Global Head of Clinical and Process Development, Personalized Medicine
Director, Cell and Gene Therapy Research and Development
Advances in cell therapy technology are fueling a wave of innovation in immune-oncology. The field can essentially be divided into allogeneic cell therapy, which entails the large-scale manufacture of “off-the-shelf” therapies from unrelated donor tissues (such as bone marrow stem cells, cord blood, and pluripotent stem cells); and autologous cell therapy, by which cells from an individual patient are collected, processed ex vivo, and returned to the same patient.
Whereas allogeneic cell therapies can be used to treat large numbers of patients (sometimes thousands), their scalability requirements present challenges that are different from those faced in the manufacturing of traditional biologics. Autologous cell therapies may involve both “scale-out” and “scale-up” strategies, and may require proximity of manufacturing to patients to reduce logistical complexities.
T-cells vs. Natural Killer (NK) Cells
Within those two main types of cell therapies lies a diverse landscape of therapeutic approaches. Many of those therapies are derived from T-cells, which have properties that are unique to their biology. The T-cell category includes chimeric antigen receptor (CAR)-T cells, transgenic T-cell receptor (TCR) T-cells, tumor-infiltrating lymphocytes (TILs), T-cell couplers, bi-specific engagers, and gamma-delta T-cells.
Whereas T-cells have mostly been used in the autologous setting, there has been recent progress in developing allogeneic cell therapies based on the concept of “universal T-cells,” which are engineered to prevent graft-versus-host disease (GvHD). This approach includes allogeneic CAR-T cells developed from healthy donor-derived peripheral blood mononuclear cells (PBMCs) or induced pluripotent stem cells (iPSCs).
Othermodalities include macrophages, dendritic cells, and natural killer (NK) cells, the latter of which are strongly positioned as the next wave of cell therapies. NK cells constitute a unique population of innate immune effector cells that possess intrinsic abilities to identify and eliminate virus-infected cells and tumor cells, and are considered an advanced type of cell therapy.
NK cells are particularly well-suited for allogeneic applications, as they do not require additional engineering steps to remove self-recognizing receptors, and are not associated with development of GvHD, thus posing lower risks to patients. NK cells can be obtained from various sources including PBMCs, iPSCs, hematopoietic stem and progenitor cells (HPSCs), cord blood, and specific cell lines (e.g., NK-92).
Leveraging Insights from CAR-T
Lonza’s experience with CAR-T cells has yielded valuable insights that can be applied to developing and commercializing cell therapies for immune-oncology. These insights enhance our capabilities to support clients with:
- Deploying synthetic receptors: Developing analytical platforms for evaluation of immune cell interaction with tumor cells via receptor-mediated redirected specificity towards the tumor, enhancing the utility of targeted immune-oncologic therapy.
- Cell editing: Through precise genetic engineering, cells can be “edited” to overcome the suppressive effects of the tumor microenvironment (TME).
- Implementing successful manufacturing models: Our experience with both distributed and point-of-care manufacturing approaches can accelerate the path to clinical translation and commercialization of novel therapies.
Addressing Manufacturing Challenges
The inherent challenges of developing immune-oncologic therapies reflect the nature of the immune cell therapy product, in that, the cells typically need to be modified and subsequently expanded. These processes add considerable manufacturing time and cost, particularly for autologous cell therapies. The efficacy and safety of the cell therapy product is often determined by the percentage of cells that undergo successful gene modification. In the autologous setting, those modifications usually comprise gene additions (e.g., CAR), whereas allogeneic cell therapies may include multiple gene edits (e.g., TCR removal in T-cells, CAR and cytokine addition in T and NK cells), which in turn may require selection of successfully-engineered cells to ensure product uniformity. Though both models hold great promise for expanding the benefits of cell therapy, the allogeneic approach may be a viable strategy to make cell therapies cost-effective and broadly accessible to patients.
Cell expansion post-modification is often a crucial step in cell therapy development, as some immune-oncology indications require large number of cells per dose. For allogeneic therapies, as we aim to treat more and more patients, solutions for larger-scale expansion must be achieved. However, both autologous and allogeneic immune cells have limited expansion potential. Moreover, culturing these cells for long periods of time could result in a product that is functionally exhausted, and possesses a lower potency index. When manufacturing cell therapies, it is important to consider cell identification, characterization, and potency, as these parameters are critical to ensuring patient safety and therapy efficacy.
