The "New Developments in CAR T Treatments" webinar series, sponsored by Johnson & Johnson and Legend Biotech, highlighted the latest advancements and ongoing research in CAR T and natural killer (NK) cell therapies. Experts, including Dr. Veronika Bachanova and Dr. Rayne Rouce, discussed scientific breakthroughs, clinical trials, and emerging trends in cell-based therapies, addressing both the scientific and clinical aspects.
Recharging NK Cells for Cancer Therapy
Dr. Veronika Bachanova focused on NK cell therapies as a promising alternative to CAR T-cell therapies, especially for hematologic malignancies and solid tumors. NK cells, part of the innate immune system, can recognize and eliminate tumor cells without prior antigen sensitization. Key mechanisms of NK cell activity include natural cytotoxicity, where NK cells identify and kill infected and cancerous cells without antigen presentation, and antibody-dependent cellular cytotoxicity (ADCC), where NK cells bind to antibodies coating tumor cells, triggering cytotoxicity.
Recent advancements in NK cell engineering include cytokine-induced memory-like (CIML) NK cells, which exhibit enhanced effector functions and persistence, and CAR-NK cells, which combine CAR technology with NK cell biology to target specific tumor antigens like CD19 and CD33. CAR-NK cells are associated with a lower risk of severe adverse effects like cytokine release syndrome (CRS) and neurotoxicity compared to CAR-T cells.
The field of NK cell therapy has expanded, with over 40 active clinical trials exploring allogeneic NK cells, which can be used in donor-derived settings without the risk of graft-versus-host disease (GVHD), offering "off-the-shelf" therapies. NK cells can be sourced from peripheral blood, umbilical cord blood (UCB), and induced pluripotent stem cells (iPSCs), with UCB NK cells being less likely to cause immunological complications and available in large numbers for expansion and genetic engineering.
Combination therapies, using checkpoint inhibitors, cytokines, or monoclonal antibodies like AFM13 for CD30+ lymphomas, can synergistically enhance NK cell therapies, particularly for solid tumors. Genetic engineering approaches, such as CRISPR-based gene editing to knock out inhibitory receptors or introduce new genes, and multi-antigen targeting CAR-NK cells, are being developed to overcome tumor immune evasion.
Addressing Challenges and Expanding Access to CAR T-Cell Therapy
Dr. Rayne Rouce addressed the logistical, manufacturing, and financial challenges associated with CAR T-cell therapies. Centralized production presents logistical and operational challenges, with the complex, multistep process involving apheresis, shipment to specialized centers, and potential delays detrimental to patients needing urgent treatment. The high cost of CAR T-cell therapies, driven by intricate manufacturing, limits accessibility.
Decentralized manufacturing, or point-of-care (POC) production, involves local production facilities within hospitals or clinical centers, reducing "vein-to-vein" time and lowering logistical expenses. Examples include the Canadian-Led Immunotherapies Collaborative (CLIC) and Spain’s development of ARI-0001, a public CAR T-cell therapy available at a lower cost. Regulatory challenges must be overcome to ensure POC facilities adhere to Good Manufacturing Practices (GMP) and secure approvals from agencies like the FDA or EMA.
The development of "off-the-shelf" products, using allogeneic T-cells or NK cells that have been pre-manufactured and stored, offers shorter treatment times, lower production costs, and broader accessibility. Challenges remain in ensuring the persistence and functionality of these cells, with ongoing research focused on genetic modifications to enhance longevity and efficacy.
Optimizing newer therapies, improving manufacturing processes, and ensuring access to these treatments remain top priorities. Global collaboration, regulatory innovation, and the exploration of new therapeutic combinations are crucial to maximizing the potential of cell-based therapies.
