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Next Generation of Adoptive T Cell Therapy Using CRISPR/Cas9 Technology: Universal or Boosted?

Part of the Methods in Molecular Biology book series (MIMB,volume 2115)

Abstract

Adoptive T cell therapy (ACT) using either chimeric antigen receptor (CAR)- or T cell receptor (TCR)-engineered lymphocytes has emerged as a promising strategy to treat cancer. However, this therapy is still facing enormous challenges such as poor quality of autologous T cells, T cell exhaustion, and the immune suppressive tumor microenvironments. Additionally, graft-versus-host disease is an issue that must be addressed to allow the use of allogeneic T cells. Strategies to overcome these therapeutic challenges using gene editing technology are now being developed. One strategy is to disrupt TCR and/or MHC expression in healthy donor T cells to generate T cells for universal use. Another strategy is to improve the quality of patient’s T cells by eliminating either the expression of selected immune checkpoint receptors or negative regulators of TCR signaling and/or T-cell homeostasis. Here, we review the use of CRISPR-Cas9 platform in T cell engineering with a focus on the development of universal T cells and boosted autologous cells for next-generation ACT.

Key words

  • Adoptive T cell therapy
  • Chimeric antigen receptor
  • T cell receptor
  • CRISPR-Cas9
  • Tumor infiltrating lymphocytes
  • Graft-versus-host disease (GvHD)
  • Gene editing

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References

  1. Singh AK, McGuirk JP (2016) Allogeneic stem cell transplantation: a historical and scientific overview. Cancer Res 76:6445–6451

    CAS  PubMed  CrossRef  Google Scholar 

  2. Norkin M, Wingard JR (2017) Recent advances in hematopoietic stem cell transplantation. F1000Res 6:870

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  3. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA et al (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319:1676–1680

    CAS  CrossRef  PubMed  Google Scholar 

  4. Geukes Foppen MH, Donia M, Svane IM, Haanen JBAG (2015) Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol Oncol 9:1918–1935

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  5. Lindenberg MA, Retèl VP, van den Berg JH, Geukes Foppen MH, Haanen JB, van Harten WH (2018) Treatment with tumor-infiltrating lymphocytes in advanced melanoma: evaluation of early clinical implementation of an advanced therapy medicinal product. J Immunother 41:413–425

    PubMed  PubMed Central  CrossRef  Google Scholar 

  6. vane IM, Verdegaal EM (2014) Achievements and challenges of adoptive T cell therapy with tumor-infiltrating or blood-derived lymphocytes for metastatic melanoma: what is needed to achieve standard of care? Cancer Immunol Immunother 63:1081–1091

    CrossRef  CAS  Google Scholar 

  7. Karagiannis P, Iriguchi S, Kaneko S (2016) Reprogramming away from the exhausted T cell state. Semin Immunol 28:35–44

    CAS  PubMed  CrossRef  Google Scholar 

  8. Zikich D, Schachter J, Besser MJ (2016) Predictors of tumor-infiltrating lymphocyte efficacy in melanoma. Immunotherapy 8:35–43

    CAS  PubMed  CrossRef  Google Scholar 

  9. Robbins PF, Lu Y-C, El-Gamil M, Li YF, Gross C, Gartner J, Lin JC, Teer JK, Cliften P, Tycksen E et al (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 19:747–752

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  10. Dembic Z, Haas W, Weiss S, McCubrey J, Kiefer H, von Boehmer H, Steinmetz M (1986) Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320:232–238

    CAS  CrossRef  PubMed  Google Scholar 

  11. Johnson LA, Heemskerk B, Powell DJ Jr, Cohen CJ, Morgan RA, Dudley ME, Robbins PF, Rosenberg SA (2006) Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J Immunol 177:6548–6559

    CAS  PubMed  CrossRef  Google Scholar 

  12. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  13. Efremova M, Finotello F, Rieder D, Trajanoski Z (2017) Neoantigens generated by individual mutations and their role in cancer immunity and immunotherapy. Front Immunol 8:1679. eCollection 2017

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  14. Zhao J, Lin Q, Song Y, Liu D (2018) Universal CARs, universal T cells, and universal CAR T cells. J Hematol Oncol 11:132

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  15. Zhang C, Liu J, Zhong JF, Zhang X (2017) Engineering CAR-T cells. Biomark Res 5:22

    PubMed  PubMed Central  CrossRef  Google Scholar 

  16. Fesnak AD, June CH, Levine BL (2016) Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16:566–581

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  17. Walseng E, Köksal H, Sektioglu IM, Fåne A, Skorstad G, Kvalheim G, Gaudernack G, Inderberg EM, Wälchli S (2017) A TCR-based chimeric antigen receptor. Sci Rep 7:10713

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  18. Mensali N, Dillard P, Hebeisen M, Lorenz S, Theodossiou T, Myhre MR, Fåne A, Gaudernack G, Kvalheim G, Myklebust JH et al (2019) NK cells specifically TCR-dressed to kill cancer cells. EBioMedicine 40:106–117

    PubMed  PubMed Central  CrossRef  Google Scholar 

  19. Sing N, Perazzelli J, Grupp SA, Barrett DM (2016) Early memory phenotypes drive T cells proliferation in patients with pediatric malignancies. Sci Transl Med 8:320ra3

    CrossRef  CAS  Google Scholar 

  20. van Loenen MM et al (2010) Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc Natl Acad Sci U S A 107:10972–10977

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  21. Stauss HJ et al (2007) Monoclonal T-cell receptors: new reagents for cancer therapy. Mol Ther 15:1744–1750

    CAS  PubMed  CrossRef  Google Scholar 

  22. Kuball J et al (2007) Facilitating matched pairing and expression of TCR chains introducd into human T cells. Blood 109:2331–2338

