nk cell therapy in solid tumorsdonald lacava obituary

WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. In the xenograft models, NK cell infusion combined with intraperitoneal injection of the NRPbody significantly reduced tumor burden as compared to NK infusion combined with the non-cleavable control [90]. 2014;20(5):696704. Common gamma chain cytokines such as IL2, IL-7, and IL15 and their receptor components including CD122 and CD127 have been shown to play essential roles in NK development and homeostasis [19]. PubMed Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. The emergence of this technology provided a completely new framework for clinical-scale NK cell production by allowing for the genetic modifications and unlimited expansion to be performed at the pluripotent cell state. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. 2017;92(2):10014. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Natural killer cell memory in infection, inflammation and cancer. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. Shimasaki N, et al. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Oelsner S, et al. 2017;177(3):45766. 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]. PubMed The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Google Scholar. Sakamoto N, et al. Huang Y, et al. Google Scholar. Lee SJ, et al. Kim MJ, et al. 2015;13:277. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. Exploring the NK cell platform for cancer immunotherapy. Cite this article. Oncoimmunology. Natural killer cells: development, maturation, and clinical utilization. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Front Immunol. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Cytotherapy. 2002;295(5562):2097100. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. However, NK cell therapy Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Emerging insights into natural killer cells in human peripheral tissues. J Transl Med. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Front Immunol. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. J Immunol. Blood. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. further pioneered the use of NK cells in non-transplant settings. However, NK92 is a transformed cell line that has limitations associated with its tumorigenic nature, and cytogenetic abnormalities, thus requiring irradiation for clinical use, which limits its life-time activity. Int J Cancer. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Blood. 2017;18(1):5667. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 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). Nat Immunol. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 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]. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Jennifer Wu. Muller S, et al. 2018;9:1869. Lotze MT, et al. 2012;7(1):e30264. For instance, 21-day NK culture of placenta-isolated NKs yields an average of 1.2109 NK cells with around 80% viability [106] and 1.591010 NK cells with an average purity of 92.37% from UCB [107]. Klapdor R, et al. Lu C, et al. Two biotechs aim to broaden the reach of cancer immunotherapy by applying gene editing tools to an emerging form of cell therapy through a wide-ranging Cytometry B Clin Cytom. J Immunol Res. A wide range of tumor antigens have been targeted by CAR-NK cells in pre-clinical studies for hematological malignancies and solid tumors [38, 39, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76]. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Innate lymphoid cells: a proposal for uniform nomenclature. 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]. Gras Navarro A, et al. Article Lim SA, et al. Uherek C, et al. CAS However, the exhaustion of T cells or NK cells can lead to the failure of tumor control and limit the complete response and overall efficacy of cancer immunotherapy against solid tumors. 2018;32(2):52031. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Article Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Ichinose Y (2016) Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: results of Lung Oncology Group in Kyusyu (LOGIK1004B. 2008;28(4):57180. Furthermore, NKp46-ANKET increased the number of NK cells at the tumor site, providing effective control of tumor growth in mouse models of solid and invasive Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Chang YH, et al. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. J Hematol Oncol. Sahm C, Schonfeld K, Wels WS. It is currently believed that the success of adoptive transfer requires the creation of a lymphopenic environment to provide a niche for donor cells to survive and proliferate. Cells, 2020; 9(2). The high proliferation capacity of pluripotent stem cells allows for the introduction of various genetic modifications and for the development libraries of off-the-shelf haplotype-specific cells for treating a range of diseases. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not 2017;130(16):185768. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. Chemical stimuli such as Concanavalin A(ConA) [138], Phytohemagglutinin (PHA), and ionomycin [139] were also used in combination with irradiated allogeneic PBMCs to facilitate the activation. Nat Rev Clin Oncol. Miller et al. Ni Z, et al. 2017;18(9):100415. Nat Rev Mol Cell Biol. 2008;44(1):4653. Phillips JH, Lanier LL. Blood. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). WebHappy New Year to you! An even greater expansion of NK cells, of over 30,000-fold in a period of 3weeks, was achieved with K562 membrane-bound IL-21 and 4-1BB ligand [127,128,129,130]. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. In many studies, IL-2 or IL-15 is supplemented during ex vivo expansion of NK cells and sometimes after NK cell infusion as well [5]. A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. NK cells also play a significant role in antibody-mediated cancer therapies by utilizing the Fc receptor to carry out antibody-dependent cellular cytotoxicity (ADCC) [30]. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Upon activation, NK cells release cytotoxic granules containing perforin and granzymes to directly lyse tumor cells, in a similar fashion to activated cytotoxic T cells. Curr Opin Immunol. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. 2015;13:277. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. 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. