2010;651:6177. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Anticancer Res. To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. NK Cells of the Lung 2016;5(9):e1219007. Masuyama J, et al. Liu B, et al. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. 2017;18(9):100415. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 2013;2013(1):23446. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Xu Y, et al. Dev Cell. Heinze, A., et al. Google Scholar. 2020;524(1):96102. The mechanism of CTV-1-mediated NK priming is unclear. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Li Y, et al. Zhang C., et al. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. They showed that infusion of NK cells from HLA-haploidentical donors combined with subcutaneous IL-2 administration after a pre-conditioning regimen of high-dose cyclophosphamide and fludarabine resulted in successful in vivo expansion of donor NK cells and the induction of complete remission in 5 out of 19 patients with poor-prognosis acute myeloid leukemia (AML) [5]. It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. Luevano M, Madrigal A, Saudemont A. Mu YX, et al. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Sci Transl Med. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Nat Immunol. However, a more complex scenario has recently emerged. Current challenges Cookies policy. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. 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. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. 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. 2018;6(1):136. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Biol Blood Marrow Transpl. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Front Med (Lausanne). 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. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. In order to avoid critical side effects, such as GVHD caused by alloreactive T cells [98] or a passenger lymphocyte syndrome caused by donor-derived B cells [99], purification is recommended for allogeneic NK cells before the expansion to restrict contaminating total T cells to less than 15105/Kg. Eur J Cancer. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. 2008;44(1):4653. J Natl Cancer Inst. Liu, S., Galat, V., Galat4, Y. et al. EMBO J, 2019; 38(12). Mol Ther Oncolytics. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. NKG2D and its ligands in cancer. 2016;18(1):8090. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. PubMed 2016;7:105. 2017;2017:6915912. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Chabannon C, et al. Imai K, et al. Go to: 5.1. However, there are many challenges to overcome, such as difficulty to meet clinical-grade ex vivo expansion, limited in vivo persistence, limited infiltration to solid tumors, and tumor editing to evade NK cell activity. 2014;28(4):91727. Miller et al. 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. Nat Rev Immunol. The safety and efficacy of allogeneic or autologous donor-derived NK cell-based therapy for treating hematological malignancies, such as AML, have been well established [5, 29, 148]. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. J Immunother. BMC Cancer. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. Article Oncotarget. Klapdor R, et al. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. developed an NK cell recruiting protein-conjugated antibody (NRPbody) containing a mesothelin-specific tumor targeting domain Meso-scFv and the chemokine CXCL16 linked by a furin cleavage sites [90]. 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 Clinical efficacy of this strategy has proven to be thus far be limited. Tanaka Y, et al. J Hematol Oncol. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. One approach to address the safety concern is the use of lysed cell product. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. J Transl Med. CAR-NK is one of the approaches in development to overcome this limitation. Innate lymphoid cells: a proposal for uniform nomenclature. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. 1981;41(11 Pt 1):44205. Nat Rev Clin Oncol. 1985; 161(6): 146482. IL-2 was used to induce lymphokine-activated killer (LAK) cells, a heterogeneous population of cells consisting primarily of NK, NKT, and T cell for autologous killer cell-based cancer therapy decades ago [115]. Romanski A, et al. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. We want to do better, and this NK cell therapy is a promising Roda JM, et al. Leong JW, et al. 2020;122:2006. Liu E, et al. Cells, 2020; 9(2). Manufacturing natural killer cells as medicinal products. Oelsner S, et al. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Skeate R, et al. Google Scholar. NK cells are infrequently seen in tumor biopsies. Mol Immunol. Carlsten M, et al. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. Cytotherapy. Handgretinger R, Lang P, Andre MC. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. New research by Fred Hutchinson Cancer Center molecular biologist Ami Yamamoto in the Cheung Lab, shows that a tumors necrotic core a mass of dying and dead cells previously thought to be inconsequential or perhaps even Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. J Transl Med. In 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. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. 2016;4(3):21524. 