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Maude, S. L. etal. Tisagenlecleucel in children and young adults with B-cell ly\ mphoblastic leukemia. N. Engl. J. Med. 378, 439 448 \(2018\).\r:57)/F 4/H/N/Rect[176.666 488.855 179.304 476.444]/Subtype/Link/Type/Annot>> endobj 4 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:8. Raje, N. etal. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory mul\ tiple myeloma. N. Engl. J. Med. 380, 1726 1737 \(2019\).\r:58)/F 4/H/N/Rect[182.157 488.855 184.795 476.444]/Subtype/Link/Type/Annot>> endobj 5 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:10. Malmberg, K.-J. etal. Natural killer cell-mediated immunosurveillance of human\ cancer. Semin. Immunol. 31, 20 29 \(2017\).\r:59)/F 4/H/N/Rect[334.642 422.855 339.761 410.444]/Subtype/Link/Type/Annot>> endobj 6 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:17. Imai, K., Matsuyama, S., Miyake, S., Suga, K. \n& Nakachi, K. Natural cytotoxic a\ ctivity of peripheral-\nblood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 35\ 6, 1795 1799 \(2000\).\r:60)/F 4/H/N/Rect[168.581 378.855 173.854 366.444]/Subtype/Link/Type/Annot>> endobj 7 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:19. Lpez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis \ by NK cells. Cancer Cell 32, 135 154 \(2017\).\r:61)/F 4/H/N/Rect[176.705 378.855 181.978 366.444]/Subtype/Link/Type/Annot>> endobj 8 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:20. Abel, A. M., Yang, C., Thakar, M. S. & Malarkannan, S. Natural killer cells: dev\ elopment, maturation, and clinical utilization. Front. Immunol. 9, 1869 \(2018\).\r:62)/F 4/H/N/Rect[334.346 334.855 339.761 322.444]/Subtype/Link/Type/Annot>> endobj 9 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:21. Dalle, J.-H. etal. Characterization of cord blood natural killer cells: implica\ tions for transplantation and neonatal infections. Pediatr. Res. 57, 649 655 \(2005\).\r:63)/F 4/H/N/Rect[334.595 257.855 339.761 245.444]/Subtype/Link/Type/Annot>> endobj 10 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:22. Strauss-Albee, D. M. etal. Human NK cell repertoire diversity reflects immune e\ xperience and correlates with viral susceptibility. Sci. Transl. Med. 7, 297ra115 297ra115 \(2015\).\r:64)/F 4/H/N/Rect[266.468 191.855 271.563 179.444]/Subtype/Link/Type/Annot>> endobj 11 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:23. Prager, I. & Watzl, C. Mechanisms of natural killer cell-mediated cellular cytot\ oxicity. J. Leukoc. Biol. 105, 1319 1329 \(2019\).\r:65)/F 4/H/N/Rect[217.015 147.855 222.383 135.444]/Subtype/Link/Type/Annot>> endobj 12 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:24. Wang, W., Erbe, A. K., Hank, J. A., Morris, Z. S. & Sondel, P. M. NK cell-mediat\ ed antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front. Immunol. 6, 368 \(2015\).\r:66)/F 4/H/N/Rect[318.691 114.855 323.979 102.444]/Subtype/Link/Type/Annot>> endobj 13 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:11. Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibitio\ n. Nat. Immunol. 9, 495 502 \(2008\).\r:67)/F 4/H/N/Rect[270.253 59.8547 275.365 47.4439]/Subtype/Link/Type/Annot>> endobj 14 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:25. O Leary, J. G., Goodarzi, M., Drayton, D. L. & von Andrian, U. H. Tcell- and B \ cell-independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 7, 507 516 \(2006\). \nThis seminal study\ demonstrates that NK cells can media:68)/F 4/H/N/Rect[460.257 664.855 465.471 652.444]/Subtype/Link/Type/Annot>> endobj 15 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:26. Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural ki\ ller cells. Nature 457, 557 561 \(2009\). \nThis important article reveals self-renewing memory  NK cell subsets that can u\ ndergo secondary expansion and elicit:69)/F 4/H/N/Rect[466.726 664.855 471.939 652.444]/Subtype/Link/Type/Annot>> endobj 16 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:26. Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural k\ iller cells. Nature 457, 557 561 \(2009\). \nThis important article reveals self-renewing memory  NK cell subsets that can \ undergo secondary expansion and elici:70)/F 4/H/N/Rect[379.901 642.855 385.245 630.444]/Subtype/Link/Type/Annot>> endobj 17 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:27. Cooper, M. A. etal. Cytokine-induced memory-like natural killer cells. Proc. N\ atl Acad. Sci. USA 106, 1915 1919 \(2009\). \nThis work pioneers the concept of cytokine-induced memory-like NK cells which e\ licit robust recall responses when tr:71)/F 4/H/N/Rect[386.564 642.855 391.908 630.444]/Subtype/Link/Type/Annot>> endobj 18 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:28. Romee, R. etal. Cytokine activation induces human memory-like NK cells. Blood\ 120, 4751 4760 \(2012\).\r:72)/F 4/H/N/Rect[369.457 477.855 374.71 465.444]/Subtype/Link/Type/Annot>> endobj 19 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:29. Romee, R. etal. Cytokine-induced memory-like natural killer cells exhibit enhan\ ced responses against myeloid leukemia. Sci. Transl. Med. 8, 357ra123 \(2016\).\r:73)/F 4/H/N/Rect[382.342 444.855 387.438 432.444]/Subtype/Link/Type/Annot>> endobj 20 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:30. Shapiro, R. M. etal. Expansion, persistence, and efficacy of donor memory-like \ NK cells infused for post-transplant relapse. J. Clin. Investig. https://doi.org/\n10.1172/JCI154334 \(2022\).\r:74)/F 4/H/N/Rect[388.634 444.855 393.729 432.444]/Subtype/Link/Type/Annot>> endobj 21 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:31. Platonova, S. etal. Profound coordinated alterations of intratumoral NK cell ph\ enotype and function \nin lung carcinoma. Cancer Res. 71, 5412 5422 \(2011\).\r:75)/F 4/H/N/Rect[520.273 389.855 525.526 377.444]/Subtype/Link/Type/Annot>> endobj 22 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:32. Sun, C. etal. High NKG2A expression contributes to NK cell exhaustion and predi\ cts a poor prognosis of patients with liver cancer. Oncoimmunology 6, e1264562 \(2017\).\r:76)/F 4/H/N/Rect[526.801 389.855 532.055 377.444]/Subtype/Link/Type/Annot>> endobj 23 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:Fig. 1 | Advantages and limitations arising from different sources of NK cells. \ Natural killer \(NK\) cells can be derived from several different sources, each of which presents its own advantages and potent\ ial challenges. Chimeric antigen rec:77)/F 4/H/N/Rect[477.489 279.855 481.865 267.444]/Subtype/Link/Type/Annot>> endobj 24 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:28. Romee, R. etal. Cytokine activation induces human memory-like NK cells. Blood\ 120, 4751 4760 \(2012\).