Pluripotent Stem Cell-Derived Natural Killer Cells For Cancer Therapy

For over 40 years, hematologists and oncologists have utilized transplantation of hematopoietic stem cells (HSC) to treat and cure hematologic malignancies. iPSCs can now be routinely derived from terminally differentiated somatic cells through the expression of several transcription factors (typically OCT4, SOX2, KLF4, c-myc or Lin28) known to promote pluripotency. iPSCs derived from mice undergo tetraploid complementation and demonstrate germ line chimerism– the most stringent test of pluripotency. hESC-derived NK (Natural Killer) cells provide a genetically defined population to study NK cell development and overcome the high level of donor heterogeneity, such as when using peripheral blood NK (PB-NK) cells. Scientists have demonstrated the ability of hESC-derived hematopoietic progenitor cells to produce functional NK cells in vitro. hESC-derived NK cells express activating and inhibitory receptors similar to peripheral blood NK (PB-NK) cells and are highly efficient at direct cell-mediated cytotoxicity, antibody dependent cell-mediated cytotoxicity, and cytokine (IFN-γ) production. According to Dr. Dipnarine Maharaj stem cells based on such approaches can be applied in the clinical aspect with more ease.  As an expert in stem cells, he is focusing on the usage of stem cells for the treatment of cancer. Stem cells can be easily extracted from the bone marrow and transplanted using an apheresis machine. Current status of NK cells for clinical adoptive immunotherapy For over two decades, Rosenberg and colleagues at the NIH have been steadily advancing immunotherapy trials using tumor infiltrating lymphocytes (TILs), in combination with high-dose interleukin-2 (IL-2), for patients with metastatic melanoma, renal cell cancer, and other malignancies. NK-cells2 They have repeatedly shown how ex vivo activation of cancer-killing lymphocytes can decrease tumor burden and significantly increase patient life-span. It has also been shown that NK cell-mediated allo-reactivity could eliminate relapse, graft rejection, and protect against graft-vs-host disease (GVHD) for patients with acute myelogenous leukemia (AML). The ability to genetically modify NK cells for more direct recognition of tumor targets could enhance their therapeutic potential against a broader range of cancers. To date, most of this work has focused on antigen-specific T cells, with less emphasis placed on engineering NK cells. However, this type of gene therapy is difficult achieve in primary peripheral blood-NKs and T cells, whereas high efficiency genetic modification is routinely feasible in hESC-derived NK cells. Based on this record of successful (though limited) NK cell-based therapies against cancer, NK cells derived from hESCs or iPSCs now provide an intriguing starting point to expand this immunotherapeutic approach. Perhaps the most promising direction for hESC-based immunotherapies is to engineer hESCs or iPSCs to express chimeric antigen receptors (CARs) capable of directing cytotoxic lymphocytes to tumor sites. CARs typically contain an extracellular domain, derived from the Fab (antigen-specific) portion of an antibody that has high specificity to recognize a tumor antigen. The external domain is genetically linked to a transmembrane domain and an intracellular signaling domain. Upon antigen binding, the CAR initiates a signaling cascade leading to release of cytotoxic granules. Several iterations of CARs have utilized distinct signaling and co-stimulatory domains in different combination to optimize function. Hematopoietic cell-based therapies are routinely utilized as effective means to cure many patients with hematologic malignancies such as leukemia, lymphoma, and myeloma. Antitumor immunotherapy using T cell and NK cell-based therapies have demonstrated the promising therapeutic potential of harnessing the cellular immune system to fight human cancer.

 Article by Jennifer Smith

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