On April 28, 2020 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported the presentation of a new off-the-shelf, iPSC-derived, chimeric antigen receptor (CAR)-targeted cell-based cancer immunotherapy program at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 23rd Annual Meeting to be virtually hosted on May 12 – 15, 2020 (Press release, Fate Therapeutics, APR 28, 2020, View Source [SID1234556688]). The new preclinical program targets MHC class I related proteins A (MICA) and B (MICB), and is supported by an exclusive license from the Dana-Farber Cancer Institute to intellectual property covering novel antibody fragments binding MICA/B for iPSC-derived cellular therapeutics. MICA and MICB are stress proteins that are selectively expressed at high levels on many solid tumors.

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"MICA and MICB are emerging as exciting pan-cancer immunotherapy targets, and we are pleased that our engineered iPSC-derived CAR-MICA/B NK cells have shown potent anti-tumor activity in preclinical studies," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "Importantly, since the shedding of MICA/B is a common escape mechanism deployed by many tumors to evade immune cell recognition, we are encouraged that our novel CAR design, which uniquely targets the α3 domain of MICA/B, prevents protein shedding and promotes NK and T cell-mediated tumor immunity."

While it is well known that tumor resistance to cytotoxic T cells is mediated by loss of MHC Class I expression, proteolytic shedding of the α1 and α2 domains of MICA/B expressed on tumor cells is a common mechanism of NK cell evasion. A recent publication in Science (DOI:10.1126/science.aao0505) by Kai W. Wucherpfennig, M.D., Ph.D., Chair of the Department of Cancer Immunology and Virology at the Dana-Farber Cancer Institute and co-leader of the Cancer Immunology Program at Dana-Farber / Harvard Cancer Center, demonstrated that antibody targeting of the MICA/B α3 domains specifically prevents MICA/B shedding and restores NK cell-mediated immunity. Additionally, in a more recent publication in Cancer Immunology Research (DOI: 10.1158/2326-6066.CIR-19-0483), Dr. Wucherpfennig also demonstrated that cancers with B2M and JAK1 inactivating mutations resulting in loss of MHC Class I expression can be effectively targeted with MICA/B α3 domain-specific antibodies to restore NK cell-mediated immunity against solid tumors resistant to cytotoxic T cells.

Using a clonal master induced pluripotent stem cell (iPSC) line previously engineered with an expression cassette introduced into the CD38 locus that encodes for a high-affinity, non-cleavable CD16 Fc receptor and an IL-15 receptor fusion, scientists from Fate Therapeutics introduced a second expression cassette encoding for the novel CAR MICA/B construct. In vitro differentiation of the clonal iPSC lines produced homogeneous NK cell populations with uniform expression of CAR MICA/B, hnCD16, and IL15RF, and without any expression of CD38. The iPSC-derived CAR NK cells displayed enhanced cytokine production and cytotoxicity against MICA/B positive tumor cells compared to non-engineered, iPSC-derived NK cells.

Other Company abstracts selected for presentation at ASGCT (Free ASGCT Whitepaper) include the derivation of clonal master engineered iPSC lines for the Company’s FT576 product candidate, an off-the-shelf, multi-antigen targeted CAR-BCMA NK cell engineered with four anti-tumor modalities for the treatment of multiple myeloma; and a study of various expression systems for the generation, engineering and cryopreservation of clonal master engineered iPSC lines.

About MICA and MICB Proteins
The major histocompatibility complex (MHC) class I related proteins A (MICA) and B (MICB) are induced by cellular stress, damage or transformation, and the expression of MICA and MICB proteins has been reported for many tumor types. Cytotoxic lymphocytes, such as NK cells and CD8+ T cells, can detect and bind the membrane-distal α1 and α2 domains of MICA/B, activating a potent cytotoxic response. However, advanced cancer cells frequently evade immune cell recognition by proteolytic shedding of the α1 and α2 domains of MICA/B. The clinical importance of proteolytic shedding is reflected in the association of high serum concentrations of shed MICA/B with disease progression in many solid tumors. Several recent publications have shown that therapeutic antibodies targeting the membrane-proximal α3 domain strongly inhibited MICA/B shedding, resulting in a substantial increase in the cell surface density of MICA/B and restoration of NK cell-mediated tumor immunity. Therapeutic approaches aimed at targeting the α3 domain of MICA/B therefore represent a potentially promising novel strategy to overcome this prominent evasion mechanism as a means of restoring anti-tumor immunity.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with cycles of other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.