\r:78)/F 4/H/N/Rect[439.86 268.855 444.86 256.444]/Subtype/Link/Type/Annot>> endobj 25 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:30. Shapiro, R. M. etal. Expansion, persistence, and efficacy of donor memory-like\ NK cells infused for post-transplant relapse. J. Clin. Investig. https://doi.org/\n10.1172/JCI154334 \(2022\).\r:79)/F 4/H/N/Rect[447.575 268.855 452.574 256.444]/Subtype/Link/Type/Annot>> endobj 26 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:28. Romee, R. etal. Cytokine activation induces human memory-like NK cells. Bloo\ d 120, 4751 4760 \(2012\).\r:80)/F 4/H/N/Rect[494.655 268.855 499.655 256.444]/Subtype/Link/Type/Annot>> endobj 27 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:30. Shapiro, R. M. etal. Expansion, persistence, and efficacy of donor memory-lik\ e NK cells infused for post-transplant relapse. J. Clin. Investig. https://doi.org/\n10.1172/JCI154334 \(2022\).\r:81)/F 4/H/N/Rect[502.369 268.855 507.369 256.444]/Subtype/Link/Type/Annot>> endobj 28 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:33. Spanholtz, J. etal. High log-scale expansion of functional human natural killer\ cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS ONE 5, e9221 \(2010\).\r:82)/F 4/H/N/Rect[508.517 268.855 513.517 256.444]/Subtype/Link/Type/Annot>> endobj 29 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:37. Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-positive lymph\ oid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:83)/F 4/H/N/Rect[516.232 268.855 521.232 256.444]/Subtype/Link/Type/Annot>> endobj 30 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:38. Gong, J.-H., Maki, G. & Klingemann, H. G. Characterization of a human cell line \ \(NK-92\) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8, 652 658 \(1994\).\r\ :84)/F 4/H/N/Rect[410.771 257.855 415.87 245.444]/Subtype/Link/Type/Annot>> endobj 31 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:40. Zhang, C. etal. Chimeric antigen receptor-engineered NK-92 cells: an off-the-sh\ elf cellular therapeutic for targeted elimination of cancer cells and induction \nof protective antitumor immunity. Front. Immu\ nol. https://doi.org/10.3389/fimm:85)/F 4/H/N/Rect[418.634 257.855 423.734 245.444]/Subtype/Link/Type/Annot>> endobj 32 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:33. Spanholtz, J. etal. High log-scale expansion of functional human natural kille\ r cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS ONE 5, e9221 \(2010\).\r:86)/F 4/H/N/Rect[415.688 246.855 420.783 234.444]/Subtype/Link/Type/Annot>> endobj 33 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:34. Dolstra, H. etal. Successful transfer of umbilical cord blood CD34+ hematopoi\ etic stem and progenitor-\nderived NK cells in older acute myeloid leukemia patients. Clin. Cancer Res. 23, 4107 4118 \(2017\)\ .\r:87)/F 4/H/N/Rect[421.979 246.855 427.075 234.444]/Subtype/Link/Type/Annot>> endobj 34 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:41. Hoogstad-van Evert, J. S. etal. Umbilical cord blood CD34+ progenitor-derived\ NK cells efficiently kill ovarian cancer spheroids and intraperitoneal tumors in NOD/SCID/IL2Rgnull mice. Oncoimmunology 6\ , e1320630 \(2017\).\r:88)/F 4/H/N/Rect[428.271 246.855 433.366 234.444]/Subtype/Link/Type/Annot>> endobj 35 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:42. Knorr, D. A. etal. Clinical-scale derivation of natural killer cells from human\ pluripotent stem cells for cancer therapy. Stem Cell Transl. Med. 2, 274 283 \(2013\).\r:89)/F 4/H/N/Rect[380.152 235.855 385.149 223.444]/Subtype/Link/Type/Annot>> endobj 36 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:43. Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-derived n\ atural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181 192.e5 \(\ 2018\). \nThis article demonstrates t:90)/F 4/H/N/Rect[386.296 235.855 391.293 223.444]/Subtype/Link/Type/Annot>> endobj 37 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:44. Goldenson, B. H. etal. Umbilical cord blood and iPSC-derived natural killer cells \ demonstrate key differences in cytotoxic activity and KIR profiles. Front. Immunol. 11, https://doi.org/10.3389/fimmu.2020\ .561553 \(2020\).\r:91)/F 4/H/N/Rect[488.001 180.855 493.096 168.444]/Subtype/Link/Type/Annot>> endobj 38 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:38. Gong, J.-H., Maki, G. & Klingemann, H. G. Characterization of a human cell line\ \(NK-92\) with phenotypical and functional characteristics of activated natural killer cells. 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Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-positive lym\ phoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:106)/F 4/H/N/Rect[262.745 235.855 267.92 223.444]/Subtype/Link/Type/Annot>> endobj 51 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:33. Spanholtz, J. etal. High log-scale expansion of functional human natural kill\ er cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS ONE 5, e9221 \(2010\).\r:155)/F 4/H/N/Rect[262.188 180.855 267.284 168.444]/Subtype/Link/Type/Annot>> endobj 52 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:34. Dolstra, H. etal. Successful transfer of umbilical cord blood CD34+ hematopo\ ietic stem and progenitor-\nderived NK cells in older acute myeloid leukemia patients. Clin. Cancer Res. 23, 4107 4118 \(2017\ \).\r:156)/F 4/H/N/Rect[264.766 136.855 269.94 124.444]/Subtype/Link/Type/Annot>> endobj 53 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:45. Zhu, H. etal. Pluripotent stem cell-derived NK cells with high-affinity nonclea\ vable CD16a mediate improved antitumor activity. Blood 135, 399 410 \(2020\).\r:157)/F 4/H/N/Rect[394.645 169.855 399.551 157.444]/Subtype/Link/Type/Annot>> endobj 54 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:46. Kim, K. etal. Epigenetic memory in induced pluripotent stem cells. Nature 46\ 7, 285 290 \(2010\).\r:158)/F 4/H/N/Rect[434.035 147.855 439.014 135.444]/Subtype/Link/Type/Annot>> endobj 55 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:47. Bar-Nur, O., Russ, H. A., Efrat, S. & Benvenisty, N. Epigenetic memory and prefe\ rential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet  cells. 