Why Roche Is Betting Over $3 Billion on iPSC-Derived Allogeneic Cell Therapies

Today, Adaptimmune Therapeutics plc announced that it has entered into a research collaboration and license agreement with Genentech, a member of the Roche Group, to jointly develop allogeneic cell therapies for the treatment of various cancers.

Adaptimmune will be responsible for utilizing an induced pluripotent stem cell (iPSC)-derived allogeneic cell technology platform to generate T cells, while Genentech will be responsible for designing T cell receptors (TCRs). The two companies will jointly develop allogeneic T cell therapies targeting five cancer-related targets, as well as personalized allogeneic T cell therapies.

Under the agreement, Adaptimmune will receive an upfront payment of $150 million and could receive more than $3 billion in R&D, regulatory, and commercial milestone payments.

The generation of natural killer (NK) cells, T cells, and macrophages using induced pluripotent stem cells (iPSCs) has emerged as a major hotspot in the field of cell therapy development in recent years. Numerous startups have recently secured funding or entered into partnership agreements, and Roche’s strategic initiatives in this area further underscore its focus on iPSC-derived cell therapies. How, then, does this approach differ from cell therapies derived from primary cells?

Advantages of iPSC-Derived Cell Therapy

Several CAR-T cell therapies have already received regulatory approval for the treatment of patients with various hematologic malignancies. However, the widespread clinical application of currently approved CAR-T therapies remains constrained by several factors. All of these therapies require the isolation of T cells from patients, ex vivo genetic engineering, and subsequent reinfusion into the patient. This manufacturing process not only entails a lengthy turnaround time that may delay treatment, but also means that some patients—due to underlying health conditions or prior therapies—may yield T cells that fail to meet the quantity and quality specifications required for production, thereby precluding them from benefiting from such treatments.

Genetically engineering T cells derived from healthy donors to generate allogeneic T cell therapies represents a strategy to overcome the limitations of autologous T cell therapies. They can be manufactured in advance and cryopreserved, thereby providing patients with an "off-the-shelf" cell therapy. However, allogeneic T cell therapies must address immune rejection challenges, including graft-versus-host disease (GvHD) caused by infused T cells attacking the host, as well as host immune rejection of the infused allogeneic cells.

Gene editing of allogeneic cells to knock out endogenous T-cell receptors, combined with further genetic engineering to enhance T-cell fitness and tolerance to immunosuppressive microenvironments, can improve the persistence and efficacy of allogeneic cell therapies. However, primary lymphocytes possess limited proliferative capacity, which restricts the number of gene editing rounds they can undergo. Furthermore, multiple rounds of gene editing significantly compromise the manufacturing yield of cell therapies.

iPSCs are characterized by their capacity for near-unlimited proliferation, similar to embryonic stem cells, and their ability to be successfully differentiated into lymphocytes, thereby providing a renewable cell source for the production of cell therapies such as T cells and NK cells. This feature addresses the challenges posed by the limited availability of primary cell sources and their restricted expansion capacity.

Furthermore, iPSCs are highly amenable to genetic engineering in vitro, enabling them to undergo multiple rounds of genetic engineering optimization steps, such as gene editing and transgene delivery, thereby enhancing their potency, persistence, and scope of application. In contrast, primary cells have limited potential for multiple rounds of genetic engineering.

The safety of cell therapies is of paramount importance. Gene editing of lymphocytes may induce "off-target" effects, necessitating rigorous safety testing of the manufactured cells upon completion of the gene editing process. Due to their unlimited proliferative capacity, iPSCs can be used to establish a master cell line after undergoing multiple genetic engineering modifications and stringent safety evaluations. This master cell line serves as a stable and secure cell source, which can be differentiated on demand to produce cell therapy products that already harbor all the intended genetic modifications and exhibit the desired characteristics.

