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Microbes & Immunity iPSC-derived NK cell immunotherapy

One notable advantage of NK cells derived from response within the tumor microenvironment and a
iPSCs is the feasibility of applying genetic modifications. reduction in tumor size.
This advantage, combined with the iPSCs’ capability for In a trial involving 15 patients with advanced solid
unlimited proliferation, facilitates the screening of positive tumors and lymphomas, including non-small cell lung
clones, leading to the production of genetically modified cancer and classical Hodgkin lymphoma, the therapeutic
NK cells of exceptional homogeneity. Various nucleic acid efficacy of iPSC-derived NK cells was evaluated. During
delivery methods and gene-editing technologies have preparation, NK cells were amplified from hematopoietic
shown significant effectiveness in iPSCs. For example, progenitor stages by over one million-fold. Although
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through transcription activator-like effector nucleases the trial is ongoing, initial results indicate a response to
(TALEN) gene-editing technology, the introduction of treatment in some patients, and the iPSC-derived NK
IL-15 and the concurrent deletion of TGFβR2 not only cells were deemed safe at a dose of 3 × 10 cells. In
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amplify the NK cells’ anti-tumor potency but also equip another clinical trial involving 13 subjects with B-cell
them to counteract the immunosuppressive impact of lymphoma, iPSC-derived NK cells were engineered to
TGF-β within the tumor microenvironment. Moreover, express a high-affinity, non-cleavable CD16 Fc receptor,
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the potent clustered regularly interspaced palindromic enhancing their capacity for NK cell-mediated ADCC. The
repeats/CRISPR-associated protein 9 (CRISPR/Cas9) trial administered doses of up to 300 million cells, which
system has been employed in iPSC-derived NK cells to were well-tolerated without any dose-limiting toxicities.
remarkable effect. Beyond developing CAR-engineered Remarkably, seven of the patients achieved a complete
NK (CAR-NK) cells using this technique, it enables the response. Whether ex vivo expanded from peripheral
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simultaneous editing of multiple genes in NK cells. It is
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important to note that editing multiple genes in one cell blood or derived from iPSCs, and regardless of genetic
does not significantly affect the genomic stability of NK modification, current clinical trial outcomes primarily
provide safety data. The effectiveness of these NK cells in
cells, highlighting the technique’s potential to significantly treating tumors still requires further clinical evidence to be
advance cancer immunotherapy.
substantiated.
3.3. Clinical trials of iPSCs-derived NK cells 4. Boosting anti-tumor efficacy of
NK cells derived from iPSCs have progressively entered iPSCs-derived NK cells through genetic
clinical trials as their safety and efficacy in treating
various diseases, including malignant tumors, are being engineering
assessed. It is interesting to note that a wide array of NK 4.1. CAR enhances the targeting of NK cells
cells is currently undergoing clinical trials including Thanks to the success of CAR-T cells in treating
both genetically modified and unmodified NK cells, hematological disorders and their potential, along with
those sourced from peripheral blood and derived from challenges, in solid tumors, CAR-NK cells have emerged as
iPSCs, as well as autologous and allogeneic NK cells. a pivotal focus in the field of genetically modified NK cells.
However, clinical trials involving iPSC-derived NK cells In addition to traditional CAR-T constructs, efforts have
predominantly utilize genetically modified versions of been made to invent CAR constructs that are better suited
these cells. In a case report, a 76 years old patient with for NK cells. CAR-NK cells based on 2B4, DAP-12, and
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diffuse large B-cell lymphoma, who had previously 109
undergone eight different treatments including ex vivo NKG2D structures have demonstrated superior efficacy,
expanded autologous NK cells, autologous stem cell particularly in terms of proliferation, cytokine secretion,
and cytotoxicity. These NK cell-specific activation motifs
transplant, and engineered autologous T cells, was treated offer a promising avenue for the development of CAR-NK
with iPSC-derived NK cells. These cells were engineered
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to express a CAR targeting CD19, a non-cleavable CD16, cell therapies and have the potential to significantly
and enhanced cytokine autocrine signaling mediated by enhance the clinical effectiveness of iPSC-derived NK cells,
IL-15 and its receptor. The treatment not only proved safe especially in the context of solid tumors.
but also showed a partial response, with a 50% reduction NK cells sourced from various tissues, including
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in tumor size. Another case report involved iPSC-derived peripheral blood, cord blood, NK-92 cell line, and
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CAR-NK cells that also targeted CD19 and augmented iPSC-derived NK cells, have all been utilized in the
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the IL-15 signaling pathway. This study additionally preparation of CAR-NK cells, yielding promising results in
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engineered the cells to knock out class I MHC molecules pre-clinical studies. Notably, several CAR-NK cell products
and enhance HLA-E expression, aiming to minimize host have progressed to clinical trials. Current CAR-NK
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rejection. The intervention led to an enhanced immune cell research predominantly targets CD19, commonly
Volume 2 Issue 1 (2025) 33 doi: 10.36922/mi.5653