Leveraging Natural Killer Cells for Cancer Immunotherapy

Grossenbacher, Steven K.; Aguilar, Ethan G.; Murphy, William J.

doi:10.2217/imt-2017-0013

Cited by 26 publications

(24 citation statements)

References 90 publications

(88 reference statements)

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“…All three of these processes likely contribute to selftolerance and are relevant to the development of more potent tumor immunotherapies that target NK-cell tolerance that could affect all three of these processes (46). Our results support the possibility that checkpoint blockade with anti-KIR2D antibodies has been ineffective in clinical trials due to unintended effects on NK-cell education and receptor expression, as has been previously hypothesized (46,47).…”

Section: Discussionsupporting

confidence: 83%

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Bern

Beckman

Ebihara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. Self–MHC-I also “licenses” NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development.

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Section: Discussionsupporting

confidence: 83%

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Bern

Beckman

Ebihara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…20,23,24 These effects lead to increased cytotoxic activity and increased proliferation of LEN-stimulated NK cells. 14,19,20 LEN has similar effects in B-NHL patients restoring synapse formation, ADCC, and cytotoxic functions in NK cells. 25,26 Of particular clinical importance, LEN allows NK cells to be activated by lower doses of RTX.…”

Section: Introductionmentioning

confidence: 89%

“…17 Lenalidomide (LEN; Revlimid; Celgene) is an immune-modulatory drug that can activate NK cells. 14,[18][19][20][21] LEN treatment during and after stem cell transplantation (SCT) increases NK cell proliferation, enhances NKp44 expression on NK cells 14 and increases circulating NK-cell numbers in leukemia patients. 22,23 LEN increases co-stimulatory receptor expression on NK cells, such as CD16 and Lymphocytes Function-associated Antigen (LFA) 14 and stabilizes NK cell:target cell immunological synapse.…”

Section: Introductionmentioning

confidence: 99%

NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment

Alexia

Allende-Vega

et al. 2017

OncoImmunology

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Obinutuzumab (OBZ) shows stronger antibody-dependent cell cytotoxicity (ADCC) compared to rituximab and improved clinical activity for treating certain CD20 C neoplasia. However, the efficacy of monoclonal antibody (mAb) as a monotherapy is limited. Natural Killer (NK) cells are mediators of ADCC. Hematological cancer patients possess antitumor NK cells that are unable to control disease, possibly because they are dysfunctional. The immunomodulatory drug lenalidomide (LEN) could be a treatment to restore exhausted NK cell cytotoxic functions. The clinical trial GALEN is a Phase Ib/II study of OBZ combined with LEN for the treatment of relapsed/refractory follicular and aggressive (DLBCL and MCL) B-cell Lymphoma. During treatment, we analyzed specific aspects of NK cell biology. Treatment reversed the immature NK phenotype of patients and increased expression of NK activating receptors. Inhibitory receptors were either unchanged or decreased. There was a strong NK response at the end of the 1st cycle: NK number and intracellular granzyme B (GrzB) expression decreased, degranulation increased and NK responded better to allogeneic target challenge. Moreover, the interaction of NK cells with B cell targets, measured by trogocytosis, decreased during treatment. At the end of treatment, when target cells had been wiped out, the proportion of reactive NK cells (CD69 C , CD45RARO C , CD107a C , CD19 C) strongly decreased. Because all patients received LEN and OBZ, it was uncertain which drug was responsible of our observations, or even if a combination of both products was necessary for the described effects on this lymphocyte lineage.

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“…2 The favorable therapeutic and safety profile of allogeneic NK cell therapy is considered as an important practical advantage over adoptive therapy of autologous T cells. 3,4 Clinically, the use of allogeneic NK cells from healthy donors offers the attractive potential to overcome cancer-treatment-caused immune defects associated with the use of patient immune cells. Significant efforts are currently undertaken to fully exploit the anti-tumor effect of NK cells in the clinic, but failures to achieve primary clinical end points, especially during the treatment of solid tumors, are still common.…”

Section: Introductionmentioning

confidence: 99%

Adoptive Transfer of NKG2D CAR mRNA-Engineered Natural Killer Cells in Colorectal Cancer Patients

et al. 2019

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By fusing the extracellular domain of the natural killer (NK) cell receptor NKG2D to DAP12, we constructed a chimeric antigen receptor (CAR) to improve NK cell tumor responses. An RNA electroporation approach that provides transient expression of the CAR was adopted as a risk mitigation strategy. Expression of the NKG2D RNA CAR significantly augmented the cytolytic activity of NK cells against several solid tumor cell lines in vitro and provided a clear therapeutic benefit to mice with established solid tumors. Three patients with metastatic colorectal cancer were then treated with local infusion of the CAR-NK cells. Reduction of ascites generation and a marked decrease in number of tumor cells in ascites samples were observed in the first two patients treated with intraperitoneal infusion of low doses of the CAR-NK cells. The third patient with metastatic tumor sites in the liver was treated with ultrasound-guided percutaneous injection, followed by intraperitoneal infusion of the CAR-NK cells. Rapid tumor regression in the liver region was observed with Doppler ultrasound imaging and complete metabolic response in the treated liver lesions was confirmed by positron emission tomography (PET)-computed tomographic (CT) scanning. Our results highlight a promising therapeutic potential of using RNA CAR-modified NK cells to treat metastatic colorectal cancer.

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Leveraging Natural Killer Cells for Cancer Immunotherapy

Cited by 26 publications

References 90 publications

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment

Adoptive Transfer of NKG2D CAR mRNA-Engineered Natural Killer Cells in Colorectal Cancer Patients

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