As emerging clinical data enhance our understanding of how cell-based therapies perform in patients, there is growing interest in identifying characteristics that are associated not only with a potent anti-tumor response, but also with persistence. Hence the integration of new analytical tools to determine treatment dose levels based on number of cells and also on product quality. That is an important consideration as cell therapy manufacturing models evolve.
Leveraging Lonza’s Capabilities
Lonza Personalized Medicine has developed the Cocoon® Cell Therapy Manufacturing Platform to enable commercialization of cell therapies. A functionally closed and automated platform, the Cocoon consolidates many unit operations, providing a solution that decreases the need for user touchpoints and streamlines the cell therapy manufacturing workflow. The Cocoon platform is applicable to both point-of-care and distributed manufacturing models and is currently in the clinic, supporting Phase I cell therapy clinical trials.
Additionally, Lonza Cell & Gene Therapy R&D has developed a process for allogeneic T-cell expansion and selection in a closed, automated, 3-liter, stirred-tank bioreactor, with scale-up potential. A recent publication describes how optimal T cell culture conditions are maintained through media perfusion and in-vessel magnetic selection. The expanded cells express high levels of “stemness” markers, compared to senescence markers, while also exhibiting polyfunctionality, suggesting strong therapeutic potential.
By streamlining workflows through automation and minimizing user touchpoints throughout the manufacturing process, we can increase the number of therapies manufactured in parallel, minimize risks associated with product manipulation, and accelerate vein-to-vein time, making potentially curative treatments available to patients sooner, while also meeting the challenge of scalability.
Solving Long-term Challenges
Cell therapies have unique attributes that present different challenges. As “living drugs”, cell therapies may evolve over time during the manufacturing process. It is therefore important to monitor this evolution and to understand the impact of process development decisions on the quality of the final product. Moreover, specific cell therapy modalities may have different requirements. Considerations regarding self/non-self-recognition are very important, and often times genetic modifications to an allogeneic cell source are required to remove the risk of immune reaction against the host. These additional steps may lead to more complex manufacturing processes. Additionally, because gene modification efficiency depends on the delivery method, the final cell therapy product will likely be a pool of modified and unmodified cells, thus limiting the potency of a given cell dose. Designing a suitable manufacturing strategy and leveraging the appropriate analytical tools for product characterization are important steps in the development of a successful cell therapy program.
The availability of off-the-shelf, universal immune cells that express a therapeutic CAR is a promising approach for ensuring the uniformity of the cell therapy product, and ultimately enhancing patient safety. At Lonza, we have developed platforms to support the manufacturing of iPSC-based cell therapies, which leverage the power of pluripotent stem cells to differentiate into therapy-relevant adult cell types in the human body, such as T cells and NK cells.
Furthermore, we continue to expand our manufacturing solutions to support the rapidly-evolving cell therapy field. As new approaches emerge with a focus on solid tumors, Lonza is positioned to support developments in various therapeutic modalities, including:
- Genetically modified TILs: This approach leverages T-cells that have already penetrated the tumor and detected a tumor antigen. TILs can be extracted from tumors, modified to increase their potency, and delivered in larger doses to provide therapeutic benefit.
- Optimized NK cells: With their intrinsic virus-targeting properties, NK cells can identify tumor cells that present viral peptides, thereby driving a stronger anti-tumor response and making the immune system more reactive to cell therapy.
- Macrophages: Similar to NK cells, macrophages have an inherent ability to traffic to tumor sites, activate immune cells, and modulate the TME.
- TCR-engineered T and NK cells: This approach enables targeting of intracellular tumor proteins, which are typically not visible to a CAR-T cell.
- Cell engagers: Loading an engager onto an immune cell and bringing the cell to the tumor site can modulate immune responses at the TME.
As these modalities gain traction, we are excited about potential opportunities to also incorporate them into allogeneic models to address challenges in immune-oncology. We at Lonza stand ready to advance these strategies to meet the field’s evolving needs and to expand the treatment options available to patients.
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