Guide to Cell Therapy GMP Manufacturing for Autologous CAR-T and Beyond

 

Autologous cell therapy, using a patient’s own cells, offers significant advantages, including reduced risk of immune rejection and infection. This personalized approach can lead to better outcomes and eliminates the need for donor matching and immunosuppressive drugs. Additionally, it enhances safety by minimizing concerns about disease transmission or genetic issues from donor cells, making it a highly promising and effective treatment option.

This blog will explore how developing customized solutions for process automation in accordance with GMP compliance addresses key technical bottlenecks, advances the manufacturing of, and ultimately improves patient access to, these life-saving medicines.

What is autologous CAR T-cell therapy?

Autologous CAR T-cell therapy is a type of immunotherapy that utilizes genetically modified T cells to target and fight cancer. This process involves collecting T cells from the patient’s blood through leukapheresis, genetically modifying them in a laboratory to express Chimeric Antigen Receptors (CARs), expanding the modified T cells, and then infusing them back into the patient. The engineered CARs on the T cells’ surface enable them to recognize and bind to specific antigens on cancer cells, allowing for targeted and effective destruction of these cells.

The evolution of autologous CAR T-cell therapy

CAR T-cell therapy has come a long way since its inception. The journey began with the first successful bone marrow transplants in the late 1960s, which laid the foundation for modern hematopoietic stem cell transplants used to treat blood cancers and disorders.¹ Over the decades, advancements in genetic engineering, stem cell research, and immunotherapy have propelled cell therapy into a new era.  Today, CAR T cell therapy has evolved into a viable treatment option for several hematological malignancies, with multiple FDA-approved therapies and ongoing research to expand its use to solid tumors.

FDA approved cell and gene therapies

The launch of Kymriah in 2017, the first CAR T-cell therapy, marked a significant milestone, paving the way for FDA approval of additional CAR T-cell products and expanding the horizons of cell therapy to treat solid tumors and other conditions.²

Therapy type	Drug name	Indication
Cell therapy	AMTAGVI (lifileucel)	Metastatic melanoma
Gene therapy	LENMELDY (atidarsagene autotemcel)	Metachromatic leukodystrophy
Cell therapy	TECELRA (afamitresgene autoleucel)	Advanced synovial sarcoma
CAR T-cell therapy	AUCATZYL (obecabtagene autoleucel)	B-cell acute lymphoblastic leukemia
Cell therapy	CASGEVY (exagamglogene autotemcel [exa-cel])	Blood and immune system disorders
Cell therapy	RYONCIL (remestemcel-L-rknd)	Steroid-refractory acute graft versus host disease

In 2024, the FDA granted accelerated approval for afami-cel (TECELRA) for adults with unresectable or metastatic synovial carcinoma, marking the first TCR-T cell therapy for a solid tumor³, and Obecabtagene Autoleucel (Aucatzyl by Autolus Inc.), a CD19-directed autologous T-cell immunotherapy for relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).⁴

The global cell and gene therapy market size was valued at USD 18.13 billion in 2023 and is projected to reach USD 97.33 billion by 2033.⁵ As of Q4 2024, there are now more than 4,238 gene, cell, and RNA therapies in development.⁶ The Cell and Gene Therapy (CGT) space is also shifting towards non-oncology indications like autoimmune and neurodegenerative diseases, with about 1,900 clinical trials occurring globally. (6) These advancements are driving improved patient outcomes across solid tumor indications, sickle cell disease, beta-thalassemia, and CAR-T therapies for earlier lines of treatment, including a first-line approval for high-risk large B-cell lymphoma.⁷

Current challenges of cell therapy GMP manufacturing

Despite its promise, cell therapy manufacturing faces significant challenges, particularly in adhering to Good Manufacturing Practices (GMP). Key issues include:

• Complexity: The manufacturing process involves multiple complex steps, each requiring precise control to ensure product quality and consistency.
• Cost: Producing autologous cell therapies is expensive, partly due to the individualized nature of the treatment and the need for specialized facilities and equipment.
• Scalability: Meeting the growing demand for these therapies necessitates scalable manufacturing solutions that maintain high standards of quality.
• Regulatory compliance: Ensuring compliance with stringent regulatory requirements across different regions adds another layer of complexity.

The role of automation in cell therapy manufacturing

Automation is central in addressing the challenges of cell therapy manufacturing. It can help bring several advantages:

• Reducing manual labor and errors: Automation minimizes human intervention, reducing the risk of errors and contamination, which is crucial for maintaining the integrity of patient-specific therapies.
• Enhancing scalability: Automated systems can handle larger volumes and more complex processes, making it feasible to produce therapies on a commercial scale.
• Improving consistency and quality: Automation ensures that each batch is produced under uniform conditions, enhancing consistency and quality, which is essential for regulatory compliance and patient safety.

Good manufacturing practices (GMP) in cell therapy

GMP guidelines are designed to ensure that products are consistently produced and controlled according to quality standards. In cell therapy manufacturing, GMP compliance is critical for several reasons:

• Ensuring product safety: GMP regulations mandate stringent controls to prevent contamination and ensure the safety of the final product. This includes maintaining clean facilities, using high-quality raw materials, and implementing robust quality control measures.
• Regulatory compliance: Adhering to GMP is essential for obtaining regulatory approval from agencies like the FDA, ensuring that the manufacturing process meets all legal and quality requirements.
• Building trust: GMP compliance builds trust with stakeholders, including patients, healthcare providers, and investors, demonstrating a commitment to quality and safety.

Thermo Fisher Scientific automated solutions for GMP cell therapy manufacturing

Thermo Fisher Scientific offers a range of automated solutions designed to streamline GMP cell therapy manufacturing. These solutions integrate seamlessly into GMP-compliant workflows, enhancing efficiency, reducing costs, and ensuring the consistent production of high-quality cell therapies.