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Cord blood NK cells engineered to express IL-15 and a CD19-target\ ed CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520 531 \(2018\). \nThis article reports the f\ irst successful clinical application :92)/F 4/H/N/Rect[494.764 301.126 499.689 291.606]/Subtype/Link/Type/Annot>> endobj 59 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:37. Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-positive lymp\ hoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:93)/F 4/H/N/Rect[500.661 301.126 505.586 291.606]/Subtype/Link/Type/Annot>> endobj 60 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:52. Imai, C., Iwamoto, S. & Campana, D. Genetic modification of primary natural kill\ er cells overcomes inhibitory signals and induces specific killing of leukemic cells. 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Leukemia 32, 520 531 \(2018\). \nThis article reports the\ first successful clinical applicatio:172)/F 4/H/N/Rect[275.956 664.855 281.282 652.444]/Subtype/Link/Type/Annot>> endobj 148 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:37. Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-positive \ lymphoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:173)/F 4/H/N/Rect[282.593 664.855 287.919 652.444]/Subtype/Link/Type/Annot>> endobj 149 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:37. Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-positive\ lymphoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:174)/F 4/H/N/Rect[274.131 620.855 279.226 608.444]/Subtype/Link/Type/Annot>> endobj 150 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:53. Ruggeri, L. etal. Effectiveness of donor natural killer cell alloreactivity in \ mismatched hematopoietic transplants. Science 295, 2097 2100 \(2002\). \nThis seminal work demonstrates that alloreactive NK\ cells confer a potent graft-versus-l:175)/F 4/H/N/Rect[461.126 719.855 466.639 707.444]/Subtype/Link/Type/Annot>> endobj 151 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:54. Ruggeri, L. etal. Role of natural killer cell alloreactivity in HLA-mismatched \ hematopoietic stem cell transplantation. Blood 94, 333 339 \(1999\).\r:176)/F 4/H/N/Rect[425.857 697.855 431.114 685.444]/Subtype/Link/Type/Annot>> endobj 152 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:57. Ciurea, S. O. etal. Decrease post-transplant relapse using donor-derived expand\ ed NK-cells. Leukemia 36, 155 164 \(2022\).\r:177)/F 4/H/N/Rect[433.957 697.855 439.214 685.444]/Subtype/Link/Type/Annot>> endobj 153 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:58. Hsu, K. C. etal. 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Med. 378, 439 448 \(2018\).\r:183)/F 4/H/N/Rect[488.682 444.855 491.373 432.444]/Subtype/Link/Type/Annot>> endobj 159 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:8. Raje, N. etal. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory mu\ ltiple myeloma. N. Engl. J. Med. 380, 1726 1737 \(2019\).\r:184)/F 4/H/N/Rect[494.279 444.855 496.971 432.444]/Subtype/Link/Type/Annot>> endobj 160 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:70. Biederstdt, A. & Rezvani, K. Engineering the next generation of CAR-NK immunoth\ erapies. Int. J. Hematol. 114, 554 571 \(2021\).\r:185)/F 4/H/N/Rect[468.544 422.855 473.704 410.444]/Subtype/Link/Type/Annot>> endobj 161 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:71. Daher, M. & Rezvani, K. Outlook for new CAR-based therapies with a focus on CAR \ NK cells: what lies beyond CAR-engineered Tcells in the race against cancer. Cancer Disco 11, 45 58 \(2021\).\r:186)/F 4/H/N/Rect[474.933 422.855 480.093 410.444]/Subtype/Link/Type/Annot>> endobj 162 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:35. Liu, E. etal. Cord blood NK cells engineered to express IL-15 and a CD19-tar\ geted CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520 531 \(2018\). \nThis article reports th\ e first successful clinical applicati:189)/F 4/H/N/Rect[376.323 108.654 381.17 98.7852]/Subtype/Link/Type/Annot>> endobj 163 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:37. Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-positi\ ve lymphoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:190)/F 4/H/N/Rect[382.101 108.654 386.948 98.7852]/Subtype/Link/Type/Annot>> endobj 164 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:43. Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-derive\ d natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181 192.e5\ \(2018\). \nThis article demonstrate:191)/F 4/H/N/Rect[387.879 108.654 392.726 98.7852]/Subtype/Link/Type/Annot>> endobj 165 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:112. Dong, H. etal. Engineered memory-like NK cars targeting a neoepitope derived \ from intracellular NPM1c exhibit potent activity and specificity against acute myeloid leukemia. Blood 136, 3 4 \(2020\).\r:\ 192)/F 4/H/N/Rect[393.657 108.654 400.927 98.7852]/Subtype/Link/Type/Annot>> endobj 166 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:264. Bachier, C. etal. A phase 1 study of NKX101, an allogeneic CAR natural killer\ \(NK\) cell therapy, in subjects with relapsed/refractory \(R/R\) acute myeloid leukemia \(AML\) or higher-risk myelodysplastic sy\ ndrome \(MDS\). Blood 136, 42 43 \(20:193)/F 4/H/N/Rect[401.859 108.654 409.128 98.7852]/Subtype/Link/Type/Annot>> endobj 167 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:94. Mensali, N. etal. NK cells specifically TCR-dressed to kill cancer cells. EBio\ Medicine 40, 106 117 \(2019\).\r:194)/F 4/H/N/Rect[546.225 108.654 551.185 98.7852]/Subtype/Link/Type/Annot>> endobj 168 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:96. Wiernik, A. etal. Targeting natural killer cells to acute myeloid leukemia inv\ itro with a CD1633 bispecific killer cell engager and ADAM17 inhibition. Clin. Cancer Res. 19, 3844 3855 \(2013\).\r:195)/F 4/H/N/Rect[468.805 88.6537 473.652 78.7852]/Subtype/Link/Type/Annot>> endobj 169 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:98. Gleason, M. K. etal. CD16xCD33 bispecific killer cell engager \(BiKE\) activates\ NK cells against primary MDS and MDSC CD33+ targets. Blood 123, 3016 3026 \(2014\).\r:196)/F 4/H/N/Rect[474.583 88.6537 479.43 78.7852]/Subtype/Link/Type/Annot>> endobj 170 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:100. Kerbauy, L. N. etal. Combining AFM13, a bispecific CD30/CD16 antibody, with cy\ tokine-activated blood and cord blood-derived NK cells facilitates CAR-like responses against CD30+ malignancies. Clin. Cance\ r Res. 27, 3744 3756 \(2021\).\r:197)/F 4/H/N/Rect[481.62 88.6537 488.89 78.7852]/Subtype/Link/Type/Annot>> endobj 171 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:102. Schmohl, J. U. etal. Tetraspecific scFv construct provides NK cell mediated AD\ CC and self-sustaining stimuli via insertion of IL-15 as a cross-linker. Oncotarget 7, 73830 73844 \(2016\).\r:198)/F 4/H/N/Rect[489.821 88.6537 497.091 78.7852]/Subtype/Link/Type/Annot>> endobj 172 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:103. Vallera, D. A. etal. IL15 trispecific killer engagers \(TriKE\) make natural ki\ ller cells specific to CD33+ targets while also inducing persistence, invivo expansion, and enhanced function. Clin. Cancer \ Res. 22, 3440 3450 \(2016\).\r:199)/F 4/H/N/Rect[498.022 88.6537 505.292 78.7852]/Subtype/Link/Type/Annot>> endobj 173 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:105. Arvindam, U. S. etal. A trispecific killer engager molecule against CLEC12A ef\ fectively induces NK-cell mediated killing of AML cells. Leukemia 35, 1586 1596 \(2021\).\r:200)/F 4/H/N/Rect[506.224 88.6537 513.493 78.7852]/Subtype/Link/Type/Annot>> endobj 174 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:106. Gauthier, L. etal. Multifunctional natural killer cell engagers targeting NKp4\ 6 trigger protective tumor immunity. Cell 177, 1701 1713.e16 \(2019\). \nThis report outlines a novel tri-specific NK cell e\ ngager molecule that cross-links the :201)/F 4/H/N/Rect[514.425 88.6537 521.694 78.7852]/Subtype/Link/Type/Annot>> endobj 175 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:275. Vallera, D. A. etal. NK-cell-mediated targeting of various solid tumors using \ a B7-H3 tri-specific killer engager invitro and invivo. 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C., Wu, J., Leong, C. & Phillips, J. H. Immunorecepto\ r DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703 707 \(1998\). \nThis s\ eminal article elucidates the role of:217)/F 4/H/N/Rect[269.512 136.855 274.85 124.444]/Subtype/Link/Type/Annot>> endobj 448 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:76. Billadeau, D. D., Upshaw, J. L., Schoon, R. A., Dick, C. J. & Leibson, P. J. NKG\ 2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat. Immunol. 4, 557 564 \(2003\).\ This article uncovers the role of :218)/F 4/H/N/Rect[277.734 136.855 283.072 124.444]/Subtype/Link/Type/Annot>> endobj 449 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:72. Lanier, L. L., Corliss, B. C., Wu, J., Leong, C. & Phillips, J. H. Immunorecept\ or DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703 707 \(1998\). \nThis \ seminal article elucidates the role o:219)/F 4/H/N/Rect[297.746 92.8547 302.873 80.4439]/Subtype/Link/Type/Annot>> endobj 450 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:76. Billadeau, D. D., Upshaw, J. L., Schoon, R. A., Dick, C. J. & Leibson, P. J. NK\ G2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat. Immunol. 4, 557 564 \(2003\)\ . This article uncovers the role of:220)/F 4/H/N/Rect[304.084 92.8547 309.211 80.4439]/Subtype/Link/Type/Annot>> endobj 451 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:72. Lanier, L. L., Corliss, B. C., Wu, J., Leong, C. & Phillips, J. H. Immunorecep\ tor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703 707 \(1998\). \nThis\ seminal article elucidates the role :221)/F 4/H/N/Rect[437.585 224.855 442.597 212.444]/Subtype/Link/Type/Annot>> endobj 452 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:76. Billadeau, D. D., Upshaw, J. L., Schoon, R. A., Dick, C. J. & Leibson, P. J. N\ KG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat. Immunol. 4, 557 564 \(2003\ \). This article uncovers the role o:222)/F 4/H/N/Rect[430.666 191.855 435.761 179.444]/Subtype/Link/Type/Annot>> endobj 453 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:77. Frigault, M. J. etal. Identification of chimeric antigen receptors that mediate\ constitutive or inducible proliferation of Tcells. Cancer Immunol. Res. 3, 356 367 \(2015\).\r:223)/F 4/H/N/Rect[424.897 125.855 430.154 113.444]/Subtype/Link/Type/Annot>> endobj 454 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:81. Feucht, J. etal. 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Cancer Res. 8, 1083 1089 \(201\ 8\).\r:207)/F 4/H/N/Rect[213.084 319.096 218.297 309.576]/Subtype/Link/Type/Annot>> endobj 462 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:279. Schubert, M.-L. etal. Third-generation CAR Tcells targeting CD19 are associat\ ed with an excellent safety profile and might improve persistence of CAR Tcells in treated patients. Blood 134, 51 51 \(201\ 9\).\r:208)/F 4/H/N/Rect[219.411 319.096 227.229 309.576]/Subtype/Link/Type/Annot>> endobj 463 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:69. Chang, Y. H. etal. A chimeric receptor with NKG2D specificity enhances natural\ killer cell activation and killing of tumor cells. Cancer Res. 73, 1777 1786 \(2013\).\r:209)/F 4/H/N/Rect[386.329 329.342 391.125 319.474]/Subtype/Link/Type/Annot>> endobj 464 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:280. Bjordahl, R. etal. Abstract 1539: development of off-the-shelf B7H3 chimeric a\ ntigen receptor NK cell therapeutic with broad applicability across many solid tumors. Cancer Res. 81, 1539 \(2021\).\r:210)/F 4/H/N/Rect[392.031 329.342 399.224 319.474]/Subtype/Link/Type/Annot>> endobj 465 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:35. Liu, E. etal. Cord blood NK cells engineered to express IL-15 and a CD19-ta\ rgeted CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520 531 \(2018\). \nThis article reports t\ he first successful clinical applicat:211)/F 4/H/N/Rect[512.889 329.342 517.684 319.474]/Subtype/Link/Type/Annot>> endobj 466 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:37. Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-posit\ ive lymphoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:212)/F 4/H/N/Rect[518.59 329.342 523.386 319.474]/Subtype/Link/Type/Annot>> endobj 467 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:90. Srivastava, S. etal. Logic-gated ROR1 chimeric antigen receptor expression resc\ ues Tcell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell 35, 489 503.e8 \(2019\).