Nucleus, CAR T

New Developments in CAR T Treatments Webinar Series Summary

The "New Developments in CAR T Treatments" webinar series, held on September 10, 2024, brought together leading experts in the field of cancer immunotherapy to discuss the latest advancements and ongoing research in chimeric antigen receptor (CAR) T and natural killer (NK) cell therapies. Sponsored by Johnson & Johnson and Legend Biotech, the event featured in-depth presentations from Dr. Veronika Bachanova (University of Minnesota) and Dr. Rayne Rouce (Baylor College of Medicine), who highlighted recent scientific breakthroughs, clinical trials, and emerging trends in cell-based therapies.

Overview of the Event

The webinar, moderated by Dr. Manuel Espinoza-Gutarra, provided insights into the mechanisms, benefits, and challenges associated with CAR and NK cell therapies. This included discussions on the design of cell-based therapies, the nuances of manufacturing and logistics, and future directions in treatment strategies. The event was structured to foster understanding of both the scientific and clinical aspects.

Key Presentations and Scientific Insights

1. Recharging NK Cells for Cancer Therapy (Dr. Veronika Bachanova)

Dr. Bachanova's presentation centered on the application of NK cell therapies, which have emerged as a promising alternative to traditional CAR T-cell therapies, especially for hematologic malignancies and solid tumors1. NK cells are innate immune cells capable of recognizing and eliminating tumor cells without prior antigen sensitization. This makes them an attractive option for immunotherapy.

Key Mechanisms of NK Cell Activity:

  • Natural Cytotoxicity: NK cells can identify and kill virally infected and cancerous cells without needing antigen presentation, thanks to their unique array of activating and inhibitory receptors. Activating receptors (e.g., NKG2D, NKp30, NKp44) recognize "stress-induced" ligands on tumor cells, while inhibitory receptors (e.g., KIRs) engage with self-HLA molecules, preventing autoimmunity.
  • Antibody-Dependent Cellular Cytotoxicity (ADCC): Through the CD16 receptor, NK cells can bind to antibodies coating tumor cells, triggering cytotoxicity. This mechanism can be enhanced by engineering NK cells to express high-affinity variants of CD16, increasing their tumor-killing potential.

Recent Advancements in NK Cell Engineering: Dr. Bachanova discussed the engineering of NK cells to improve their efficacy2, including:

  • Cytokine-induced Memory-like (CIML) NK Cells: These cells, stimulated with cytokines (IL-12, IL-15, IL-18), acquire enhanced effector functions, including increased persistence and cytotoxicity3. CIML NK cells retain their memory-like behavior, allowing for a rapid response upon encountering tumor cells.
  • CAR-NK Cells: By incorporating CARs, NK cells can be directed to target specific tumor antigens (e.g., CD19, CD33), combining the advantages of CAR technology with the inherent benefits of NK cell biology4. Notably, CAR-NK cells are associated with a lower risk of severe adverse effects like CRS and neurotoxicity, making them safer than CAR-T cells in certain scenarios.

Clinical Development and Trials: The field of NK cell therapy has expanded significantly, with over 40 active clinical trials exploring various approaches:

  • Allogeneic NK Cells: Unlike T cells, NK cells can be used in an allogeneic (donor-derived) setting without the risk of GVHD. This allows for "off-the-shelf" therapies that can be readily available to patients without the need for personalized manufacturing.
  • Sources of NK Cells: Dr. Bachanova detailed different sources for NK cell therapies, including peripheral blood (PB), umbilical cord blood (UCB), and induced pluripotent stem cells (iPSCs). Each source has its own benefits; for example, UCB NK cells are less likely to cause immunological complications and are available in large numbers for expansion and genetic engineering5.

Current Trends and Future Directions

Combination Therapies: Combining NK and CAR-NK cells with other therapeutic agents is a growing area of interest. Using checkpoint inhibitors, cytokines, or monoclonal antibodies (e.g., AFM13 for CD30+ lymphomas) can synergistically enhance the effectiveness of NK cell therapies. This strategy is particularly promising for solid tumors, where monotherapy with CAR-NK cells alone might be less effective due to the immunosuppressive tumor microenvironment.

Genetic Engineering to Overcome Tumor Resistance: Several approaches are being developed to address the issue of tumor immune evasion, including:

  • Gene Editing: Using tools like CRISPR to knock out inhibitory receptors or introduce new genes that enhance NK cell function. For example, editing NK cells to resist immunosuppressive signals within the tumor microenvironment could improve their ability to infiltrate and eradicate solid tumors.
  • Multi-Antigen Targeting: Designing CAR-NK cells to target multiple antigens can prevent tumor escape due to antigen loss. For example, dual-target CAR-NK cells that can recognize both CD19 and CD22 on B-cell malignancies.

2. Addressing the Challenges and Expanding Access to CAR T-cell Therapy (Dr. Rayne Rouce)

Dr. Rouce’s talk highlighted the logistical, manufacturing, and financial challenges associated with the use of CAR T-cell therapies. While CAR T-cell treatments have revolutionized the management of certain hematologic cancers, their widespread use is hampered by the complexities of manufacturing and the high costs involved.