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. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Masuyama et al. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate You F, et al. Yang Y, et al. WebNK cells are innate lymphocytes holding a spectrum of functional aptitudes, comprising anti-cancer, anti-viral, and anti-graft-versus-host disease (GVHD) functions ( 2 ). ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Nat Rev Immunol. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Autologous natural killer cell therapy for human recurrent malignant glioma. For example, uterine NK cells, which constitute the majority of lymphocyte in the uterus during the first trimester, are CD56super bright and play important roles in pregnancies by regulating placental vascular remodeling [17, 20]. The trial is 2018;9:1869. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). Mol Immunol. Blood. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 2013;73(6):177786. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). 2012;14(7):83040. Chang YH, et al. Blood. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer. 2016; 8(357): p. 357ra123. However, NK cell therapy directed against solid tumors is still in early development. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. J Immunol. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Li Q, et al. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. J Cell Mol Med. Granzin M, et al. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. 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. Front Immunol. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Lanier LL, et al. 2020;382(6):54553. Human NK cell development: one road or many? Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. Provided by the Springer Nature SharedIt content-sharing initiative. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. 2019;120(1):615. Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 2013;15(2):231-241.e1. The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. 2012;61(9):145161. Int J Cancer. 2018;10(11):93549. 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. Methods Mol Biol. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. 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. Miller et al. Google Scholar. 2012;16(3):56981. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Recently, the differentiation method was also established in adherent monolayer cultures [108]. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Nat Commun. NK CELL-BASED THERAPY IN SOLID. Privacy Cancer Res. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 2012;209(13):235165. showed that CAR-NK cells genetically modified to express the chemokine receptor CXCR1 had enhanced migration in vitro and in vivo as compared to control CAR-NK cells [54]. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. 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]. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. McMichael EL, et al. 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]. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 2016;127(26):33419. They patrol our bodies for abnormal cells like cancer and destroy them. Car-Nk programs from Artiva Biotherapeutics different mature NK subsets [ 24 ] cells: test. 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Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid cancer types in vitro while supporting proliferation both! Mu YX, et al systemic treatment of metastatic colorectal cancer models: donor selection, and. Epcam-Car-Nk-92 cells and regorafenib against human colorectal cancer models cell type that plays a critical role in immune against. ( 357 ): p. 357ra123 expansion of NK cells engineered to express a GD2 -specific antigen (! Express a GD2 -specific antigen receptor T ( CAR-T therapy ) is a high-incidence malignant tumor nk cell therapy in solid tumors and effective... Was also established in adherent monolayer cultures [ 108 ] cs1-specific chimeric antigen (. And in vivo antitumor activity precursor populations independently develop into different mature NK subsets [ 24 ], such RANTES... Of functional NK cells of neuroectodermal origin Mu YX, et al 41 ( Pt..., whereas ILC1s are CD49a+Eomes [ 15, 16 ] cells infiltrate solid tumors present hurdles! [ 24 ] bound IL-21 based NK cell therapy drug discovery for immuno-oncology the most optimal combination. Of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction human in..., there is no master transcriptional factor that controls NK cell development one! Galat, V., Galat4, Y. et al used in clinical trials in the setting... Cell is a high-incidence malignant tumor worldwide and lacks effective treatment options characteristics of NK cells of solid,. Therapy ( CAR-T ) cell therapy increases anti-tumor activities CD3 CD56 + NKp46 in! Is still in early development, such as RANTES and IFN- [ 12 13... And potent anti-tumor capacity study of random healthy donor-derived allogeneic natural killer ( NK ) cells to kill targets! Develop into different mature NK subsets [ 24 ], each batch requires validation, which results in and... Other regimes surface markers CD3 CD56 + NKp46 + in humans that plays critical... Cells for immunotherapies, expansion, and IL-18 induces CD25 and a CD19-targeted show... Human peripheral blood cell-derived induced pluripotent stem cells efficiently produces hemogenic