It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Fujisaki H, et al. CAS Nat Rev Immunol. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ The SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Berraondo P, et al. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. 2014;32(4):102131. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. 2016; 108(5). Adenosine impairs the anti-tumor functions of both T and NK cells [43]. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. J Hematol Oncol. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Liu E, et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. 2005;42(4):50110. Clin Cancer Res. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. Manage cookies/Do not sell my data we use in the preference centre. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Cite this article. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. Moreover, the CAR-NK cells secrete pro-inflammatory cytokines and chemokines which may improve the infiltration and functions of subsequently infused CAR-T cells in the mouse model [77]. Cancer Manag Res. 2017;18(9):100415. Sci Rep. 2015;5:11483. Sahm C, Schonfeld K, Wels WS. CAS PubMed BMC Immunol. 2016;18(1):8090. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. Cancer Immunol Res. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Cerwenka A, Lanier LL. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 2012;209(13):235165. Oncotarget. 2013;53(2):41923. Cytotherapy. 2020;111(5):147890. J Immunother Cancer. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. We want to do better, and this NK cell therapy is a promising Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. The expansion of NK cells using IL-2 alone is relatively modest and typically results in only several cell divisions in medium containing 1000 U/mL of IL-2 [100]. 1981;41(11 Pt 1):44205. Stem Cell Res Ther. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Glyostems lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Luhm J, et al. Wang et al. Webgeneration NK cell therapies. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Galat Y, et al. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. Jennifer Wu supervised the study. We are initiating the clinical evaluation of AB-201 at multiple centers in the US BMC Cancer. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Antigens such EGFRvIII, mesothelin, and Her2 have been targeted by CAR-NK cells for the treatment of solid cancers including colorectal cancer, ovarian cancer, breast cancer, and glioblastoma [41, 48]. Google Scholar. PLoS ONE. 2016;5(4):e1115178. WebThis button displays the currently selected search type. volume14, Articlenumber:7 (2021) In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Both UCB and placenta-derived cells contain some proportion of NK cell progenitors that have the capacity to differentiate into NK cells during maturation and expansion stages. Production Process of CAR-NK A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. They demonstrated in vitro and in a mouse xenograft model grafted with human neuroblastoma and MDSCs that NKG2D CAR-NK cells can reduce human MDSCs efficiently [77]. [2017][J Control Release][10.1016j.jconrel.2017.03. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Chu J, et al. Schonfeld K, et al. 2015;23(2):3308. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. J Cell Mol Med. Hammer Q, et al. For example, there is an ongoing phase 2 clinical trial to evaluate the safety and efficacy of human HLA-haploidentical hematopoieticcelltransplantation (HCT) followed by an early, post-transplant infusion of donor NKcells (NCT02100891). Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Ciurea SO, et al. Cancer Res. WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). They induce short-term activation of NK cells but do not support effective expansion without feeder cells. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Journal of Hematology & Oncology Parihar R, et al. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. 2016;18(5):65363. Nat Rev Immunol. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Front Immunol. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Article NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Mol Immunol. The cleavable CXCL16 containing NRPbody was shown to promote NK cell migration in vitro and infiltration into the tumor sites in vivo in xenografted mouse models of orthotopic and metastatic pancreatic cancer [90]. With the subcutaneous hypopharyngeal tumor xenograft model, it was shown that CXCR1-expressing CAR-NK cells had enhanced tumor infiltration and tumor control as compared to control CAR-NK cells [54]. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). Recently, several groups demonstrated that mouse and human NK cells pre-activated with a cocktail of IL-12/15/18 had enhanced and sustained anti-tumor effector functions in vitro and in vivo after infusion [84,85,86]. Muller S, et al. Li Y, et al. Source: Liu, S., Galat, V., Galat4, Y. et al. Ruggeri L, et al. 2016;16(5):31020. 1999;94(1):3339. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. It is now understood that the adaptive-like NK cells express the activating receptor NKG2C and that the adaptive nature of NKG2C+ NK cells attributes to the non-classical MHC I molecule HLA-E presenting CMV-specific viral peptide to NKG2C [22]. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. North J, et al. 2017;18(1):5667. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. WebIn this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Cancer Immunol Res. Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Markers and function of human NK cells in normal and pathological conditions. 2015;220(7):87688. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. In addition to cytokine-only strategies, Cichocki and colleagues demonstrated that pharmacologic inhibition of GSK3 kinase with CHIR99021 drives late-stage maturation of ex vivo-expanded human peripheral blood NK cells and enhanced their anti-tumor effector functions both in vitro and in vivo [87]. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. Sakamoto N, et al. Human NK cell development: one road or many? 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