Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors

Liu, Enli; Marín, David; Banerjee, Pinaki P.; Macapinlac, Homer A.; Thompson, Philip A.; Basar, Rafet; Kerbauy, Lucila Nassif; Overman, Bethany J; Thall, Peter F.; Kaplan, Mecit; Nandivada, Vandana; Kaur, Indresh; Cortes, Ana Nunez; Cao, Kai; Daher, May; Hosing, Chitra; Cohen, Evan N.; Kebriaei, Partow; Mehta, Rohtesh S.; Neelapu, Sattva S.; Nieto, Yago; Wang, Michael; Wierda, William G.; Keating, Michael J.; Champlin, Richard E.; Shpall, Elizabeth J.; Rezvani, Katayoun

doi:10.1056/nejmoa1910607

Cited by 1,314 publications

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“…These CAR NK cells are potently cytotoxic and are more robustly activated in response to CD19 + target cells than their untransfected counterparts. As the transfection is mRNA-mediated and thus transient, this approach might mitigate the need for a suicide switch, as was used in the recent clinical trial of virally transduced CAR NK cells 5 . Further studies will need to examine whether sufficient numbers of CART-generated CAR NK cells can be readily generated, and to assess their lifespan in vivo in order to determine if this technique would be superior to lentiviral transduction for CAR NK cell preparation.…”

Section: Discussionmentioning

confidence: 99%

“…Upon activation through a combinatorial array of germline-encoded inhibitory and activating receptors, NK cells can directly kill their targets via targeted release of perforin- and granzyme-containing granules, as well as coordinate the downstream immune response by secreting pro-inflammatory cytokines like IFNγ and TNFα 3,4 . The rapid and robust cytotoxicity of NK cells makes them excellent assets for antiviral and anticancer immunotherapy, an enthusiasm most recently bolstered by the use of chimeric antigen receptor (CAR) NK cells in treating CD19 + lymphoid cancers with high efficacy and low toxicity 5–13 . Despite their clinical promise, several fundamental facets of human NK cell biology are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…NK cells are notoriously difficult to manipulate, presenting challenges both for a deeper understanding of fundamental NK cell biology and for the use of NK cells in clinical applications 17–21 . Most clinical trials involving genetically-modified NK cells utilize viral transduction (NCT02944162, NCT02892695, NCT03056339, NCT03579927) 5,22 . While viral transduction enables stable transgene expression, it is costly, laborious, and induces robust NK cell activation and apoptosis due to triggering of innate nucleic acid sensors, limiting its practicality for mechanistic studies of NK cell biology 8,18,23–28 .…”

Section: Introductionmentioning

confidence: 99%

“…While viral transduction enables stable transgene expression, it is costly, laborious, and induces robust NK cell activation and apoptosis due to triggering of innate nucleic acid sensors, limiting its practicality for mechanistic studies of NK cell biology 8,18,23–28 . Further, in clinical applications, viral transduction carries the risks of sustained adverse effects and oncogenic potential due to insertional mutagenesis, requiring the co-delivery of caspase-based suicide switches 5,6,29 . Most non-viral gene delivery methods, while easier to use for mechanistic studies, have generally only proven efficacious for immortalized NK cell lines with limited efficiency in primary NK cells 30,31,32,33 .…”

Section: Introductionmentioning

confidence: 99%

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Charge-Altering Releasable Transporters Enable Specific Phenotypic Manipulation of Resting Primary Natural Killer Cells

Wilk

Benner

Vergara

et al. 2020

Preprint

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22 Natural killer (NK) cells are capable of rapid and robust cytotoxicity, making them excellent tools 23 for immunotherapy. However, their recalcitrance to standard transfection techniques has limited 24 both mechanistic studies and clinical applications. Current approaches for NK cell manipulation 25 rely on viral transduction or methods requiring NK cell activation, which can alter NK cell 26 function. Here, we report that non-viral Charge-Altering Releasable Transporters (CARTs) 27 efficiently transfect primary human NK cells with mRNA without relying on NK cell activation. 28 Compared to electroporation, CARTs transfect NK cells two orders of magnitude more 29 efficiently, better preserve cell viability, and cause minimal reconfiguration of NK cell phenotype 30 and function. Finally, we use CARTs to generate highly cytotoxic primary human chimeric 31 antigen receptor NK cells, indicating potential therapeutic utility of this technique. To our 32 knowledge, CARTs represent the first efficacious transfection technique for resting primary NK 33 cells that preserves NK cell phenotype, and can drive new biological discoveries and clinical 34 applications of this understudied lymphocyte subset. 35 36 37 38 Natural killer (NK) cells are a group of innate lymphocytes that coordinate and execute 39 the rapid elimination of neoplastic and virus-infected cells 1,2 . Upon activation through a 40 combinatorial array of germline-encoded inhibitory and activating receptors, NK cells can 41 directly kill their targets via targeted release of perforin-and granzyme-containing granules, as 42 well as coordinate the downstream immune response by secreting pro-inflammatory cytokines 43 like IFNγ and TNFα 3,4 . The rapid and robust cytotoxicity of NK cells makes them excellent 44 assets for antiviral and anticancer immunotherapy, an enthusiasm most recently bolstered by 45 the use of chimeric antigen receptor (CAR) NK cells in treating CD19 + lymphoid cancers with 46 high efficacy and low toxicity 5-13 . Despite their clinical promise, several fundamental facets of 47 human NK cell biology are poorly understood. For example, the molecular underpinnings of 48 human NK cell memory 14-16 and the precise roles of various NK cell receptors in target cell 49 recognition remain unknown. 50 NK cells are notoriously difficult to manipulate, presenting challenges both for a deeper 51 understanding of fundamental NK cell biology and for the use of NK cells in clinical 52 applications 17-21 . Most clinical trials involving genetically-modified NK cells utilize viral 53 transduction (NCT02944162, NCT02892695, NCT03056339, NCT03579927) 5,22 . While viral 54 transduction enables stable transgene expression, it is costly, laborious, and induces robust NK 55 cell activation and apoptosis due to triggering of innate nucleic acid sensors, limiting its 56 practicality for mechanistic studies of NK cell biology 8,18,23-28 . Further, in clinical applications, 57 viral transduction carries the risks of sustained adverse effects and oncogenic potential ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Charge-Altering Releasable Transporters Enable Specific Phenotypic Manipulation of Resting Primary Natural Killer Cells

Wilk

Benner

Vergara

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…While umbilical cord blood banks make CB-derived NK cells a feasible starting product, the small volume obtained from cord blood requires the NK cells to undergo a large number of cell divisions before obtaining sufficient cell numbers required for infusion [83]. Nonetheless, clinical CAR-NK cell products have been manufactured from CB NK cells and are currently being tested in the clinic [89].…”

Section: Cord Blood Nk Cellsmentioning

confidence: 99%

You Have Got a Fast CAR: Chimeric Antigen Receptor NK Cells in Cancer Therapy

Pfefferle

Huntington

2020

Cancers

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The clinical success stories of chimeric antigen receptor (CAR)-T cell therapy against B-cell malignancies have contributed to immunotherapy being at the forefront of cancer therapy today. Their success has fueled interest in improving CAR constructs, identifying additional antigens to target, and clinically evaluating them across a wide range of malignancies. However, along with the exciting potential of CAR-T therapy comes the real possibility of serious side effects. While the FDA has approved commercialized CAR-T cell therapy, challenges associated with manufacturing, costs, and related toxicities have resulted in increased attention being paid to implementing CAR technology in innate cytotoxic natural killer (NK) cells. Here, we review the current landscape of the CAR-NK field, from successful clinical implementation to outstanding challenges which remain to be addressed to deliver the full potential of this therapy to more patients.

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Characteristics of Registered Studies of Chimeric Antigen Receptor Therapies

Banerjee

Prasad

2021

JAMA Netw Open

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IMPORTANCE Hundreds of chimeric antigen receptor (CAR) therapies are under investigation for hematologic malignant cancers and solid malignant tumors. As the field of modern CAR therapy enters its second decade, clinical trials that demonstrate the efficacy of CAR therapies using randomized clinical trials (RCTs) and/or investigate methods to optimize patient outcomes with commercially available CAR therapies are increasingly important. OBJECTIVE To analyze the landscape of registered CAR-related trials with dual focuses on trial methods and intent. EVIDENCE REVIEW This systematic review identified 1304 ongoing or upcoming CAR-related trials registered at ClinicalTrials.gov as of December 22, 2020, and excluded 513 trials that did not pertain to cell-based therapy. Both CAR-related and trial-related variables, including target antigens and countries of origin, were recorded. Trials were categorized as non-RCTs that compared CAR with non-CAR therapies or RCTs in which every arm received CAR therapy. Trial intent was separately categorized as demonstrating the efficacy of a CAR therapy, optimizing patient outcomes with established CAR therapies using adjunctive non-CAR modalities, or miscellaneous.FINDINGS Of 778 relevant trials, 587 (75%) involved blood cancers, whereas 182 (23%) involved solid tumor cancers; the remaining 9 (1%) involved nonmalignant diseases. A total of 433 trials (56%) were from China and 288 from the US (37%). Ten RCTs (1%) compared CAR therapies with non-CAR therapies, including phase 3 RCTs for 4 of 5 CAR therapies (80%) that are currently commercially available. Twenty-eight studies (4%) sought to optimize outcomes with established CAR therapies using non-CAR drugs or radiotherapy, whereas 3 studies (0.4%) sought to optimize supportive care during CAR therapy.CONCLUSIONS AND RELEVANCE This systematic review found that randomized and optimizationfocused trials are comparatively rare within the landscape of ongoing and upcoming CAR-related trials. As the field of modern CAR therapy enters its second decade, additional studies of these characteristics are necessary to strengthen the evidence base for CAR therapy and improve patient outcomes.

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Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors

Cited by 1,314 publications

References 31 publications

Charge-Altering Releasable Transporters Enable Specific Phenotypic Manipulation of Resting Primary Natural Killer Cells

Charge-Altering Releasable Transporters Enable Specific Phenotypic Manipulation of Resting Primary Natural Killer Cells

You Have Got a Fast CAR: Chimeric Antigen Receptor NK Cells in Cancer Therapy

Characteristics of Registered Studies of Chimeric Antigen Receptor Therapies

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