Barriers to Traditional CAR T-cell Manufacturing:

  • Centralized Production: CAR T-cell therapies are produced in centralized facilities, a model that presents logistical and operational challenges6. The production of CAR T-cells involves a complex, multistep process that starts with the collection of a patient's T-cells through apheresis, followed by shipment of these cells to specialized manufacturing centers. Shipping cells across long distances can introduce delays, complications, and risks of contamination. Dr. Rouce emphasized that delays are particularly detrimental for patients who need urgent treatment, highlighting the need for faster and more localized solutions.
  • Cost and Accessibility: The intricate process of manufacturing drives the price of CAR T-cell therapies into the hundreds of thousands of dollars per patient. This limits accessibility, particularly for patients without adequate insurance coverage or those living in countries where healthcare systems cannot afford such high-priced therapies.

Decentralized Manufacturing and Point-of-Care (POC) Solutions:

Dr. Rouce advocated for a decentralized manufacturing model known as point-of-care (POC) production. This model involves setting up local production facilities within hospitals or clinical centers, allowing CAR T-cells to be manufactured closer to the patient.

  • Benefits of Decentralized Models: Decentralized manufacturing offers numerous advantages, starting with the reduction in "vein-to-vein" time (the time from the collection of T-cells to infusion back into the patient)7. POC facilities can dramatically shorten this timeline, providing life-saving therapies more quickly. By streamlining processes and lowering logistical expenses, local manufacturing can also make CAR T-cell therapy more cost-effective for both healthcare providers and patients.
  • Regulatory Considerations: While decentralized manufacturing presents an opportunity to expand access to CAR T-cell therapy, significant regulatory challenges must be overcome. POC facilities must adhere to the same rigorous standards as centralized manufacturing sites, including compliance with Good Manufacturing Practices (GMP). Furthermore, local production centers will need to navigate complex regulatory frameworks, including securing approval from agencies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

Examples of Decentralized and Alternative Manufacturing Models:

Dr. Rouce provided real-world examples of decentralized manufacturing models that have been successfully implemented:

  • Canadian-Led Immunotherapies Collaborative (CLIC): This initiative, spearheaded by Canadian researchers, has created a collaborative platform for developing and deploying CAR T-cell therapies across Canada. By fostering partnerships between institutions and establishing local manufacturing capabilities, the CLIC initiative has been able to reduce costs and accelerate the production of CAR T-cells.
  • Spain’s Development of ARI-0001: ARI-0001 is a CAR T-cell therapy produced in Spain for adult patients with acute lymphoblastic leukemia (ALL). Developed as a public CAR T-cell product, ARI-0001 is available at approximately one-third of the cost of traditional CAR T therapies. This is achieved by manufacturing within public healthcare institutions using local resources and infrastructure.

Current Trends and Future Directions

Off-the-Shelf Solutions: The next frontier in CAR T and NK cell therapies is the development of "off-the-shelf" products that do not require individualized manufacturing. Traditional CAR T-cell therapies rely on the patient’s own T-cells, which must be collected, modified, and expanded. In contrast, off-the-shelf therapies use allogeneic (donor-derived) T-cells or NK cells that have been pre-manufactured, stored, and are ready for immediate use. These products can be produced in bulk, allowing for rapid deployment to patients.

  • Advantages of Off-the-Shelf Therapies: These therapies could offer key advantages, including shorter treatment times and lower production costs. Moreover, off-the-shelf products can be made available to a larger number of patients, making these therapies more scalable and accessible.
  • Challenges and Future Developments: However, there are still challenges to address, such as ensuring the persistence and functionality of these off-the-shelf cells once they are infused into patients. Research is ongoing to develop genetic modifications that can enhance the longevity and efficacy of these therapies.

Conclusion and Key Takeaways

The webinar emphasized that while dramatic progress has been made in cell therapies, optimizing newer therapies, improving manufacturing processes, and ensuring access to these treatments remain top priorities. The event also underscored the importance of global collaboration, regulatory innovation, and the exploration of new therapeutic combinations to maximize the potential of these cell-based therapies.

With continued investment in research, engineering, and infrastructure, the potential to expand the reach of CAR T and NK cell therapies to a broader patient population is within reach, promising new hope for individuals battling cancers that have been resistant to conventional therapies.

References:

1. Lamers-Kok N, Panella D, Georgoudaki AM, et al. Natural killer cells in clinical development as non-engineered, engineered, and combination therapies. J Hematol Oncol. 2022;15(1):164. Published 2022 Nov 8. doi:10.1186/s13045-022-01382-5

2. Bachanova V, Cooley S, Defor TE, et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood. 2014;123(25):3855-3863. doi:10.1182/blood-2013-10-532531

3. Gang M, Wong P, Berrien-Elliott MM, Fehniger TA. Memory-like natural killer cells for cancer immunotherapy. Semin Hematol. 2020;57(4):185-193. doi:10.1053/j.seminhematol.2020.11.003

4. Laskowski TJ, Biederstädt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022;22(10):557-575. doi:10.1038/s41568-022-00491-0

5. Marin D, Li Y, Basar R, et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat Med. 2024;30(3):772-784. doi:10.1038/s41591-023-02785-8

6. Rossig C, Pearson AD, Vassal G, et al. Chimeric Antigen Receptor (CAR) T-Cell Products for Pediatric Cancers: Why Alternative Development Paths Are Needed. J Clin Oncol. 2024;42(3):253-257. doi:10.1200/JCO.23.01314

7. Al Hadidi S, Szabo A, Esselmann J, et al. Clinical outcome of patients with relapsed refractory multiple myeloma listed for BCMA directed commercial CAR-T therapy. Bone Marrow Transplant. 2023;58(4):443-445. doi:10.1038/s41409-022-01905-1