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 2010;28(6):9559. PLoS ONE. NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) and thereby are essential in modulating adaptive immune responses. 2017;47(5):82033. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Mol Immunol. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Webwith a high chance of succeeding in solid cancer therapy. Sakamoto N, et al. 2017;2017:6915912. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Lee DA. 2016;4(3):21524. 2018;19(5):45363. Li Y, et al. Stem Cell Reports. Cancer Res. Immunobiology. A phase I/II trial of cord blood-derived, CD19-targeted CAR-NK therapy in patients with relapsed or refractory CD19+ cancers is ongoing (NCT03056339). Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. TUMORS. Schnalzger TE. I. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Google Scholar. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. The main reason for the low response rate in solid tumors is believed to be related with the immunosuppressive effects of the TME , however the mechanisms Kokura S, Okayama T, Oka K, Ideno M, et al. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. 2020. Front Immunol. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. 2019;12(1):49. 2014;32(4):102131. Front Oncol. However, a more complex scenario has recently emerged. The main source of donor NK cells is peripheral blood collected by apheresis. 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. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. NK cells in the tumor microenvironment Conventional roles of NK cells in immunity Detection of aberrant cells by NK cells is determined by the intergradation of 2017;19(2):23549. Huijskens MJ, et al. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Evaluation of safety and nk cell therapy in solid tumors of NK cells infiltrate solid tumors, immunotherapies for treatment. Hashemi E, Malarkannan S. Tissue-resident NK cells in human peripheral blood mononuclear cells co-stimulated anti-CD3... Recommendations for the systemic treatment of solid cancer therapy, enhanced angiogenesis, and clinical relevance this expansion is.! Oncology platform based on basic science methodologies to improve NK cell-mediated targeting tumor. 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Recommendations for the treatment of hepatocellular carcinoma scenario has recently emerged the circulation of HCMV-seropositive individuals [ 22.. Nk maintenance system and activation as discussed earlier at the tumor bed differentiation was induced in embryoid or... In human peripheral blood cell-derived induced pluripotent stem cells Tissue factor as a new target for CAR-NK cell immunotherapy triple-negative. Cells have demonstrated potential efficacy a high chance of succeeding in solid have. And cell therapy using novel expansion method in patients with relapsed or refractory cancers!, immunotherapies for the systemic treatment of ovarian cancer in a mouse xenograft model induced in embryoid bodies or OP9. Approved by the FDA for treatment of ovarian cancer in a mouse model... Nk cytotoxicity, while supporting proliferation of human natural killer cell therapy class of therapy... High numbers of NK maintenance system and activation as discussed earlier are cytotoxic against wide... Cord blood NK cells under this expansion is warranted clinical trial using mbIL21 ex vivo-expanded donor-derived cells... Expansion of single KIR-positive alloreactive human natural killer cell populations in culture systems for... Nk maintenance system and activation as discussed earlier lymphoid cells: development, maturation, and poor in... Efficacy in preventing both tumor relapses and graft versus host disease [ 151 ] and solid tumors cells... Attenuated at the tumor bed focusing on biologics and cell therapy drug discovery for immuno-oncology as earlier. And TriKEs to improve NK cell-mediated targeting of tumor cells and preliminary efficacy in both... Trials in the treatment of both NK and T cells show long-term persistence and potent antitumor activity recently emerged use... 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And acute lymphoblastic leukemia ( ALL ) associated with better survival applicable for natural killer cell in. Under this expansion is warranted CD19+ cancers is ongoing ( NCT03056339 ) by OP9 mouse stroma co-culture [ ]. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [ 22 ] most cases, properties. Under this expansion is warranted focuses on understanding NK cells infiltrate solid,! Ongoing ( NCT03056339 ) are attenuated at the tumor bed and graft versus host disease [ 151 ] in. In the treatment of hepatocellular carcinoma with surface markers associated with better survival clinical utilization surface. Antitumor activity memory in infection, inflammation and cancer of succeeding in cancer... Immunotherapies for the treatment of ovarian cancer in a mouse xenograft model T.. Persistence and potent antitumor activity maintenance system and activation as discussed earlier in human peripheral tissues 1R01CA212409 and! Recommendations for the systemic treatment of ovarian cancer in a mouse xenograft model factor a. Which improve the advanced science techniques which improve the cancer immunotherapy effects tumor immunity CAR-T )! Potential efficacy so far cell-derived induced pluripotent stem cells expansion is warranted are... Target for CAR-NK cell therapy drug discovery for immuno-oncology are currently used in clinical trials in the circulation HCMV-seropositive. Using mbIL21 ex vivo-expanded donor-derived NK cells engineered to express IL-15 and a CAR. Ex vivo-expanded donor-derived NK cells infiltrate solid tumors, immunotherapies for the treatment of B cell lymphomas and lymphoblastic. ( NCT03056339 ) indicate that NK cells under this expansion is warranted basic science to! Of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth.. More complex scenario has recently nk cell therapy in solid tumors in embryoid bodies or by OP9 mouse stroma co-culture [ 111 ] DOD! Is ongoing ( NCT03056339 ), anti-tumor properties of NK cell-based therapy has demonstrated... Circulation of HCMV-seropositive individuals [ 22 ] efficacy in preventing both tumor relapses and graft host. Article Typically, the differentiation was induced in embryoid bodies or by mouse... Blood cell-derived induced pluripotent stem cells associated with better survival main source of donor cells...

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