Off the shelf and into the lab

Fate Therapeutics and Memorial Sloan Kettering to develop off-the-shelf T cell product candidates

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SAN DIEGO & NEW YORK—In a West to East partnership, Fate Therapeutics Inc. and Memorial Sloan Kettering Cancer Center have teamed up in a three-year collaboration to develop off-the-shelf T cell product candidates. Dr. Michel Sadelain, director of the Center for Cell Engineering and the Stephen and Barbara Friedman Chair at Memorial Sloan Kettering Cancer Center, will lead research and development activities.
Fate Therapeutics has a proprietary, patent-protected platform that enables it to generate, genetically engineer, isolate and bank pluripotent cell lines. For its part, Memorial Sloan Kettering is a leader in generating pluripotent cell-derived, tumor-targeting T cells that can engender significant tumor clearance in vivo. They will be uniting their skill sets to develop pluripotent cell lines engineered for enhanced antigen specificity and functionality, optimize T cell differentiation protocols and clinically translate off-the-shelf engineered T cell product candidates.
Under this partnership, Fate Therapeutics has exclusively licensed intellectual property covering induced pluripotent cell-derived immune cells, including T cells and NK cells derived from pluripotent cells engineered with chimeric antigen receptors, from Memorial Sloan Kettering. It holds an option to exclusively license intellectual property that results from the research and development work of this partnership. No financial details were disclosed.
Fate Therapeutics also announced the launch of Tfinity Therapeutics Inc., a new venture company that will focus on advancing off-the-shelf T cell immunotherapies across a wide range of diseases using Fate’s proprietary, patent-protected pluripotent cell platform. Tfinity Therapeutics is a majority-owned subsidiary of Fate Therapeutics, and has an option to license intellectual property covering pluripotent cell-derived T cell immunotherapies from Fate Therapeutics.
“This partnership brings together Memorial Sloan Kettering’s excellence in the manufacture and delivery of cell-based immunotherapies and our established expertise in pluripotent cell generation, engineering and differentiation,” said Scott Wolchko, president and CEO of Fate Therapeutics. “Together, we are at the forefront of an off-the-shelf paradigm shift, seeking to broaden patient access to revolutionary T cell immunotherapies through a renewable, robust and standardized product approach.”
At present, the cellular immunotherapies being tested in clinical trials are patient-specific, which requires drawing cells from an individual, engineering them, expanding them into a suitably large population and then returning them to the body. This avoids the issue of immune system rejection, but is both expensive and complicated. The benefit of induced pluripotent cells is that they are both self-renewing and have the potential to differentiate into all cell types, including T cells. As such, engineered pluripotent cell lines can produce clonal populations of T cells that offer broad histocompatibility and enhanced effector functions.
“Engineering therapeutic attributes into pluripotent cell lines—such as antigen specificity, lack of alloreactivity, enhanced persistence and histocompatibility—is a breakthrough approach to renewably generate potent T cell immunotherapies,” said Sadelain. “This unique approach offers the prospect for off-the-shelf delivery of T cell immunotherapies with enhanced safety and therapeutic potential at the scale necessary to serve significant numbers of patients.”
This isn’t the only news out of Memorial Sloan Kettering focused on T cell efforts. The organization shared some promising new work led by its own Dr. Hans-Guido Wendel and collaborator Karin Tarte of the University of Rennes, France, that demonstrates how chimeric antigen receptor (CAR) T cells can serve as targeted delivery vehicles, “micro-pharmacies” as it were, for precise therapeutic delivery. Their research appeared online in Cell in a paper titled “Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.”
The researchers found a critical pathway that is disrupted in roughly 75 percent of human follicular lymphoma, a subset of B cell lymphoma. The HVEM receptor gene is mutated in about 50 percent of cases, and those mutations interrupt the interaction with the inhibitory receptor BTLA, which leads to lymphoma growth. The authors noted in their abstract that “HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression.”
The team also found that the key molecules in this pathway can be targeted therapeutically. Their approach consisted of using an engineered CD19-directed CAR T cell in vivo to deliver the HVEM protein directly to lymphomas in hopes of restoring HVEM function. The designed cells continuously produce soluble HVEM protein locally, and can specifically target tumor sites by identifying B cells that express CD19 and remaining in that area to distribute HVEM. When tested in animal models, the team saw significant therapeutic responses that proved more effective than control CAR T cells and CD19 CAR T cells.

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