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  23. Wherry EJ, Kurachi M (2015) Molecular and cellualer insigjhts into T cell exhaustion. Nat Rev Immunol 15:486–499

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  24. Nassereddine S, Rafei H, Elbahesh E, Tabbara I (2017) Acute graft Versus host disease: a comprehensive review. Anticancer Res 37:1547–1555

    CAS  PubMed  CrossRef  Google Scholar 

  25. Okamoto S et al (2009) Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR. Cancer Res 69:9003–9011

    CAS  PubMed  CrossRef  Google Scholar 

  26. Urnov FD et al (2010) Genome editing with engineered zinc finger nucleases. Nat Rev Genet 11:636–646

    CAS  PubMed  CrossRef  Google Scholar 

  27. Bogdanove AJ, Voytas DF (2011) TAL effectors: customizable proteins for DNA targeting. Science 333:1843–1846

    CAS  PubMed  CrossRef  Google Scholar 

  28. Doudna JA, Charpentier E (2014) Genome editing. The new frontier of genome engineering with CRISPR-Cas 9. Science 346:1258096

    PubMed  CrossRef  CAS  Google Scholar 

  29. Salsman J, Dellaire G (2017) Precision genome editing in the CRISPR era. Biochem Cell Biol 95:187–201

    CAS  PubMed  CrossRef  Google Scholar 

  30. Wiedenheft B, Sternberg SH, Doudna JA (2012) RNA-guided genetic silencing slencing systems in bacteria and archaea. Nature 482:331–338

    CAS  PubMed  CrossRef  Google Scholar 

  31. Qasim W et al (2017) Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl med 9:eaaj2013

    PubMed  CrossRef  Google Scholar 

  32. Liu XX, Zhang Y, Cheng C, Cheng AW, Zhang X, Li N, Xia C, Wei X, Liu XX, Wang H (2017) CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res 27:154–157

    PubMed  CrossRef  CAS  Google Scholar 

  33. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y (2017) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res 23:2255–2266

    CAS  PubMed  CrossRef  Google Scholar 

  34. Georgiadis C, Preece R, Nickolay L, Etuk A, Petrova A, Ladon D, Danyi A, Humphryes-Kirilov N, Ajetunmobi A, Kim D et al (2018) Long terminal repeat CRISPR-CAR-coupled “universal” T cells mediate potent anti-leukemic effects. Mol Ther 26:1215–1227

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  35. Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJC, Hamieh M, Cunanan KM, Odak A, Gönen M, Sadelain M (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543:113–117

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  36. Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, Rouce RH, Bao G, Brenner MK, Mamonkin M (2017) CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood 130:285–296

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  37. Cooper ML, Choi J, Staser K, Ritchey JK, Devenport JM, Eckardt K, Rettig MP et al (2018) An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 32:1970–1983

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  38. Humbert O, Laszlo GS, Sichel S, Ironside C, Haworth KG, Bates OM, Beddoe ME, Carrillo RR, Kiem H-P, Walter RB (2019) Engineering resistance to CD33-targeted immunotherapy in normal hematopoiesis by CRISPR/Cas9-deletion of CD33 exon 2. Leukemia 33:762–808

    PubMed  CrossRef  Google Scholar 

  39. Kim MY, Yu K-R, Kenderian SS, Ruella M, Chen S, Shin T-H, Aljanahi AA, Schreeder D, Klichinsky M, Shestova O et al (2018) Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid Leukemia. Cell 173:1439–1453. e19

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  40. Gao Q, Dong X, Xu Q, Zhu L, Wang F, Hou Y, Chao CC (2019) Therapeutic potential of CRISPR/Cas9 gene editing in engineered T-cell therapy. Cancer Med 8(9):4254–4264. https://doi.org/10.1002/cam4.2257

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  41. Sioud M (2018) T-cell cross-reactivity may explain the large variation in how cancer patients respond to checkpoint inhibitors. Scand J Immunol 87. https://doi.org/10.1111/sji.12643.

    CrossRef  CAS  Google Scholar 

  42. Zhang C, Peng Y, Hublitz P, Zhang H, Dong T (2018) Genetic abrogation of immune checkpoints in antigen-specific cytotoxic T-lymphocyte as a potential alternative to blockade immunotherapy. Sci Rep 8:5549

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  43. Hu W, Zi Z, Jin Y, Li G, Shao K, Cai Q, Ma X, Wei F (2019) CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions. Cancer Immunol Immunother 68:365–377

    CAS  PubMed  CrossRef  Google Scholar 

  44. Su S, Zou Z, Chen F, Ding N, Du J, Shao J, Li L, Fu Y, Hu B, Yang Y et al (2017) CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer. Oncoimmunology 6:e1249558

    PubMed  CrossRef  CAS  Google Scholar 

  45. Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ, Lim WA, Marson A (2017) CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep 7:737

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  46. Zhang Y, Zhang X, Cheng C, Mu W, Liu X, Li N, Wei X, Liu X, Xia C, Wang H (2017) CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. Front Med 11:554–562

    PubMed  CrossRef  Google Scholar 

  47. Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y (2017) A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8:17002–17011

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Norwegian Cancer Society and South-Eastern Norway Regional Health Authority.

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Correspondence to Mouldy Sioud .

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Wälchli, S., Sioud, M. (2020). Next Generation of Adoptive T Cell Therapy Using CRISPR/Cas9 Technology: Universal or Boosted?. In: Sioud, M. (eds) RNA Interference and CRISPR Technologies. Methods in Molecular Biology, vol 2115. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0290-4_22

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  • DOI: https://doi.org/10.1007/978-1-0716-0290-4_22

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