\r\ :213)/F 4/H/N/Rect[479.479 299.342 484.464 289.474]/Subtype/Link/Type/Annot>> endobj 468 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:92. Garrison, B. S. etal. FLT3 OR CD33 NOT EMCN logic gated CAR-NK cell therapy \(SE\ NTI-202\) for precise targeting of AML. Blood 138 \(suppl. 1\), 2799 \(2021\).\r:214)/F 4/H/N/Rect[485.464 299.342 490.449 289.474]/Subtype/Link/Type/Annot>> endobj 469 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:93. Gonzalez, A. etal. Abstract LB028: Development of logic-gated CAR-NK cells to r\ educe target-mediated healthy tissue toxicities. 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Romee, R. etal. Cytokine-induced memory-like natural killer cells exhibit enha\ nced responses against myeloid leukemia. Sci. Transl. Med. 8, 357ra123 \(2016\).\r:255)/F 4/H/N/Rect[306.819 719.855 311.88 707.444]/Subtype/Link/Type/Annot>> endobj 1680 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:100. Kerbauy, L. N. etal. Combining AFM13, a bispecific CD30/CD16 antibody, with\ cytokine-activated blood and cord blood-derived NK cells facilitates CAR-like responses against CD30+ malignancies. Clin. Ca\ ncer Res. 27, 3744 3756 \(2021\).:256)/F 4/H/N/Rect[313.059 719.855 320.652 707.444]/Subtype/Link/Type/Annot>> endobj 1681 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:109. Rosario, M. etal. The IL-15-based ALT-803 complex enhances FcRIIIa-triggered \ NK cell responses and invivo clearance of B cell lymphomas. Clin. 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Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-posi\ tive lymphoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:271)/F 4/H/N/Rect[286.687 378.855 291.784 366.444]/Subtype/Link/Type/Annot>> endobj 1696 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:48. Goodridge, J. P. etal. FT596: translation of first-of-kind multi-antigen targ\ eted off-the-shelf CAR-NK cell with engineered persistence for the treatment of B cell malignancies. Blood 134, 301 301 \(20\ 19\).\r:272)/F 4/H/N/Rect[292.982 378.855 298.079 366.444]/Subtype/Link/Type/Annot>> endobj 1697 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:49. Bachanova, V. etal. Safety and efficacy of FT596, a first-in-class, multi-an\ tigen targeted, off-the-shelf, iPSC-derived CD19 CAR NK cell therapy in relapsed/refractory B-cell lymphoma. 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Liu, E. etal. Use of CAR-transduced natural killer cells in CD19-pos\ itive lymphoid tumors. N. Engl. J. Med. 382, 545 553 \(2020\).\r:279)/F 4/H/N/Rect[334.463 202.855 339.761 190.444]/Subtype/Link/Type/Annot>> endobj 1704 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:118. Felices, M. etal. Continuous treatment with IL-15 exhausts human NK cells via \ a metabolic defect. JCI Insight https://doi.org/10.1172/jci.insight.96219 \(2018\).\r:280)/F 4/H/N/Rect[332.245 147.855 339.761 135.444]/Subtype/Link/Type/Annot>> endobj 1705 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:119. Sarhan, D. etal. Adaptive NK cells resist regulatory T-cell suppression driven\ by IL37. Cancer Immunol. Res. 6, 766 775 \(2018\).\r:281)/F 4/H/N/Rect[384.659 675.855 392.365 663.444]/Subtype/Link/Type/Annot>> endobj 1706 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:122. Zalfa, C. & Paust, S. Natural killer cell interactions with myeloid derived sup\ pressor cells in the tumor microenvironment and implications for cancer immunotherapy. Front. Immunol. https://doi.org/\n10.\ 3389/fimmu.2021.633205 \(2021\).\r:282)/F 4/H/N/Rect[395.147 675.855 402.853 663.444]/Subtype/Link/Type/Annot>> endobj 1707 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:123. Ni, J. etal. Single-cell RNA sequencing of tumor-infiltrating NK cells reveals\ that inhibition of transcription factor HIF-1 unleashes NK cell activity. Immunity 52, 1075 1087.e8 \(2020\).\r:283)/F 4/H/N/Rect[384.375 642.855 392.018 630.444]/Subtype/Link/Type/Annot>> endobj 1708 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:109. Rosario, M. etal. The IL-15-based ALT-803 complex enhances FcRIIIa-triggered\ NK cell responses and invivo clearance of B cell lymphomas. Clin. 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K) -3LjOwzT!-b4U9&  [^v6{KJ?G$b="1{t-мSdr< &_&ߌMݯH\ǣDB&"HqY)P!׆^`^+E]KϢr(fAMhߴ RkS*iyCb\[?Xu$(g?|Gʘ|r-KuqY֔t8S!vWg/KbA endstream endobj 1723 0 obj <> endobj 1724 0 obj [1725 0 R 1726 0 R 1727 0 R 1728 0 R 1729 0 R 1730 0 R 1731 0 R 1732 0 R 1733 0 R 1734 0 R 1735 0 R 1736 0 R 1737 0 R 1738 0 R 1739 0 R 1740 0 R 1741 0 R 1742 0 R 1743 0 R 1744 0 R 1745 0 R 1746 0 R] endobj 1725 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:138. Kim, T.-D. etal. Human microRNA-27a* targets Prf1 and GzmB expression to regul\ ate NK-cell cytotoxicity. Blood, J. Am. Soc. Hematol. 118, 5476 5486 \(2011\).\r:307)/F 4/H/N/Rect[184.492 235.855 192.338 223.444]/Subtype/Link/Type/Annot>> endobj 1726 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:139. Yvon, E. S. etal. Cord blood natural killer cells expressing a dominant negati\ ve TGF- receptor: implications for adoptive immunotherapy for glioblastoma. Cytotherapy 19, 408 418 \(2017\).\r:308)/F 4/H/N/Rect[331.86 213.855 339.761 201.444]/Subtype/Link/Type/Annot>> endobj 1727 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:140. Daher, M. etal. The TGF-/SMAD signaling pathway as a mediator of NK cell dys\ function and immune evasion in myelodysplastic syndrome. Blood 130, 53 53 \(2017\).\r:309)/F 4/H/N/Rect[235.218 180.974 242.857 168.444]/Subtype/Link/Type/Annot>> endobj 1728 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:141. Shaim, H. etal. Targeting the v integrin/TGF- axis improves natural killer \ cell function against glioblastoma stem cells. J. Clin. Investig. https://doi.org/10.1172/JCI142116 \(2021\).\r:310)/F 4/H/N/Rect[188.74 147.855 196.383 135.444]/Subtype/Link/Type/Annot>> endobj 1729 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:142. Stojanovic, A., Fiegler, N., Brunner-Weinzierl, M. \n& Cerwenka, A. CTLA-4 Is ex\ pressed by activated mouse NK cells and inhibits NK cell IFN- production in response to mature dendritic cells. J. Immunol. \ 192, 4184 4191 \(2014\).\r:311)/F 4/H/N/Rect[502.274 158.855 510.1 146.444]/Subtype/Link/Type/Annot>> endobj 1730 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:149. Dong, W. etal. The mechanism of anti-PD-L1 antibody efficacy against PD-L1-neg\ ative tumors identifies NK cells expressing PD-L1 as a cytolytic effector. Cancer Discov. 9, 1422 1437 \(2019\).