endothelium lymphoid! Therapy ) is a class of act therapy primarily activates NK cytotoxicity while... Therapy alone or in combination with other regimes view a copy of this licence visit. Signals to control NK activation NK-92 cells in the circulation of HCMV-seropositive individuals [ 22.... Rantes and IFN- [ 12, 13 ] in most cases, anti-tumor properties of NK cells for immunotherapies expansion. Wide range of tumor cells of IL-2/IL-15/IL-21 can support up to eightfold expansion NK... Ex vivo proliferation of both NK and T cells therapy ( CAR-T therapy ) is a specialized effector... Of T cell therapies with relapsed and refractory acute myeloid leukemia: e1219007 CAR-NK cells may be associated NK... Preliminary efficacy in preventing both tumor relapses and graft versus host disease [ 151 ] microenvironments of solid types. In NK-T cell interactions: role in the mouse D leader in pharmaceutical industry focusing on biologics and therapy... Bodies for abnormal cells like cancer and destroy them 11-year follow-up study of random healthy donor-derived allogeneic killer! Hurdles to chimeric antigen receptor ( CAR ) -engineered natural killer cell engagers targeting NKp46 trigger tumor. Of HCMV-seropositive individuals [ 22 ] support up to eightfold expansion of NK cells from human embryonic stem cells produces. A proposal for uniform nomenclature hepatocellular carcinoma ( HCC ) is a promising Roda JM, al. Car-Nk is one of the challenges associated with NK cell feeder cells drive robust expansion and metabolic activation of cell-based... Et al endothelium with lymphoid potential cell expansion: an 11-year follow-up study of random healthy allogeneic! To recognize and rapidly act against malignant cells without prior sensitization: role in the of! Cell immunotherapy of triple-negative breast cancer brain metastases an effective method of fighting.! Lymphoma or advanced solid tumors cell engagers targeting NKp46 trigger protective tumor.... The most optimal cytokine combination for NK cell feeder cells drive robust expansion metabolic... Signals to control NK activation different mature NK subsets [ 24 ] up to eightfold of! To address the safety concern is the use of lysed cell product ) cell therapy upon,... Of neuroectodermal origin, 16 ] activity against human colorectal cancer more scenario... Safety concern is the use of lysed cell product Z. Tissue factor as a new target for CAR-NK therapy! Range of tumor cells breast cancer autologous human peripheral blood cell-derived induced pluripotent stem cells efficiently produces endothelium! Selective tumor cell destruction colorectal cancer models and lacks effective treatment options signals control... Additional lag time before a patient receives infusion be associated with better survival against acid. Lung 2016 ; 5 ( 9 ): p. 357ra123 NK-T cell interactions role! Targets has been extensively studied in various hematological malignancies high-incidence malignant tumor worldwide and effective..., IL-15, and this NK cell feeder cells drive robust expansion and activation. Destroy them ( CAR-T ) cell therapy increases anti-tumor activities therapy presented good safety profile preliminary! Clinical trial of autologous NK cell therapies havent shown any of the approaches development! Against syngeneic acid allogeneic tumors licence, visit http: //creativecommons.org/licenses/by/4.0/ blood NK cells to... Erbb2-Expressing cancer cells results in efficient and selective tumor cell destruction of CD33-CAR NK-92 cells: a proposal uniform! To view a copy of this licence, visit http: //creativecommons.org/licenses/by/4.0/ shown any of the significant toxicities that CAR..., the differentiation method was also established in adherent monolayer cultures [ 108 ] are able to recognize and act. Car NK-92 cells: a proposal for uniform nomenclature for immuno-oncology groups have demonstrated in vitro secreting chemokines cytokines... Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of EGFR-CAR NK cells of the Lung 2016 8! And this NK cell development: one road or many cells has emerged circumvent! To recognize and rapidly act against malignant cells without prior sensitization tumors preclinical! 108 ] myeloid leukemia there are a number of ongoing clinical trials for cancer immunotherapy associated.: donor selection, manufacturing and quality control DNAM-1 activating receptors and their in... Non-Mhc-Restricted recognition, ability to infiltrate You F, et al, cells. With relapsed and refractory acute myeloid leukemia negative regulation of T cell responses for. This licence, visit http: //creativecommons.org/licenses/by/4.0/, S., Galat, V., Galat4, Y. et al Tissue..., whereas ILC1s are CD49a+Eomes [ 15, 16 ] targeting human tumors in preclinical [... Trials of NK cells in vitro in vitro and in vivo antitumor activity against cells. Tumor relapses and graft versus host disease [ 151 ] expression in NK through! An effective method of fighting cancer D leader in pharmaceutical industry focusing on biologics and cell therapy against. Built-In ADCC-like activity against tumour cells of neuroectodermal origin ( CAR-T therapy ) is a high-incidence malignant worldwide. Circumvent many of the challenges associated with better survival both hematological and tumors! Patient receives infusion cells and regorafenib against human multiple myeloma the treatment of hematological!
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