RNA, or another therapeutic molecule in EVs that are then put in patients. Like other cell and gene therapies, though, EVs would face their own challenges. For one thing, Morris and his colleagues pointed out that “a perfect EV product will be challenging to produce at clinical scale.”

Another consideration is whether a given delivery mechanism can provide the intended dose of a therapy. “STRM.BIO recently demonstrated large cargo capacity that accommodates larger disease-specific payloads and tunable cargo loading of DNA, RNA, and CRISPR-Cas ribonucleoprotein complexes for in vivo targeting to hematopoietic stem and progenitor cells, which allows for lower therapeutic doses and minimizes off-target effects,” Thon says.

Instead of changing the biology of delivery, some scientists are exploring other approaches to getting a therapy into a patient. Instead of an intravenous path, maybe a gene therapy could be delivered across the skin, so-called transdermal delivery. As explained by Thanh Nguyen, PhD, an associate professor of mechanical engineering at the University of Connecticut, and his colleagues, transdermal delivery “can minimize the requirement of trained personnel for administration, cause little to no pain and offer a minimally invasive method.”⁴ For this to work, though, the therapy must be delivered below the stratum corneum, the top layer of the skin. That can be done in many ways, from microneedles to ultrasound. Like seemingly all methods of delivering cell and gene therapies, transdermal approaches come with their own challenges. As examples, Nguyen and his colleagues pointed out the need for a complicated manufacturing process, as well as challenges in keeping the loaded genes stable and scaling up to commercial levels of production.

Nature also offers some methods of injection worth exploring. For instance, Feng Zhang, PhD, of the Broad Institute of MIT and Harvard, and his colleagues noted: “Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology.”⁵ For example, these bacteria have extracellular contractile injection systems that Zhang and his colleagues described as “syringe-like macromolecular complexes that inject protein payloads into eukaryotic cells by driving a spike through the cellular membrane.” The scientists showed that these bacterial injection systems can be engineered to inject therapeutic proteins into human cells, which might offer another option for delivering gene therapies.

The indications addressed with gene therapies can also expand beyond diseases to injuries, but delivery remains a challenge there, as well. As one example, scientists at the Hand Surgery Research Center at the Medical School of Nantong University in China reviewed the potential for using gene therapy to repair a damaged tendon.⁶ Such an application could address an important medical need, because, the authors state: “The tendon, as a compact connective tissue, is difficult to treat after an acute laceration or chronic degeneration.” The density of a tendon, however, also creates a challenge for gene therapy, because a considerable volume must be delivered over time. Delivering a gene therapy with nanoparticles might be one way to solve that challenge, because this method’s efficiency, as these scientists noted, “decreases the dose needed.”

Patient-produced CAR-T cells

Among oncology treatments, therapies based on CAR-T cells gain some of the biggest buzz, and for good reason. “When the current ex vivo CAR-T process works perfectly, the treatment outcomes for patients are transformational—especially compared to treatment options that were available prior to the FDA approval of the early cell therapies in 2017 and 2018,” says Andrew Scharenberg, MD, co-founder and CEO of Umoja Biopharma.

Nonetheless, the existing procedure is complicated, expensive, and sometimes even off-putting to patients. “The entire process of delivering CAR-T cell therapies today is arguably one of the most complex treatment administration experiences in healthcare,” Scharenberg says. Briefly, the process includes these steps: T cells are collected from a patient and shipped to a facility that turns these cells into cancer-fighting CAR-T cells; when the CAR-T cells are ready, which can take as long as a month, the patient undergoes a few days of chemotherapy; and then the patient receives the CAR-T cells intravenously. This process creates many challenges: cost, required expertise, and, crucially for cancer patients, time.

In addition, the cost and complexity limit the availability of CAR-T therapies. “Very few hospitals across the country can handle the complex logistics and treatment follow-up, with prohibitive drug and treatment costs typically being hundreds of thousands of dollars per patient,” Scharenberg says. “Tragically, somewhere between 50 to 80% of patients who could benefit from today’s cell therapies are not able to access them.”

Scharenberg and his colleagues want to fix that problem. “We aim to engineer the CAR-T cells directly within a patient’s own body using our platform technologies, like VivoVec, which delivers a CAR payload directly to the patient’s own T-cells,” Scharenberg explains. “A patient can receive a dose of a VivoVec-based drug product off the shelf, and in essence ‘manufacture’ their own CAR T-cell therapy internally, meaning no shipping and logistics to a centralized manufacturing plant, no months of waiting, and a reduction in the overall complexity of the administration experience.”

Soon, Umoja Biopharma hopes to extend the use of its VivoVec in vivo delivery program in CAR-T therapy, including expanding access to patients, lowering the costs, improving efficacy across hematologic indications, and expanding applications into solid tumors.

Realizing the possibilities

The field of cell and gene therapy promises advances in treatments for many conditions, from autoimmune diseases to various cancers and beyond. Reaching those goals, however, depends on resolving a spectrum of challenges whose solutions, Jewell says, would require additional R&D resources in academia and industry. He adds that “investing in advanced tools—for example, single-cell sequencing, bioinformatics, and AI—and interdisciplinary teams are critical to attack these challenges.”⁷

Extending the reach of these therapies to patients depends on simplifying, accelerating, and reducing the cost of the process. None of the challenges will be easy to overcome, but the potential benefits to patients make it worth the investment.

References

1. Cell and gene therapy market size, growth, trends, forecast Report 2022-2030. Biospace. (2022).
2. Cell and gene therapy market. Precedence Research. (2022).
3. Cecchin, R., Troyer, Z., Witwer, K, et al. Extracellular vesicles: The next generation in gene therapy delivery. Molecular Therapy (2023). doi.org/10.1016/j.ymthe.2023.01.021
4. Singh, P., Muhammad, I., Nelson, N.E., et al. Transdermal delivery for gene therapy. Drug Delivery and Translational Research, 12:2613–2633 (2022).
5. Kreitz, J., Friedrich, M.J., Guru, A., et al. Programmable protein delivery with a bacterial contractile injection system. Nature, 616:357–364 (2023).
6. Jin, J., Yang, Q.Q., Zhoum Y.L. Non-viral delivery of gene therapy to the tendon. Polymers, 14(16):3338. (2022).
7. Jewell, C.M., Miljković, MD, Oakes, R.S. Transforming bioengineering with unbiased teams and tools. Nature Reviews Bioengineering (2023). doi.org/10.1038/s44222-023-00058-0

Mike May, is a freelance writer and editor with more than 30 years of experience. He earned an MS in biological engineering from the University of Connecticut and a PhD in neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of more than 1,000 articles for clients that include GEN, Nature, Science, Scientific American, and many others. In addition, he served as the editorial director of many publications, including several Nature Outlooks and Scientific American Worldview.

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