\r:312)/F 4/H/N/Rect[512.923 158.855 520.748 146.444]/Subtype/Link/Type/Annot>> endobj 1731 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:Fig. 4 | Genetic engineering strategies to overcome suppressors of NK cell funct\ ion. a f | Immune cell function is severely compromised by the hostile tumour microenvironment \(TME\)134. Current st\ rategies leverage engineering tools :313)/F 4/H/N/Rect[539.86 158.855 548.615 146.444]/Subtype/Link/Type/Annot>> endobj 1732 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:146. Judge, S. J., Murphy, W. J. & Canter, R. J. Characterizing the dysfunctional NK\ cell: assessing the clinical relevance of exhaustion, anergy, and senescence. Front. Cell Infect. Microbiol. 10, 49 49 \(20\ 20\).\r:314)/F 4/H/N/Rect[414.545 125.855 422.109 113.444]/Subtype/Link/Type/Annot>> endobj 1733 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:150. Newman, J. & Horowitz, A. NK cells seize PD1 from leukaemia cells. Nat. Rev. I\ mmunol. 21, 345 345 \(2021\).\r:315)/F 4/H/N/Rect[423.279 125.855 430.843 113.444]/Subtype/Link/Type/Annot>> endobj 1734 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:151. Wilk, A. J. etal. A single-cell atlas of the peripheral immune response in pat\ ients with severe COVID-19. Nat. Med. 26, 1070 1076 \(2020\).\r:316)/F 4/H/N/Rect[407.797 81.8547 415.851 69.4439]/Subtype/Link/Type/Annot>> endobj 1735 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:152. da Silva, I. P. etal. Reversal of NK-cell exhaustion in advanced melanoma by T\ im-3 blockade. Cancer Immunol. Res. 2, 410 422 \(2014\).\r:317)/F 4/H/N/Rect[472.124 70.8547 479.846 58.4439]/Subtype/Link/Type/Annot>> endobj 1736 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:153. Farkas, A. M. etal. Tim-3 and TIGIT mark natural killer cells susceptible to e\ ffector dysfunction in \nhuman bladder cancer. J. Immunol. 200, 124.114 \(2018\).\r:318)/F 4/H/N/Rect[481.068 70.8547 488.79 58.4439]/Subtype/Link/Type/Annot>> endobj 1737 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:134. Young, A. etal. Co-inhibition of CD73 and A2AR adenosine signaling improves an\ ti-tumor immune responses. Cancer Cell 30, 391 403 \(2016\).\r:289)/F 4/H/N/Rect[183.773 364.911 191.43 355.391]/Subtype/Link/Type/Annot>> endobj 1738 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:156. Zhang, Q. etal. Blockade of the checkpoint receptor TIGIT prevents NK cell exh\ austion and elicits potent anti-tumor immunity. Nat. Immunol. 19, 723 732 \(2018\).\r:290)/F 4/H/N/Rect[85.8539 305.157 93.5348 295.289]/Subtype/Link/Type/Annot>> endobj 1739 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:164. Kamiya, T., Seow, S. V., Wong, D., Robinson, M. & Campana, D. Blocking expressi\ on of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. J. Clin. Investig. 129, 2094 2106 \(2019\).\r:291)/F 4/H/N/Rect[94.6035 305.157 102.284 295.289]/Subtype/Link/Type/Annot>> endobj 1740 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:167. Daher, M. etal. Targeting a cytokine checkpoint enhances the fitness of armore\ d cord blood CAR-NK cells. Blood 137, 624 636 \(2021\).\r:292)/F 4/H/N/Rect[103.353 305.157 111.034 295.289]/Subtype/Link/Type/Annot>> endobj 1741 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:168. Zhu, H. etal. Metabolic reprograming via deletion of CISH in human iPSC-derive\ d NK cells promotes invivo persistence and enhances anti-tumor activity. Cell Stem Cell 27, 224 237.e6 \(2020\).\r:293)/F 4/H/N/Rect[112.103 305.157 119.783 295.289]/Subtype/Link/Type/Annot>> endobj 1742 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:140. Daher, M. etal. The TGF-/SMAD signaling pathway as a mediator of NK cell dysf\ unction and immune evasion in myelodysplastic syndrome. Blood 130, 53 53 \(2017\).\r:294)/F 4/H/N/Rect[257.889 295.65 266.072 284.184]/Subtype/Link/Type/Annot>> endobj 1743 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:141. Shaim, H. etal. Targeting the v integrin/TGF- axis improves natural killer c\ ell function against glioblastoma stem cells. J. Clin. Investig. https://doi.org/10.1172/JCI142116 \(2021\).\r:295)/F 4/H/N/Rect[267.308 295.65 275.491 284.184]/Subtype/Link/Type/Annot>> endobj 1744 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:135. Young, A. etal. A2AR adenosine signaling suppresses natural killer cell matura\ tion in the tumor microenvironment. Cancer Res. 78, 1003 \(2018\).\r:296)/F 4/H/N/Rect[78.4336 285.157 85.9383 275.289]/Subtype/Link/Type/Annot>> endobj 1745 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:281. Basar, R. etal. Generation of glucocorticoid-resistant SARS-CoV-2 Tcells for \ adoptive cell therapy. Cell Rep. https://doi.org/10.1016/j.celrep.2021.109432 \(2021\).\r:297)/F 4/H/N/Rect[380.281 335.157 388.121 325.289]/Subtype/Link/Type/Annot>> endobj 1746 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:50. Goodridge, J. P. etal. Abstract 1550: FT576 path to first-of-kind clinical tria\ l: translation of a versatile multi-antigen specific off-the-shelf NK cell for treatment of multiple myeloma. 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Immunol. 19, 723 732 \(2018\).\r:321)/F 4/H/N/Rect[192.573 730.855 200.35 718.444]/Subtype/Link/Type/Annot>> endobj 5130 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:157. Ali, A. etal. LAG-3 modulation of natural killer cell immunoregulatory functio\ n. J. Immunol. 202, 76.77 \(2019\).\r:322)/F 4/H/N/Rect[258.566 730.855 266.343 718.444]/Subtype/Link/Type/Annot>> endobj 5131 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:158. Kohrt, H. E. etal. Anti-KIR antibody enhancement of anti-lymphoma activity of \ natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123, 678 686 \(2014\).\r:323)/F 4/H/N/Rect[258.904 609.855 266.813 597.444]/Subtype/Link/Type/Annot>> endobj 5132 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:159. Vey, N. etal. 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N. & Fry, T. J. Mechanisms of resistance to CAR Tcell therapy. Nat. \ Rev. Clin. Oncol. 16, 372 385 \(2019\).\r:364)/F 4/H/N/Rect[533.635 125.855 541.51 113.444]/Subtype/Link/Type/Annot>> endobj 5173 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:193. Strati, P. & Neelapu, S. S. CAR-T failure: beyond antigen loss and Tcells. Bl\ ood 137, 2567 2568 \(2021\).\r:365)/F 4/H/N/Rect[542.783 125.855 550.658 113.444]/Subtype/Link/Type/Annot>> endobj 5174 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 5175 0 obj <>stream x}$G~K!u&>19$Uy3+X=طWf~GDVq84+2"=33Ͼ)Uw}Ow7>ܜߥ  w2usnټ[?uV|w]֕E<[5Ui[ٿy$Vy|77$oVyVefVu֥ZuQu]`2kUUW\YW&Jvur/LR{x5BMoӿ=uMϕ[Y>Lyknl:ibUbK ǐϓY5xԋ + &s&h̲5*/UV{鳟ׇ><]ֻ??3_Uwz37.aޗyծjۦFeՌ/°qյ^\ #-Q+=&KV^Yԛ)Y~S<{pwi+Y{oT@n'2ڮBQ‡-3>2۶uyqIrئW{#&ZlOq[UVֆ#]S-CVdknc=m?3i}G`, AO:%tlCt'=_TO|)e8)R/TzLoUۤY~`leA ?