Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy

Woan, Karrune; Kim, Hansol; Bjordahl, Ryan; Davis, Zachary; Gaidarova, Svetlana; Goulding, John; Hancock, B. L.; Mahmood, Sajid; Abujarour, Ramzey; Wang, Hongbo; Tuininga, Katie; Zhang, Bin; Wu, Cheng‐Ying; Kodal, Behiye; Khaw, Melissa; Bendzick, Laura; Rogers, Paul; Ge, Moyar; Bonello, Greg; Meza, Miguel; Felices, Martin; Huffman, Janel; Dailey, Thomas; Lee, Tom T.; Walcheck, Bruce; Malmberg, Karl Johan; Blazar, Bruce R.; Bryceson, Yenan T.; Valamehr, Bahram; Miller, Jeffrey S.; Cichocki, Frank

doi:10.1016/j.stem.2021.08.013

Cited by 98 publications

(92 citation statements)

References 47 publications

(56 reference statements)

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“…The combination of metabolic regulators with proteasome inhibitors may induce synthetic lethality, prevent the activation of resistance mechanisms and increase efficacy [ 141 , 149 ]. Recently, preclinical studies have shown that adaptive natural killer cells have decreased CD38 expression and enhanced metabolic fitness by resisting oxidative stress, which may lead to improved anti-myeloma activity in the relapsed disease setting [ 150 , 151 ]. Furthermore, the vast majority of anti-myeloma regimens contain a high load of dexamethasone, which may alter the metabolic profile substantially.…”

Section: Myeloma Treatment and Metabolismmentioning

confidence: 99%

Metabolic Disorders in Multiple Myeloma

Gavriatopoulou

Paschou

Ntanasis‐Stathopoulos

et al. 2021

IJMS

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Multiple myeloma (MM) is the second most common hematological malignancy and is attributed to monoclonal proliferation of plasma cells in the bone marrow. Cancer cells including myeloma cells deregulate metabolic pathways to ensure proliferation, growth, survival and avoid immune surveillance, with glycolysis and glutaminolysis being the most identified procedures involved. These disorders are considered a hallmark of cancer and the alterations performed ensure that enough energy is available for rapid cell proliferation. An association between metabolic syndrome, inflammatory cytokinesand incidence of MM has been also described, while the use of metformin and statins has been identified as a positive prognostic factor for the disease course. In this review, we aim to present the metabolic disorders that occur in multiple myeloma, the potential defects on the immune system and the potential advantage of targeting the dysregulated pathways in order to enhance antitumor therapeutics.

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Section: Myeloma Treatment and Metabolismmentioning

confidence: 99%

Metabolic Disorders in Multiple Myeloma

Gavriatopoulou

Paschou

Ntanasis‐Stathopoulos

et al. 2021

IJMS

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“…Pre-clinical studies and clinical trials of cellular therapies have demonstrated that improved CAR-T cell persistence corresponds with better treatment efficacy (37,38). Similar studies for NK cells have also shown that persistence in pre-clinical in vivo models correlates with better tumor killing (39,40). Therefore, this limited expansion and persistence after being administered to patients may account for the limited efficacy of NK-92 cells in several clinical trials (41,42).…”

Section: Nk Cells As Cellular Therapymentioning

confidence: 97%

“…The stably engineered iPSCs can then be differentiated into NK cells and expanded for clinical use. This approach was recently described for a product with expression the non-cleavable, high-affinity version of CD16 to allow improved ADCC combined with an IL15-receptor fusion protein to enhance expansion of the cells (40). Additionally, as these NK cells are intended to be combined with an anti-CD38 antibody (Daratumumab) to target multiple myeloma, CD38 was deleted from the iPSCs to produce CD38-knockout (KO) iPSC-NK cells that also contain the engineered CD16 and IL15 molecules.…”

Section: Engager Molecules Direct Ipsc-nk Cells To Target Amlmentioning

confidence: 99%

“…Additionally, as these NK cells are intended to be combined with an anti-CD38 antibody (Daratumumab) to target multiple myeloma, CD38 was deleted from the iPSCs to produce CD38-knockout (KO) iPSC-NK cells that also contain the engineered CD16 and IL15 molecules. Since CD38 also mediated NAD metabolism, these CD38-KO iPSC-NK cells have features similar to so-called adaptive NK cells that arise after cytomegalovirus infection (40). Interestingly, while these triple-engineered iPSC-NK cells demonstrate potent anti-tumor activity in vitro, they were no better than iPSC-NK cells with just the engineered CD16 and IL15 receptor (and not the CD38-KO) in killing tumor cells in vivo using myeloma and AML xenograft models (40).…”

