OUR BACKGROUND
Chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapy has led to the paradigm shift in cancer treatment. Since 2017, U.S. Food and Drug Administration (FDA) has approved six CAR-T drugs for the treatment of certain blood cancers, including lymphoma, acute lymphoblastic leukemia, and multiple myeloma. However, there are several limitations associated with the traditional CAR-T cell therapy:
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- Limited commercial potential due to its autologous nature among all marketed CAR-T drugs.
- Market access hurdle due to their high price tag ($373 – 475K per treatment).
- Safety concerns caused by cytokine release syndrome and neurotoxicity.
- Lack of efficacy in solid tumors.
- Approved indications limited to CD19-targeted B-cell lymphoma and acute lymphoblastic leukemia, and BCMA-targeted multiple myeloma.
- CAR-T cell fratricide by self-killing, leading to insufficient numbers of CAR-T cells for infusion in T-cell malignancies.
- CRISPR/cas9-mediated genome editing needed for allogeneic CAR-T and unconfirmed safety associated with editing.
At ImmunoKite, we focus on harnessing NKT cells to fight cancer and autoimmune disorders. NKT cell therapy is an emerging class of immunotherapy as they play a critical role in tumor immunosurveillance and anti-tumor immunity. We believe NKT cell therapy can address some limitations associated with CAR-T therapy.
NKT cells are a well-defined non-conventional T cell subset that exhibit characteristics from both natural killer (NK) cells and conventional T cells and recognize lipid antigens presented by the major histocompatibility complex (MHC) class I-like CD1d molecules. NKT cells typically arise in the thymus and are considered an “innate-like’ lymphocyte that bridges the innate and adaptive immunity.
Based on their T cell receptor (TCR) repertoire, antigen specificity and CD1d dependence, NKT cells have been divided into three categories: type I, type II, and type III NKT cells (see the table below for more details).
Note: a-GalCer* reactive - α-Galactosylceramide (a-GalCer) is a potent activator of iNKT cells, and a model CD1d antigen
Type I NKT, also known as invariant NKT (iNKT) cells express a semi-invariant TCR and have several unique properties that make them well suited for CAR-T therapy over conventional T cells. Since these T cells are not MHC-restricted, but instead recognize antigens presented by nonpolymorphic CD1d molecules, they are almost entirely devoid of alloreactivity. Thus, iNKT cells can be used as allogeneic, off-the-self therapy.
iNKT cells can directly kill cancer cells that express CD1d and NKG2D ligands through their endogenous invariant TCR (iTCR) or NKG2D. They infiltrate into tumor tissues rapidly and remodel the tumor microenvironment by selectively eliminating tumor-associated macrophage (TAM) and promoting myeloid-derived suppressor cell (MDSC) maturation into functional antigen-presenting cells (APCs). They can also promote dendritic cell maturation and cross-presentation of tumor-associated antigens to bystander T cells, thus inducing long-lasting memory T cell responses.
There are some perceived advantages of CAR-iNKT cell therapy over CAR-T cell therapy:
