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Current Hematologic Malignancy Reports
Published in: Current Hematologic Malignancy Reports 6/2017

01-12-2017 | CART and Immunotherapy (M Ruella, Section Editor)

Genome-Editing Technologies in Adoptive T Cell Immunotherapy for Cancer

Authors: Nathan Singh, Junwei Shi, Carl H. June, Marco Ruella

Published in: Current Hematologic Malignancy Reports | Issue 6/2017

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Abstract

Purpose of Review

In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy.

Recent Findings

Engineered T cell therapies targeting cancer antigens have demonstrated significant efficacy in specific patient populations. Most impressively, CD19-directed chimeric antigen receptor T cells (CART19) have led to impressive responses in patients with B-cell leukemia and lymphoma. CTL019, or KYMRIAH™ (tisagenlecleucel), a CD19 CAR T cell product developed by Novartis and the University of Pennsylvania, was recently approved for clinical use by the Food and Drug Administration, representing a landmark in the application of adoptive T cell therapies. As CART19 enters routine clinical use, improving the efficacy of this exciting platform is the next step in broader application.

Summary

Novel gene-editing technologies like CRISPR-Cas9 allow facile editing of specific genes within the genome, generating a powerful platform to further optimize the activity of engineered T cells.
Literature
1.
Mitchison NA. Studies on the immunological response to foreign tumor transplants in the mouse. I. The role of lymph node cells in conferring immunity by adoptive transfer. J Exp Med. 1955;102(2):157–77.CrossRefPubMedPubMedCentral
2.
Barnes DW, Loutit JF. Treatment of murine leukaemia with x-rays and homologous bone marrow. II. Br J Haematol. 1957;3(3):241–52.CrossRefPubMed
3.
Mathe G, Amiel JL, Schwarzenberg L, Cattan A, Schneider M. Adoptive immunotherapy of acute leukemia: experimental and clinical results. Cancer Res. 1965;25(9):1525–31.PubMed
4.
Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300(19):1068–73.CrossRefPubMed
5.
Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood. 1991;78(8):2120–30.PubMed
6.
Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76(12):2462–5.PubMed
7.
Higano CS, Brixey M, Bryant EM, Durnam DM, Doney K, Sullivan KM, et al. Durable complete remission of acute nonlymphocytic leukemia associated with discontinuation of immunosuppression following relapse after allogeneic bone marrow transplantation. A case report of a probable graft-versus-leukemia effect. Transplantation. 1990;50(1):175–7.CrossRefPubMed
8.
Porter DL, Connors JM, Van Deerlin VM, Duffy KM, McGarigle C, Saidman SL, et al. Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies. J Clin Oncol. 1999;17(4):1234.CrossRefPubMed
9.
Loren AW, Porter DL. Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant. 2008;41(5):483–93.CrossRefPubMed
10.
Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233–9.CrossRefPubMedPubMedCentral
11.
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13.CrossRefPubMed
12.
13.
Parkhurst M, Gros A, Pasetto A, Prickett T, Crystal JS, Robbins P, et al. Isolation of T-cell receptors specifically reactive with mutated tumor-associated antigens from tumor-infiltrating lymphocytes based on CD137 expression. Clin Cancer Res. 2017;23(10):2491–505.CrossRefPubMed
14.
•• Rosenberg SA, Tran E, Robbins PF. T-cell transfer therapy targeting mutant KRAS. N Engl J Med. 2017;376(7):e11. Seminal report of the clinical use of mutated RAS-specific TILs. CrossRefPubMed
15.
16.
Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914–21.CrossRefPubMedPubMedCentral
17.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.CrossRefPubMedPubMedCentral
18.
Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25.CrossRefPubMedPubMedCentral
19.
Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.CrossRefPubMed
20.
Singh N, Perazzelli J, Grupp SA, Barrett DM. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci Transl Med. 2016;8(320):320ra3.CrossRefPubMed
21.
Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell. 2013;154(6):1380–9.CrossRefPubMedPubMedCentral
22.
23.
24.
