HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM)

Sharifzad, Farzaneh; Mardpour, Soura; Mardpour, Saeid; Fakharian, Esmaeil; Khani, Adeleh Taghi; Sharifzad, Amirhosein; Kiani, Sahar; Heydari, Yasaman; Łos, Marek; Azizi, Zahra; Ghavami, Saeid; Hamidieh, Amir Ali; Ebrahimi, Marzieh

doi:10.20944/preprints202002.0364.v1

Cited by 12 publications

(5 citation statements)

References 51 publications

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“…The TKD peptide, a 14-amino acid sequence from the Heat shock protein 70 (HSP70), has been demonstrated to stimulate the cytolytic, proliferative and migratory ability of NK cells against target cells, expressing the membrane form of HSP70 on their surface, through the engagement of CD94 [ 93 , 94 ]. TKD-expanded and activated NK cells by the Royan Institute and Tehran University of Medical Sciences are tested against patient-derived glioblastoma cells with membrane-bound HSP70 (Additional file 1 : Table S1, row 16) [ 95 ]. Moreover, priming agents, such as the IL-15 superagonist ALT-803 and the IL-2 recombinant fusion protein ALT-801 from Altor Bioscience, have been tested in combination with NK cells in a few clinical studies (Additional file 3 : Table S3, rows 3 [ 96 ] and 6 [ 97 ]).…”

Section: Clinical Manufacturing Of Nk Cell Therapiesmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.

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Section: Clinical Manufacturing Of Nk Cell Therapiesmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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“…The declined cytotoxic function of Hsp70-treated NK cells against K562 and SKOV3 cells in the present study (Fig. 5 ; Additional file 3 : Figure S3) can be explained by the dual function of Hsp70 which can also promote the cancer cells viability [ 27 , 43 – 47 ]. Furthermore, considering the qRT-PCR results, it can be claimed that treating with Hsp70 led to a reduction in the NK cell lysis capacity compared to the other group.…”

Section: Discussionmentioning

confidence: 80%

“…Functionality can be induced using exogenous molecules regulating the NK cells effector factors such as IL-2, IL-15 and IL-21. They do so by increasing the expression of co-inhibitory receptors (PD-1), inhibitory receptors (NKG2A) and the upregulation of the activating receptors like NKG2D.All these changes can impair the balance of activating/inhibitory signals and consequently result in the exhaustion of NK cell functions [ 20 , 21 , 27 , 39 – 41 ]. Other factors that can suppress NK cells function during differentiation and activation are suppressive cytokines such as TGF-β which induces the downregulation of activating receptors [ 12 , 13 , 20 , 40 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

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Overcoming the UCB HSCs –Derived NK cells Dysfunction through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways

et al. 2021

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Background The natural killer (NK) cells differentiated from umbilical cord blood (UCB) hematopoietic stem cells (HSCs) may be more suitable for cell-based immunotherapy compared to the NK cells from adult donors. This is due to the possibility to choose alloreactive donors and potentially more robust in vivo expansion. However, the cytotoxicity of UCB-HSC-derived NK cells against cancer cells might be suboptimal. To overcome this obstacle, we attempted to generate NK cells with potent antitumor activity by targeting RAS/MAPK, IGF-1R and TGF-β signaling pathways using IL-15, IGF-1 and SIS3 respectively. Methods The CD34 + cells were isolated from human UCB mononuclear cells through magnetic activation cell sorting (MACS) with purity of (≥ 90%) and were subjected to differentiate into NK cells. After 21 days of induction with SFTG36 (SCF, FLt-3L, TPO, GM-CSF, IL-3 and IL-6), IS721 (IGF-1, SIS3, IL-7 and IL-21) and IL-15/Hsp70 media, NK cells phenotypes were studied and their cytotoxicity against K562 human erythroleukemia cells and SKOV3 ovarian carcinoma cells was analyzed. Results The NK cells induced in SFTG36/IS721 medium were selected for activation due to their higher expression of CD56 + 16 + CD3 − (93.23% ± 0.75) and mean fluorescence intensity (MFI) of NKG2D + (168.66 ± 20.00) and also a higher fold expansion potential (11.893 ± 1.712) compared to the other groups. These cells once activated with IL-15, demonstrated a higher cytotoxicity against K562 (≥ 90%; P ≤ 0.001) and SKOV3 tumor cells (≥ 65%; P ≤ 0.001) compared to IL-15/Hsp70-activated NK cells. Conclusions The differentiation of ex vivo expanded CD34 + cells through manipulation of RAS/MAPK, IGF-1R and TGF-β signaling pathways is an efficient approach for generating functional NK cells that can be used for cancer immunotherapy.

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“…Relevant teams analyzed the glioma data obtained from TCGA and verified the expression of differential proteins in the tissues or body fluids of glioma patients, animal models and cell lines. Common targets are GFAP (Wang et al, 2018), HSP70 (Sharifzad et al, 2020), VEGF (Nicolas et al, 2019), BDNF (Huo & Chen, 2019, ECM (Tejero et al, 2019), FN1 (Yu et al, 2020;Gu, Gu & Shou, 2014;Guo, Heller & Thorslund, 2016;Liao et al, 2018), CD44 (Mooney et al, 2016), Fransgelin-2, Short Hairpin RNAGLN and GRN (Ness, Riemenschneider & Baches., 2009;Trigos et al, 2019) etc. Previous research suggested that TAGLN2 might be involved in progression due to its higher expression in glioblastomas compared to IDH1/2 WT gliomas of lower grades (Beyer et al, 2018;Han et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Identification of robust diagnostic and prognostic gene signatures in different grades of gliomas: a retrospective study

Liu

Zhang

et al. 2021

PeerJ

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Background Gliomas are the most common primary tumors of the central nervous system. The complexity and heterogeneity of the tumor makes it difficult to obtain good biomarkers for drug development. In this study, through The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA), we analyze the common diagnostic and prognostic moleculer markers in Caucasian and Asian populations, which can be used as drug targets in the future. Methods The RNA-seq data from Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) were analyzed to identify signatures. Based on the signatures, the prognosis index (PI) of every patient was constructed to predict the prognostic risk. Also, gene ontology (GO) functional enrichment analysis and KEGG analysis were conducted to investigate the biological functions of these mRNAs. Glioma patients’ data in the CGGA database were introduced to validate the effectiveness of the signatures among Chinese populations. Excluding the previously reported prognostic markers of gliomas from this study, the expression of HSPA5 and MTPN were examined by qRT-PCR and immunohistochemical assay. Results In total, 20 mRNAs were finally selected to build PI for patients from TCGA, including 16 high-risk genes and four low-risk genes. For Chinese patients, the log-rank test p values of PI were both less than 0.0001 in two independent datasets. And the AUCs were 0.831 and 0.907 for 3 years of two datasets, respectively. Moreover, among these 20 mRNAs, 10 and 15 mRNAs also had a significant predictive effect via univariate COX analysis in CGGA_693 and CGGA_325, respectively. qRT-PCR and Immunohistochemistry assay indicated that HSPA5 and MTPN over-expressed in Glioma samples compared to normal samples. Conclusion The 20-gene signature can forecast the risk of Glioma in TCGA effectively, moreover it can also predict the risks of Chinese patients through validation in the CGGA database. HSPA5 and MTPN are possible biomarkers of gliomas suitable for all populations to improve the prognosis of these patients.

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HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM)

Cited by 12 publications

References 51 publications

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Overcoming the UCB HSCs –Derived NK cells Dysfunction through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways

Identification of robust diagnostic and prognostic gene signatures in different grades of gliomas: a retrospective study

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