Human induced pluripotent stem cells (iPSCs) have the unique capacity to be indefinitely expanded and differentiated in culture into any type of cell in the body. The groundbreaking discovery that fully differentiated human cells can be induced to a pluripotent state through the expression of certain genes was recognized with the award of the 2012 Nobel Prize in Science and Medicine. iPSCs represent an ideal cell source for creating cell therapy products that are well-defined, uniform in composition, have a consistent and dose-dependent pharmacology profile, and can be delivered off-the-shelf for the treatment of large numbers of patients. We are applying our expertise in induced pluripotent stem cell biology to genetically engineer, single-cell isolate and select iPSCs for clonal expansion as master iPSC lines. We direct the fate of master iPSC lines to create cells of the immune system, including NK cells, T cells and CD34+ cells, and are advancing a pipeline of off-the-shelf cellular immunotherapies derived from master iPSC lines.
As a key component of the innate immune system, Natural Killer, or NK, cells are the body’s first line of defense against disease. NK cells can directly seek out and kill abnormal cells, such as cancer or virally-infected cells, while leaving normal cells unharmed. Unlike T cells that require tumor-antigen recognition for effector function, NK cells can selectively identify stress ligands commonly expressed on tumor cells and secrete cytotoxic granules, triggering rapid cell death. Additionally, NK cells can also release pro-inflammatory cytokines after engaging tumor cells, stimulating a durable anti-tumor response by other immune cells. Through these direct and indirect anti-tumor mechanisms, NK cells can bridge innate and adaptive immunity and drive a potent, multi-dimensional, and long-lived immunological response for the treatment of cancer.
We are developing a pipeline of activated and engineered NK cell products for the treatment of cancer, including through our collaborations with the University of Minnesota and Oslo University Hospital. We are executing on a multi-pronged clinical development strategy addressing both hematologic and solid tumor malignancies, including investigation of our NK cell products as monotherapy and in combination with other anti-tumor agents such as monoclonal antibodies.
T cells play a central role in adaptive immunity. T cells are distinguished from other immune cells by their expression of T cell receptors (TCRs) on their cell surface that can recognize a specific antigen on a cancer cell. Upon antigen recognition, binding of the TCR and the antigen mediates T-cell activation, resulting in cytokine release and target cell death. T-cell cancer immunotherapy today is a personalized treatment, requiring the sourcing, isolation, engineering and expansion of T cells from an individual patient for subsequent delivery back to that same patient.
We believe that engineering functionality into master iPSC lines is a potential breakthrough approach to T-cell cancer immunotherapy, and that iPSC-derived T-cell products can be efficiently and consistently manufactured, and safely and reliably delivered, at the scale necessary to support broad patient access and wide-spread commercialization. We are developing a pipeline of engineered iPSC-derived T-cell products for the treatment of cancer through our collaboration with Memorial Sloan Kettering Cancer Center.
CD34+ cells are multipotent hematopoietic cells that can give rise to all cell types in blood. These cells are known to play a key role in immune surveillance, and their trafficking in peripheral circulation and homing to specific sites in the body is regulated by chemokines, cytokines, proteolytic enzymes and adhesion molecules. It has been shown, for example, that CD34+ cells can traffic to sites of inflammation and inhibit disease causing T cells through immune-checkpoint pathways including PD-L1 and IDO1.
In collaboration with Boston Children’s Hospital, we are exploiting the immuno-regulatory potential of hematopoietic cells. We have established a manufacturing process to generate off-the-shelf immuno-regulatory hematopoietic cells from master iPSC lines, and we are assessing the cells’ potential to tolerize the immune system for the treatment of autoimmunity and inflammatory diseases.