ڐ/ =>?>xҬ5CQ$yG:yHeA-̟n+?vdeN6ɋztLGyƑ}1t:#<lH 5Ew~J2+1 }o?lX;07gd^ƜUEBvp4,G 3p#[OgQk)Vك OD݉] ^ܟΎoٌR_'z'p?u=~ }GX~Cq+OJ5׻\8zս2$R[ɸ/zfJZx<Ư $=,Fp_ߚ}cdxJxƾ% 7ُ{p&[<;6 )]||'>5;@ܹ;'>m-~bNv8gv3?!b7Wƭ؅Vf8+G`(G39ZD]!EHbY .5-Nx`/Ic"r=;*'l^OJ(XJoaa8uV']}L.( i| "ckHWt8ց akwx"@毑"Fyuv"Fu=, D wv삷oEܼ'9Cn.Z ytlnB{E9rNe ϜQQq1a Z|`)`:\׌ݭ9+b ؐI9{HdIK'Xdx op:Sa5Qч6yG_p#J`ҢkbQ2T]iSͤCmߥ|]C:H:[y[vMi)Ņ~_JAgp;ol'X{=֙-5+vTv> ,YsjjB^ZNԧSA*THM=4`m `:7@;"оΚr/ Vde l3hVãXTO/\N!\T9H!>ts4Άf/MO@;=6VUU,-E o@8S(USMuܮ>F";CY(F6&WImZXdg &A8_ht`a_;DF=ѫDCטLK+i &\ɷ/ၶ?2bAmQRb'k#6vM"m*ڸsd薻#>7ļq5-3^~UwH3ڣiapp[3{xUOYՠ{#{_Y:@WKf`E^ꋴH5?VU^ ɢ8bԺa2&Ŋ2]ь A1VS$4;+Ѳ:a,MuV {&7Vez-+?{qX7S ij"DBF}rpQ>VoznYO ._V+$ZGZyd:Qt4eg~َݼ_ wȔ; S^DfJ6V/3D`M:c'L GEг{k^kQ pw؈Up t$TQ="vt! 0iHݺjB]ۘ^ ~XFΠZo`FjDs(Y *̮|o<;Ba)3`ʇoHDx*F[ gGq{jv -Θku׹*mbj2b%S{)uu~JZ-YR5 Qt,"3+}Q?Z{9],M; wc8JZҍ_޻Gi᜸ vc{Ԛ 3% 1z@x\μȓF#,06M≬RiJAڳ&.+iVGw@|:cH8w:\?SdN.bԆ՜ ';7ORX Ek 8Jh.FC@Јq#S{i@RLi@(x#3+Bx햶>Чv39/sj?®`rE *JGMA=fkx#TX4vy<3Oz$U2\427Zނj]߈^McLz}Q$b#Ly2CELnmdpImĊF&*$~MnBj瓔0zH`ornpt88*% Nd8Y:{@O3\gd/[,LV,&-TޖU)ZMһڼԍeܸ j3yFJk&.7"VmՔi]g,t4_hj4zLy/zׂFH@*/Q&:H01 Pj(n WK<^Z2-3R>Mط)&4KR11hĚ5ǼD[jG,FZzzb] k5ؒ08 a {eaE9mgsEA.Zt+Fb^cu /r1 kD"o Kl6O{񚑏0.}AZ‹|uߢkx+bMt: |yͮeHXep >-֒9x2dM~Nr=E/5. >t63Fe\v,;zlW+Lji/c`ɀZO,&d[HPaG_AӲ o2ظނ5*E߇dG6 3Mm:'LЈ] v)#7rT+N"<6J'bv{$6M0yq֢t^_K CkKp= Ob}R;aT>qs$HR=>3[H2g7f9y}`<.\52;16 |LI1\Se1-x,[GildM+MNzFI愱DQ*qT-pUע}[P^QZꞦp, ˚'1> XQ ;Tpg C㑈 IwOrp@Cr=PzCCFd\&7R2jr0ٚvu7+d"i5oY ;(%DG^D zdNMƁȷ%@dd}t;\LxIOv1@N/p)*/%i~r9a.g;W$l[f̈́fJI37[Q5Bז@L~e%{y`Fd9c2`zCc jY<,MK>B"7dR0(RZ?| :L[T[VF2Q{RVabiͰ%z 8>{HԐ7$hw-|S-e³KWcM^w`8D:FIهJ"]柄QUMZ+I8pF|ce쵟~X" 80Nr{%,Cw870*Q!hz@XΐHC4$f*vϛrcoOcn; ǐ@W^<}=!Ha%P TfeD,<1=>b$w;)A P&dIOYs,`+JR-NUJ}ܞN4arkE5'ca ~St&2^=/QCt G?m̰4l%b@;b4_e0JΆ>\d U%Vj}$b{RgeR2"I E$Le,:2+$XQG[[ӶO1h&J8,nnc]vh#Rn滾*l>5z}U\m{$L$hHQ0,3g?FY E#1 HlР"$s*d(<^OL[ohI/ b̚ne]y1CA&b  ֣/p \R7dX]UUj܁66)eAڈQ{)E1,HEȢh2,P#n\r#-1xb1WF]uSJ(/\usG8y\$s 4bb 9"CHtתMi38- D!мsnrXX}Ƞ^Ī-iepW!R#E׉|4~&6[cV.ZGR/}%ngs䆓ɰ<@UsklE) jjf䷻9Ӈ;go@3iPjVi r^y ϝ! 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Biederstdt, A. & Rezvani, K. How I treat high-risk acute myeloid leukemia usin\ g pre-emptive adoptive cellular immunotherapy. Blood https://doi.org/\n10.1182/blood.2021012411 \(2022\).\r:366)/F 4/H/N/Rect[332.229 697.855 339.761 685.444]/Subtype/Link/Type/Annot>> endobj 5179 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:28. Romee, R. etal. Cytokine activation induces human memory-like NK cells. Bl\ ood 120, 4751 4760 \(2012\).\r:367)/F 4/H/N/Rect[248.745 609.855 253.901 597.444]/Subtype/Link/Type/Annot>> endobj 5180 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:30. Shapiro, R. M. etal. Expansion, persistence, and efficacy of donor memory-\ like NK cells infused for post-transplant relapse. J. Clin. Investig. https://doi.org/\n10.1172/JCI154334 \(2022\).\r:368\ )/F 4/H/N/Rect[256.694 609.855 261.85 597.444]/Subtype/Link/Type/Annot>> endobj 5181 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:33. Spanholtz, J. etal. 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Med. 382, 545 553 \(2020\).\r:371)/F 4/H/N/Rect[275.841 609.855 280.998 597.444]/Subtype/Link/Type/Annot>> endobj 5184 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:39. Tang, X. etal. First-in-man clinical trial of CAR NK-92 cells: safety test o\ f CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am. J. Cancer Res. 8, 1083 1089 \(20\ 18\).\r:372)/F 4/H/N/Rect[282.224 609.855 287.38 597.444]/Subtype/Link/Type/Annot>> endobj 5185 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:48. Goodridge, J. P. etal. FT596: translation of first-of-kind multi-antigen ta\ rgeted off-the-shelf CAR-NK cell with engineered persistence for the treatment of B cell malignancies. Blood 134, 301 301 \(\ 2019\).\r:373)/F 4/H/N/Rect[288.607 609.855 293.763 597.444]/Subtype/Link/Type/Annot>> endobj 5186 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:49. Bachanova, V. etal. 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Curre\ nt strategies leverage engineering t:376)/F 4/H/N/Rect[222.421 499.855 230.924 487.444]/Subtype/Link/Type/Annot>> endobj 5189 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:100. Kerbauy, L. N. etal. Combining AFM13, a bispecific CD30/CD16 antibody, wi\ th cytokine-activated blood and cord blood-derived NK cells facilitates CAR-like responses against CD30+ malignancies. 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Immunol. 22, 1008 1019 \(2021\). \nThis article \ elucidates how exhausted Tcell subset:379)/F 4/H/N/Rect[465.471 466.855 473.349 454.444]/Subtype/Link/Type/Annot>> endobj 5192 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:196. Yates, K. B. etal. Epigenetic scars of CD8+ Tcell exhaustion persist after \ cure of chronic infection in humans. Nat. 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CRISPR screening of CAR Tcells and cancer stem cells reveals c\ ritical dependencies for cell-based therapies. Cancer Discov. 11, 1192 1211 \(2021\).\r:408)/F 4/H/N/Rect[144.921 103.021 152.121 93.7551]/Subtype/Link/Type/Annot>> endobj 5206 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:294. Roth, T. L. etal. Pooled knockin targeting for genome engineering of cellular \ immunotherapies. Cell 181, 728 744.e21 \(2020\).\r:409)/F 4/H/N/Rect[92.1794 83.0211 99.379 73.7551]/Subtype/Link/Type/Annot>> endobj 5207 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:295. Legut, M. etal. A genome-scale screen for synthetic drivers of Tcell prolifer\ ation. 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Saha, K. etal. The NIH Somatic Cell Genome Editing program. Nature 592, 19\ 5 204 \(2021\). \nThis report lays out the aims and scope of the NIH SCGE Consortium.\r:411)/F 4/H/N/Rect[160.831 81.8547 168.801 69.4439]/Subtype/Link/Type/Annot>> endobj 5218 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:201. Tsai, S. Q. etal. GUIDE-seq enables genome-wide profiling of off-target cleava\ ge by CRISPR Cas nucleases. Nat. Biotechnol. 33, 187 197 \(2015\).\r:412)/F 4/H/N/Rect[188.414 59.8547 196.39 47.4439]/Subtype/Link/Type/Annot>> endobj 5219 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:202. Tsai, S. Q. etal. CIRCLE-seq: a highly sensitive \ninvitro screen for genome-w\ ide CRISPR Cas9 nuclease off-targets. Nat. Methods 14, 607 614 \(2017\).