Engineered ipsc and persistent immune effector cells
AssigneeFate Therapeutics, Inc.
InventorsBahram VALAMEHR, Eigen PERALTA, Chia-Wei CHANG
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Abstract
Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. The iPSC-derived cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the use thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.
Claims60
A cell or a population thereof, wherein (a) the cell comprises a polynucleotide encoding a recombinant cytokine signaling complex, and optionally a chimeric antigen receptor (CAR);
- (b) the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, a feeder cell, an induced pluripotent cell (iPSC), or a derivative cell differentiated therefrom;
- and (c) the cytokine signaling complex comprises (i) a full or partial cytokine and (ii) a full or partial IL7 receptor, IL2 receptor, IL4 receptor, IL9 receptor, IL21 receptor, or γC receptor.
A method for improving T lineage cell expansion and/or tumor cell control and clearance, the method comprising introducing an IL7 cytokine signaling complex to the T lineage cell, thereby producing a T lineage cell having improved cell expansion and/or tumor cell control and clearance as compared to a counterpart cell without the cytokine signaling complex, wherein the T lineage cell optionally further comprises a chimeric antigen receptor (CAR).
A method of manufacturing a derivative effector cell comprising a cytokine signaling complex and optionally, a CAR, wherein the method comprises:
- (i) differentiating a genetically engineered iPSC to the derivative effector cell, wherein the iPSC comprises a polynucleotide encoding the cytokine signaling complex and optionally the CAR;
- and (ii) expanding the derivative effector cell in a culture medium that does not contain exogenous IL15, and wherein the derivative effector cell has therapeutic properties comprising one or more of:
- (a) increased cytotoxicity;
- (b) improved persistency and/or survival;
- (c) enhanced ability in migrating, and/or activating or recruiting bystander immune cells, to tumor sites;
- (d) improved tumor penetration;
- (e) enhanced ability to reduce tumor immunosuppression;
- (f) improved ability in rescuing tumor antigen escape;
- (g) controlled apoptosis;
- (h) enhanced or acquired ADCC;
- and
- (i) ability to avoid fratricide,
- in comparison to a cell cultured in a culture medium containing exogenous IL15.
A method of producing a clonal master engineered iPSC line using CRISPR mediated editing of a clonal iPSC, wherein the editing comprises a knock-in of a polynucleotide encoding a cytokine signaling complex and optionally a CAR to the clonal iPSC, wherein the cytokine signaling complex comprises an IL7 receptor fusion (IL7RF), thereby producing the clonal master engineered iPSC line.
Dependencies are inferred from the claim text.