Fate Therapeutics, Inc. products

The oncology therapeutic landscape has been transformed with the use of checkpoint inhibitor therapy. Despite the clinical benefit conferred by approved checkpoint inhibitor therapy against a variety of tumor types, these therapies are not curative and, in most cases, patients either fail to respond or their disease progresses on these agents. Resistance to checkpoint inhibitor therapy has been linked to impaired immune cell infiltration into the tumor, impaired cytokine response, and deficiencies in antigen presentation including altered expression of major histocompatibility (MHC) class I complex. As a result, there is significant unmet need for novel therapeutic approaches to overcome resistance to checkpoint inhibitor therapy.

NK cells play a major role in the anti-tumor efficacy of certain tumor-antigen targeting antibodies. NK cells express CD16, an activating receptor that binds to the Fc portion of IgG antibodies. Once activated through CD16, NK cells are able to destroy antibody-coated target cells and secrete cytokines, such as interferon gamma, to recruit and potentiate adaptive immune cells, including T cells. This mechanism of action, referred to as antibody-dependent cellular cytotoxicity (ADCC), is believed to be important for the treatment of a wide range of human tumor types

MICA and MICB (MICA/B) are stress proteins expressed on a broad range of solid and hematopoietic tumor cells and serve as an activation signal for NKG2D+ NK and T cells. However, MICA/B are frequently shed as an immune escape mechanism, preventing recognition and destruction of tumor cells by the immune system. Proteolytic shedding of MICA/B can be inhibited by monoclonal antibodies targeting the membrane proximal α3 domain, which stabilizes MICA/B on the cell surface.

T cells engineered with chimeric antigen receptors (CARs) have shown exceptional promise as a potentially curative therapy for patients with certain hematologic malignancies. While most researchers and clinical investigators continue to focus on the development of autologous or allogeneic CAR T-cell therapies, we are developing CAR NK cell product candidates created from clonal master engineered iPSC lines as off-the-shelf cancer immunotherapies for the treatment of hematologic malignancies and solid tumors.

Multiple myeloma is a hematologic malignancy characterized by the proliferation of malignant plasma cells. In multiple myeloma, malignant plasma cells accumulate in the bone marrow and produce abnormal antibodies called M proteins, which can cause kidney damage, bone destruction, and impaired immune function. While multiple approved drugs with novel mechanisms have improved disease management over the past decade, multiple myeloma is rarely curable and a significant number of patients are expected to relapse. One such approved drug, daratumumab, is an IgG1 monoclonal antibody targeting CD38, which is overexpressed in multiple myeloma cells and induces cell death through multiple mechanisms, including ADCC. However, because CD38 is also expressed on the surface of activated NK cells, daratumumab treatment can induce NK cell fratricide, which may impair the effectiveness of ADCC-mediated targeting and the destruction of multiple myeloma cells. 

B7H3 belongs to the B7 family of immune checkpoint inhibitors and is expressed on a wide range of solid and hematologic malignancies. B7H3 is an important mediator of tumor angiogenesis and metastasis, and higher expression is associated with a poor prognosis for patients. We are developing FT573, an investigational, universal, off-the-shelf NK cell cancer immunotherapy derived from a clonal master engineered iPSC line. FT573 incorporates four functional modifications: a proprietary CAR that targets B7H3; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor that augments ADCC; an IL-15 receptor fusion (IL-15RF) that promotes enhanced NK cell activity; and the elimination of CD38 expression which enhances NK cell metabolic fitness, persistence and anti-tumor functionality.

In addition to CD38 targeting in multiple myeloma, targeting of other tumor-associated cell-surface proteins has been clinically investigated. Of these antigens, the TNF-superfamily member B-cell Maturation Antigen (BCMA) is among the most researched. Several clinical trials in multiple myeloma have shown promising initial results targeting BCMA with CAR T cells.

CAR T-cell therapy has recently emerged as a revolutionary and potentially curative therapy for patients with certain hematologic malignancies, including refractory cancers. In 2017, two CAR T-cell therapies were approved by the FDA for the treatment of relapsed / refractory B-cell precursor acute lymphoblastic leukemia (ALL) and relapsed / refractory diffuse large B-cell lymphoma (DLBCL). While most researchers and clinical investigators continue to focus on the development of autologous or donor-derived CAR T-cell therapies, we are developing CAR T-cell product candidates created from clonal master engineered iPSC lines as off-the-shelf cancer immunotherapies for the treatment of hematologic malignancies and solid tumors.