Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19

Lu, Ting; Ma, Rui; Dong, Wenjuan; Teng, Kun-Yu; Kollath, Daniel S; Li, Zhiyao; Yi, Jinhee; Bustillos, Christian; Ma, Shoubao; Tian, Lei; Mansour, Anthony G.; Li, Zhenlong; Settles, Erik W.; Zhang, Jianying; Keim, Paul; Barker, Bridget M.; Caligiuri, Michael A.; Yu, Jianhua

doi:10.1038/s41467-022-30216-8

Cited by 30 publications

(18 citation statements)

References 52 publications

(47 reference statements)

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“…This approach is expected to reduce inefficacies due to suboptimal IFN levels and hyperinflammation caused by excess infusion, both of which have been reported as adverse effects of systemic infusions 23,25,39,41 . The anti-SARS Tcell Biofactory adds to the growing portfolio of cell-based interventions for viral diseases [43][44][45] .…”

Section: Discussionmentioning

confidence: 99%

Antiviral T-cell Biofactory platform for SARS-CoV-2

Ssemadaali

Newmyer

Radhakrishnan

et al. 2022

Preprint

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1.0AbstractVaccines help reduce new infections, but interventions that can prevent the disease from transitioning to a severe stage are rather limited. Dysregulated IFN kinetics are mostly exploited by pathogenic viruses, including SARS-CoV-2. The clinical benefits of systemically infused IFN are, unfortunately, mired by undesired side effects. To address this situation, we engineered a T cell to synthesize interferons (IFNs) as antiviral proteins upon recognizing the virus envelop protein of SARS-CoV-2, i.e.,anti-SARS T-cell Biofactory. The T-cell Biofactory, capable of regulating the IFN expression with spatiotemporal resolution within the infected tissues, can mitigate these concerns. In this work, we determined the prophylactic and therapeutic effects of the type-I and type-III IFNs produced from the T-cell Biofactory against SARS-CoV-2 infection in host cells and investigated the expression profiles of ensuing IFN-stimulated genes (ISGs). To enable the translation of T-cell Biofactory as an effective antiviral countermeasure, we also investigated an irradiation dose that renders the T-cell Biofactory non-proliferative and thus non-oncogenic. The ongoing public health crisis motivated us to direct the T-cell Biofactory technology to target SARS-CoV-2. The T-cell Biofactory, based on T cells engineered with chimeric antigen receptors (CAR T cells), is a platform technology that can be rapidly re-engineered and become available for targeting any new pathogen.

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Section: Discussionmentioning

confidence: 99%

Antiviral T-cell Biofactory platform for SARS-CoV-2

Ssemadaali

Newmyer

Radhakrishnan

et al. 2022

Preprint

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“…NK cells are innate immune cells specialized for recognizing and rapidly killing abnormal cells, such as infected cells and tumor cells. 121 Unlike the priming of T cells, the activation of NK cells is independent of antigen presentation. NK cells are effector cells that function by releasing perforin and granzymes upon their activation to lyse abnormal cells.…”

Section: Macrophagesmentioning

confidence: 99%

Chemically engineering cells for precision medicine

Wang

et al. 2023

Chem. Soc. Rev.

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“…We recently generated ACE2-CAR NK cells that target the spike protein of SARS-CoV-2, and tested them in the K18-hACE2 animal model. 286 Also, NK cells co-expressing NKG2D- and ACE2-CAR have been designed to treat patients with COVID-19, an infectious disease caused by SARS-CoV-2 (NCT04324996). For details of clinical trials, please see Table 3 .…”

Section: Strategies To Improve Car Nk Cell Efficiency To Enhance Nk C...mentioning

confidence: 99%

Natural killer cell homing and trafficking in tissues and tumors: from biology to application

Ran

Lin

Tian

et al. 2022

Sig Transduct Target Ther

125

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Natural killer (NK) cells, a subgroup of innate lymphoid cells, act as the first line of defense against cancer. Although some evidence shows that NK cells can develop in secondary lymphoid tissues, NK cells develop mainly in the bone marrow (BM) and egress into the blood circulation when they mature. They then migrate to and settle down in peripheral tissues, though some special subsets home back into the BM or secondary lymphoid organs. Owing to its success in allogeneic adoptive transfer for cancer treatment and its “off-the-shelf” potential, NK cell-based immunotherapy is attracting increasing attention in the treatment of various cancers. However, insufficient infiltration of adoptively transferred NK cells limits clinical utility, especially for solid tumors. Expansion of NK cells or engineered chimeric antigen receptor (CAR) NK cells ex vivo prior to adoptive transfer by using various cytokines alters the profiles of chemokine receptors, which affects the infiltration of transferred NK cells into tumor tissue. Several factors control NK cell trafficking and homing, including cell-intrinsic factors (e.g., transcriptional factors), cell-extrinsic factors (e.g., integrins, selectins, chemokines and their corresponding receptors, signals induced by cytokines, sphingosine-1-phosphate (S1P), etc.), and the cellular microenvironment. Here, we summarize the profiles and mechanisms of NK cell homing and trafficking at steady state and during tumor development, aiming to improve NK cell-based cancer immunotherapy.

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Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19

Cited by 30 publications

References 52 publications

Antiviral T-cell Biofactory platform for SARS-CoV-2

Antiviral T-cell Biofactory platform for SARS-CoV-2

Chemically engineering cells for precision medicine

Natural killer cell homing and trafficking in tissues and tumors: from biology to application

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