\r:413)/F 4/H/N/Rect[250.294 59.8547 258.27 47.4439]/Subtype/Link/Type/Annot>> endobj 5220 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:203. Dobosy, J. R. etal. RNase H-dependent PCR \(rhPCR\): improved specificity and s\ ingle nucleotide polymorphism detection using blocked cleavable primers. BMC Biotechnol. 11, 80 \(2011\).\r:414)/F 4/H/N/Rect[316.426 59.8547 324.403 47.4439]/Subtype/Link/Type/Annot>> endobj 5221 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:204. Hu, J. etal. Detecting DNA double-stranded breaks in mammalian genomes by line\ ar amplification-mediated high-throughput genome-wide translocation sequencing. Nat. Protoc. 11, 853 871 \(2016\).\r:415)/F 4/H/N/Rect[508.92 675.855 516.779 663.444]/Subtype/Link/Type/Annot>> endobj 5222 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:205. Gillmore, J. D. etal. CRISPR Cas9 invivo gene editing for transthyretin amylo\ idosis. N. Engl. J. Med. 385, 493 502 \(2021\). \nThis seminal work demonstrates the first successful clinical application o\ f invivo CRISPR Cas9 gene editing.:416)/F 4/H/N/Rect[388.759 521.855 396.583 509.444]/Subtype/Link/Type/Annot>> endobj 5223 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:206. Aghajanian, H. etal. Targeting cardiac fibrosis with engineered Tcells. Natu\ re 573, 430 433 \(2019\).\r:417)/F 4/H/N/Rect[423.969 466.855 432.152 454.444]/Subtype/Link/Type/Annot>> endobj 5224 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:207. Rurik, J. G. etal. CAR Tcells produced invivo to treat cardiac injury. Scie\ nce 375, 91 96 \(2022\). \nThis study demonstrates the first successful invivo engineering of CAR Tcells using a CD5-direct\ ed lipid nanoparticle containing CAR-:418)/F 4/H/N/Rect[433.528 466.855 441.711 454.444]/Subtype/Link/Type/Annot>> endobj 5225 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:208. Bender, R. R., Muth, A., Schneider, I. C., Maisner, A. \n& Buchholz, C. J. Devel\ oping an engineered nipah virus glycoprotein based lentiviral vector system retargeted to cell surface receptors of choice. Mo\ l. Ther. 23, S2 \(2015\).\r:419)/F 4/H/N/Rect[405.814 422.855 413.616 410.444]/Subtype/Link/Type/Annot>> endobj 5226 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:209. Micklethwaite, K. P. etal. Investigation of product-\nderived lymphoma followin\ g infusion of piggyBac-\nmodified CD19 chimeric antigen receptor Tcells. Blood 138, 1391 1405 \(2021\).\r:420)/F 4/H/N/Rect[451.25 169.855 458.842 157.444]/Subtype/Link/Type/Annot>> endobj 5227 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:254. Wu, L. etal. lenalidomide enhances natural killer cell and monocyte-mediated a\ ntibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin. Cancer Res. 14, 4650 4657 \(2008\).\r\ :388)/F 4/H/N/Rect[322.036 688.074 329.424 678.554]/Subtype/Link/Type/Annot>> endobj 5228 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:255. Tai, Y. T. etal. Immunomodulatory drug lenalidomide \(CC-5013, IMiD3\) augments\ anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 65, 11712 11720 \(2005\)\ .\r:389)/F 4/H/N/Rect[330.395 688.074 337.858 678.554]/Subtype/Link/Type/Annot>> endobj 5229 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:256. Nahas, M. R. etal. Hypomethylating agent alters the immune microenvironment in\ acute myeloid leukaemia \(AML\) and enhances the immunogenicity of a dendritic cell/AML vaccine. Br. J. Haematol. 185, 679 6\ 90 \(2019\).\r:390)/F 4/H/N/Rect[322.036 674.175 329.424 664.655]/Subtype/Link/Type/Annot>> endobj 5230 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:257. Hicks, K. C. etal. Epigenetic priming of both tumor and NK cells augments anti\ body-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types. OncoIm\ munology 7, e1466018 \(2018\).\r:391)/F 4/H/N/Rect[330.395 674.175 337.858 664.655]/Subtype/Link/Type/Annot>> endobj 5231 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:258. Leung, E. Y. L. etal. NK cells augment oncolytic adenovirus cytotoxicity in ov\ arian cancer. Mol. Ther. Oncolytics 16, 289 301 \(2020\).\r:392)/F 4/H/N/Rect[322.036 629.025 329.424 619.505]/Subtype/Link/Type/Annot>> endobj 5232 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:259. Marotel, M., Hasim, M. S., Hagerman, A. & Ardolino, M. The two-faces of NK cell\ s in oncolytic virotherapy. Cytokine Growth Factor. Rev. 56, 59 68 \(2020\).\r:393)/F 4/H/N/Rect[330.395 629.025 337.858 619.505]/Subtype/Link/Type/Annot>> endobj 5233 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:260. Cichocki, F. etal. GSK3 inhibition drives maturation of NK cells and enhances \ their antitumor activity. Cancer Res. 77, 5664 5675 \(2017\).\r:394)/F 4/H/N/Rect[322.036 547.874 329.424 538.354]/Subtype/Link/Type/Annot>> endobj 5234 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:261. Parameswaran, R. etal. Repression of GSK3 restores NK cell cytotoxicity in AML\ patients. Nat. Commun. 7, 11154 \(2016\).\r:395)/F 4/H/N/Rect[330.395 547.874 337.858 538.354]/Subtype/Link/Type/Annot>> endobj 5235 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCan_491.indd:149. Dong, W. etal. The mechanism of anti-PD-L1 antibody efficacy against PD-L1-ne\ gative tumors identifies NK cells expressing PD-L1 as a cytolytic effector. 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IL15 stimulation with TIGIT blockade reverses CD155-media\ ted NK-cell dysfunction in melanoma. Clin. 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immunotherapy Tamara J. Laskowski Alexander Biederstädt Katayoun Rezvani Springer 2022-09-21T15:27:49+05:30 2022-09-21T15:26:49+05:30 2022-09-21T15:27:49+05:30 True uuid:20a5e683-1db4-48b0-b8c2-0c5edc4cebbc uuid:2b3bd810-d928-4fea-99d1-7c66628717a8 default 1 converted uuid:e279ece1-e010-4864-8da6-56361bb33a54 converted to PDF/A-2b pdfToolbox 2022-09-21T15:27:49+05:30 2 B http://ns.adobe.com/pdf/1.3/ pdf Adobe PDF Schema internal A name object indicating whether the document has been modified to include trapping information Trapped Text http://ns.adobe.com/pdfx/1.3/ pdfx Adobe Document Info PDF eXtension Schema internal ID of PDF/X standard GTS_PDFXVersion Text internal Conformance level of PDF/X standard GTS_PDFXConformance Text internal Company creating the PDF Company Text internal Date when document was last modified SourceModified Text http://ns.adobe.com/xap/1.0/mm/ xmpMM XMP Media Management Schema internal UUID based identifier for specific incarnation of a document InstanceID URI internal The common identifier for all versions and renditions of a document. 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