Section: Engager Molecules Direct Ipsc-nk Cells To Target Amlmentioning

confidence: 99%

“…Since CD38 also mediated NAD metabolism, these CD38-KO iPSC-NK cells have features similar to so-called adaptive NK cells that arise after cytomegalovirus infection (40). Interestingly, while these triple-engineered iPSC-NK cells demonstrate potent anti-tumor activity in vitro, they were no better than iPSC-NK cells with just the engineered CD16 and IL15 receptor (and not the CD38-KO) in killing tumor cells in vivo using myeloma and AML xenograft models (40). Clinical trials utilizing these engineered iPSC-NK cells are underway.…”

Section: Engager Molecules Direct Ipsc-nk Cells To Target Amlmentioning

confidence: 99%

See 2 more Smart Citations

iPSC-Derived Natural Killer Cell Therapies - Expansion and Targeting

2022

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Treatment of cancer with allogeneic natural killer (NK) cell therapies has seen rapid development, especially use against hematologic malignancies. Clinical trials of NK cell-based adoptive transfer to treat relapsed or refractory malignancies have used peripheral blood, umbilical cord blood and pluripotent stem cell-derived NK cells, with each approach undergoing continued clinical development. Improving the potency of these therapies relies on genetic modifications to improve tumor targeting and to enhance expansion and persistence of the NK cells. Induced pluripotent stem cell (iPSC)-derived NK cells allow for routine targeted introduction of genetic modifications and expansion of the resulting NK cells derived from a clonal starting cell population. In this review, we discuss and summarize recent important advances in the development of new iPSC-derived NK cell therapies, with a focus on improved targeting of cancer. We then discuss improvements in methods to expand iPSC-derived NK cells and how persistence of iPSC-NK cells can be enhanced. Finally, we describe how these advances may combine in future NK cell-based therapy products for the treatment of both hematologic malignancies and solid tumors.

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iPSC‐derived NK cells with site‐specific integration of CAR19 and IL24 at the multi‐copy rDNA locus enhanced antitumor activity and proliferation

Zhang,

Shi,

Wang

et al. 2024

MedComm

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The generation of chimeric antigen receptor‐modified natural killer (CAR‐NK) cells using induced pluripotent stem cells (iPSCs) has emerged as one of the paradigms for manufacturing off‐the‐shelf universal immunotherapy. However, there are still some challenges in enhancing the potency, safety, and multiple actions of CAR‐NK cells. Here, iPSCs were site‐specifically integrated at the ribosomal DNA (rDNA) locus with interleukin 24 (IL24) and CD19‐specific chimeric antigen receptor (CAR19), and successfully differentiated into iPSC‐derived NK (iNK) cells, followed by expansion using magnetic beads in vitro. Compared with the CAR19‐iNK cells, IL24 armored CAR19‐iNK (CAR19‐IL24‐iNK) cells showed higher cytotoxic capacity and amplification ability in vitro and inhibited tumor progression more effectively with better survival in a B‐cell acute lymphoblastic leukaemia (B‐ALL) (Nalm‐6 (Luc1))‐bearing mouse model. Interestingly, RNA‐sequencing analysis showed that IL24 may enhance iNK cell function through nuclear factor kappa B (NFκB) pathway‐related genes while exerting a direct effect on tumor cells. This study proved the feasibility and potential of combining IL24 with CAR‐iNK cell therapy, suggesting a novel and promising off‐the‐shelf immunotherapy strategy.

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Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy

Cited by 98 publications

References 47 publications

Metabolic Disorders in Multiple Myeloma

Metabolic Disorders in Multiple Myeloma

iPSC-Derived Natural Killer Cell Therapies - Expansion and Targeting

iPSC‐derived NK cells with site‐specific integration of CAR19 and IL24 at the multi‐copy rDNA locus enhanced antitumor activity and proliferation

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