These GMP-compliant, closed automated manufacturing solutions facilitate process optimization while automating key unit operations such as cell isolation, activation, and gene editing. This allows customers to choose which unit operations to automate while still providing scalability. Gibco CTS instruments address the challenges of open manual systems by offering closed, automated systems that minimize contamination risks and reduce the need for cleanroom environments. These systems improve process consistency and reliability by reducing operator variability and hands-on time, leading to widespread adoption among process developers in the cell therapy field.

These instruments, along with their supporting consumables and software products, enable GMP compliance. They can be physically integrated to remove open processes, minimizing contamination risk and offering greater control over processes. Digital integration via tools such as CTS Cellmation software improves record keeping and maintains data integrity.

Integrating automation and GMP for cell therapy manufacturing

Cell therapy represents the frontier of medical science, offering great potential to treat diseases that were once considered incurable. However, the complexity and specificity of these therapies necessitate a robust framework that ensures their success. Developing a flexible and agnostic approach can significantly enhance the effectiveness and scalability of biological processes in cell and gene therapy.

Below are a few tips that can help achieve a flexible, agnostic approach:

• Implement Modular Platforms: Use platforms that support plug-and-play components, making it easier to test and integrate new technologies.
• Invest in Scalable Solutions: Ensure that the technologies you adopt can be scaled up or down based on the requirements of the process.
• Ensure Regulatory Compliance: Choosing a system that supports CFR 21 part 11 compliance should help streamline clinical translation and manufacturability. Investing in a closed modular, flexible automated system before regulatory approval can reduce risks and save time compared to manual systems during the transition to commercialization.
• Select Digital Integration Platforms: Opting for Cell therapy software solutions like Gibco™ CTS™ Cellmation™ Software that can seamlessly integrate with automation tools, providing real-time monitoring, data analytics, and process control.
• Quality & Regulatory Compliant Reagents: Plan for scaling by partnering with a reputable vendor to ensure a timely supply of high-quality reagents. Choose GMP-manufactured products that are tailored for cell and gene therapy, supporting your transition from discovery to clinical and commercial manufacturing.

The future of autologous CAR T cell therapy lies in the seamless integration of automation and GMP compliance. Modular manufacturing solutions cater to the diverse needs of cell therapy manufacturers, whether scaling up for allogeneic or scaling down for autologous production. This adaptability enables manufacturers to continuously advance their therapies, whereas a more rigid, singular approach limits flexibility and the ability to pivot when necessary.

By embracing these advancements, the industry can overcome current limitations, ensuring that innovative therapies reach more patients safely and efficiently. As technology continues to evolve, the potential for further improvements in cell therapy manufacturing is immense, promising a new era of medical breakthroughs.

Recommended cell therapy GMP manufacturing resources

• Publication: Accelerating CAR T cell manufacturing with an automated next-day process 
• App Note: Efficient CAR T cell manufacturing using a closed and integrated instrument workflow
• Whitepaper: Enhancing the efficiency of CAR T cell therapy manufacturing through automated bioprocessing
• Whitepaper: Autologous CAR T cell manufacturing using a semiautomatic, closed, modular workflow
• Publication: An automated 24-hour CAR-T manufacturing process

References

1. First Successful Bone Marrow Transplant Led to Today’s Immunotherapies – Wisconsin Medical Alumni Association. https://wmaa.med.wisc.edu/quarterly/vol-20/no-2/golden-anniversary-bone-marrow-transplant/ (accessed Apr 28, 2025).
2. First-Ever CAR T-cell Therapy Approved in U.S.; Cancer Discovery, American Association for Cancer Research. https://aacrjournals.org/cancerdiscovery/article/7/10/OF1/6073/First-Ever-CAR-T-cell-Therapy-Approved-in-U-S (accessed Apr 28, 2025).
3. Adaptimmune Receives U.S. FDA Accelerated Approval of TECELRA® (Afamitresgene Autoleucel), the First Approved Engineered Cell Therapy for a Solid Tumor; Adaptimmune (ADAP). https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/271/adaptimmune-receives-u-s-fda-accelerated-approval-of (accessed Apr 28, 2025).
4. Autolus Therapeutics Announces FDA Approval of AUCATZYL® (Obecabtagene Autoleucel – Obe-cel) for Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL); Autolus Therapeutics plc. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-announces-fda-approval-aucatzylr (accessed Apr 28, 2025).
5. Mitra, S.; Lankford, C.; McBride, A. Manufacturing CAR T Cells: The Next Frontier in Cell Therapy. In Cell Therapy: Current Challenges and Future Directions; National Center for Biotechnology Information (US): Bethesda, MD, 2023. https://www.ncbi.nlm.nih.gov/books/NBK600652/ (accessed Apr 28, 2025).
6. 2024 Cell, Gene & RNA Landscape Report; American Society of Gene & Cell Therapy and Citeline. https://www.asgct.org/global/documents/asgct-citeline-q4-2024-report.aspx (accessed Apr 28, 2025).
7. FDA D.I.S.C.O. Burst Edition: FDA Approval Yescarta (Axicabtagene Ciloleucel) for Adult Patients with Large B-Cell Lymphoma; FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-yescarta-axicabtagene-ciloleucel-adult-patients-large-b-cell (accessed Apr 28, 2025).
8. Khang, M.; Suryaprakash, S.; Kotrappa, M.; Mulyasasmita, W.; Topp, S.; Wu, J. Manufacturing Innovation to Drive Down Cell Therapy Costs. Trends Biotechnol. 2023, 41 (10), 1216–1219. https://doi.org/10.1016/j.tibtech.2023.04.006.