Urnov FD, Miller JC, Lee YL, Beausejour CM, Rock JM, Augustus S, et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature. 2005;435(7042):646–51.CrossRefPubMed
25.
26.
Porteus MH, Baltimore D. Chimeric nucleases stimulate gene targeting in human cells. Science. 2003;300(5620):763.CrossRefPubMed
27.
Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326(5959):1509–12.CrossRefPubMed
28.
Miller JC, Tan S, Qiao G, Barlow KA, Wang J, Xia DF, et al. A TALE nuclease architecture for efficient genome editing. Nat Biotechnol. 2011;29(2):143–8.CrossRefPubMed
29.
30.
Wiedenheft B, Sternberg SH, Doudna JA. RNA-guided genetic silencing systems in bacteria and archaea. Nature. 2012;482(7385):331–8.CrossRefPubMed
31.
Barrangou R, Horvath P. A decade of discovery: CRISPR functions and applications. Nat Microbiol. 2017;2:17092.CrossRefPubMed
32.
33.
•• Torikai H, Reik A, Liu PQ, Zhou Y, Zhang L, Maiti S, et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood. 2012;119(24):5697–705. One of the first reports of zinc-finger nucleases to generate TCR knockout in T cells. CrossRefPubMedPubMedCentral
34.
•• Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S, et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res. 2015;75(18):3853–64. One of the first reports of the use of TALEN to generate TCR and CD52 knockout in CAR T cells. CrossRefPubMed
35.
•• Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9(374). The first report on the use of TALEN-edited CART19 for B-ALL.
36.
•• Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255–66. Important paper describing the generation and the activity of PD-1 knocked-out T cells. CrossRefPubMed
37.
•• Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7. Seminal report on the specific insertion of the CAR19 gene in the TCR locus. CrossRefPubMedPubMedCentral
38.
•• Torikai H, Reik A, Soldner F, Warren EH, Yuen C, Zhou Y, et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood. 2013;122(8):1341–9. Interesting work aimed at reducing rejection of universal T cells by the knock out of HLA. CrossRefPubMedPubMedCentral
39.
•• Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, et al. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget: Important paper describing the generation of multiplex knock out in T cells; 2017.
40.
ASGCT 19th Annual Meeting: abstracts. Molecular therapy : the journal of the American Society of Gene Therapy. 2016;24 Suppl 1:S1–S304.
41.
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415–26.CrossRefPubMed
42.
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33.CrossRefPubMed
43.
Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.CrossRefPubMedPubMedCentral
44.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.CrossRefPubMedPubMedCentral
45.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.CrossRefPubMedPubMedCentral
46.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRefPubMedPubMedCentral
47.
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311–9.CrossRefPubMed
48.
Yousefi H, Yuan J, Keshavarz-Fathi M, Murphy JF, Rezaei N. Immunotherapy of cancers comes of age. Expert Rev Clin Immunol. 2017:1–15.
49.
Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, et al. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget. 2017;8(10):17002–11.PubMedPubMedCentral
50.
Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008;26(7):808–16.CrossRefPubMedPubMedCentral
51.
•• Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901–10. First and seminal report of the clinical use of HIV-resistant T cells. CrossRefPubMedPubMedCentral
52.
Kim MY. Genome editing using CRISPR-Cas9 to increase the therapeutic index of antigen-specific immunotherapy in acute myeloid leukemia. Mol Ther. 2016;24(S1):pS108.CrossRef
53.
Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, et al. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood. 2017;130(3):285–96.CrossRefPubMed
Metadata
Title
Genome-Editing Technologies in Adoptive T Cell Immunotherapy for Cancer
Authors
Nathan Singh
Junwei Shi
Carl H. June
Marco Ruella
Publication date
01-12-2017
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 6/2017
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-017-0417-7

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