Finally, a critical factor influencing the persistence of T-cell therapy is T-cell fitness. Primary T cells may enter an "exhausted" state due to the patient's clinical condition or as a result of excessive ex vivo expansion and differentiation, which substantially diminishes their antitumor efficacy. In contrast, generating T cells from iPSCs holds the potential to yield T cells with stem-like characteristics and enhanced persistence through precise control of the T-cell differentiation process.

Challenges in iPSC-Derived Cell Therapy

In addition to the aforementioned advantages, iPSC-derived cell therapies also face unique challenges. Among them, a critical hurdle to overcome for clinical application is the establishment of effective cell differentiation strategies that meet clinical-grade requirements. Although numerous studies in basic research have reported the successful differentiation of iPSCs into T cells and NK cells, many of these protocols involve multiple steps and require murine-derived culture components or feeder cells, rendering such approaches unsuitable for human clinical use. Furthermore, the iPSC differentiation strategy directly influences whether the phenotype of the resulting T cells or NK cells matches that of naturally occurring cells in the human body.

Furthermore, safety assessment of cells derived from iPSC differentiation remains critically important. Given that iPSCs possess unlimited proliferative potential, the administration of undifferentiated iPSCs to patients may carry a tumorigenic risk. Therefore, it is essential to establish safety evaluation protocols or genetic engineering strategies to minimize this risk.

Multiple Emerging Companies Poised for Launch

In recent years, with the continuous optimization of protocols for differentiating iPSCs into lymphocytes, numerous emerging companies have been dedicated to developing iPSC-derived cell therapies. In the oncology sector, the primary development focus currently lies in iPSC-derived NK cell therapy and T cell therapy.

The differentiation of iPSCs into NK cells is comparatively easier than T cell generation, and the corresponding differentiation protocols are more mature. Furthermore, allogeneic NK cells do not induce graft-versus-host disease (GvHD), thereby offering a superior safety profile. In contrast, allogeneic T cells express endogenous T-cell receptors (TCRs) and typically require gene editing to knock out these endogenous TCRs to enhance safety. Beyond T cell generation, using iPSCs to produce NK cells is also a key development direction for multiple companies.

Among these companies, Fate Therapeutics has already advanced multiple iPSC-NK cell and iPSC-CAR-NK cell candidate therapies into clinical trials and reported early clinical trial results. In August this year, the company also completed the first patient dosing for its first iPSC-CAR-T cell therapy.

Beyond today’s collaboration with Roche, other pharmaceutical companies have also positioned themselves in this field by partnering with firms and institutions dedicated to the research and development of iPSC-derived cell therapies. For instance, Takeda is collaborating with Professor Shinya Yamanaka at Kyoto University and several other stem cell experts to develop iPSC-based cell therapies. Recently, Kite, a Gilead Sciences company, also partnered with Shoreline Biosciences to develop iPSC-derived NK cell therapies. Additionally, Fate Therapeutics has entered into a collaboration with Janssen to co-develop CAR-NK and CAR-T therapies.

References:

[1] Adaptimmune Enters into a Strategic Collaboration with Genentech to Research, Develop, and Commercialize Cancer-targeted Allogeneic T-cell Therapies. Retrieved September 7, 2021, from https://www.adaptimmune.com/investors-and-media/news-events/press-releases/detail/197/adaptimmune-enters-into-a-strategic-collaboration-with

[2] Adaptimmune Corporate Presentation. Retrieved September 7, 2021, from https://d1io3yog0oux5.cloudfront.net/_6ef0335d524831866fffec5c2a965dcc/adaptimmune/db/249/3267/pdf/Corporate+Deck_June+2021+updated%281%29.pdf

[3] Nianias and Themeli., (2019). Induced Pluripotent Stem Cell (iPSC)–Derived Lymphocytes for Adoptive Cell Immunotherapy: Recent Advances and Challenges. Curr. Hematol. Malig. Rep., doi: 10.1007/s11899-019-00528-6

[4] Fate Therapeutics Corporate Presentation. Retrieved September 7, 2021, from https://ir.fatetherapeutics.com/static-files/726ecee3-28ab-4276-a7dd-885544972a16

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