Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Unleashing the Therapeutic Potential of CAR-T Cell Therapy Using Gene-Editing Technologies

  • Received : 2018.05.31
  • Accepted : 2018.08.07
  • Published : 2018.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Chimeric antigen receptor (CAR) T-cell therapy, an emerging immunotherapy, has demonstrated promising clinical results in hematological malignancies including B-cell malignancies. However, accessibility to this transformative medicine is highly limited due to the complex process of manufacturing, limited options for target antigens, and insufficient anti-tumor responses against solid tumors. Advances in gene-editing technologies, such as the development of Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9), have provided novel engineering strategies to address these limitations. Development of next-generation CAR-T cells using gene-editing technologies would enhance the therapeutic potential of CAR-T cell treatment for both hematologic and solid tumors. Here we summarize the unmet medical needs of current CAR-T cell therapies and gene-editing strategies to resolve these challenges as well as safety concerns of gene-edited CAR-T therapies.

Keywords

References

  1. Amir, A.L., van der Steen, D.M., Hagedoorn, R.S., Kester, M.G., van Bergen, C.A., Drijfhout, J.W., de Ru, A.H., Falkenburg, J.H., van Veelen, P.A., and Heemskerk, M.H. (2011). Allo-HLA-Reactive T cells inducing graft-versus-host disease are single peptide specific. Blood 118, 6733-6742. https://doi.org/10.1182/blood-2011-05-354787
  2. Chen, K.H., Wada, M., Pinz, K.G., Liu, H., Lin, K.W., Jares, A., Firor, A.E., Shuai, X., Salman, H., Golightly, M., et al. (2017). Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia 31, 2151-2160. https://doi.org/10.1038/leu.2017.8
  3. Cooper, M.L., Choi, J., Staser, K., Ritchey, J.K., Devenport, J.M., Eckardt, K., Rettig, M.P., Wang, B., Eissenberg, L.G., Ghobadi, A., et al. (2018a). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia doi: 10.1038/s41375-018-0065-5. [Epub ahead of print].
  4. Cooper, M.L., Choi, J., Staser, K., Ritchey, J.K., Devenport, J.M., Eckardt, K., Rettig, M.P., Wang, B., Eissenberg, L.G., Ghobadi, A., et al. (2018b). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia doi: 10.1038/s41375-018-0065-5. [Epub ahead of print].
  5. Eyquem, J., Mansilla-Soto, J., Giavridis, T., van der Stegen, S.J.C., Hamieh, M., Cunanan, K.M., Odak, A., Gönen, M., and Sadelain, M. (2017). Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113. https://doi.org/10.1038/nature21405
  6. Fleischer, L.C., Raikar, S.S., Moot, R., Knight, K.A., Doering, C.B., and Spencer, H.T. (2017). Engineering CD5-targeted chimeric antigen receptors and edited T cells for the treatment of T-Cell Leukemia. Blood 130, 1914-1914.
  7. Gaj, T., Gersbach, C.A., and Barbas, C.F. (2013). ZFN, TALEN and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31, 397-405. https://doi.org/10.1016/j.tibtech.2013.04.004
  8. Gajewski, J.L., LeMaistre, C.F., Silver, S.M., Lill, M.C., Selby, G.B., Horowitz, M.M., Rizzo, J.D., Heslop, H.E., Anasetti, C., and Maziarz, R.T. (2009). Impending challenges in the hematopoietic stem cell transplantation physician workforce. Biol. Blood Marrow Transplant. 15, 1493-1501. https://doi.org/10.1016/j.bbmt.2009.08.022
  9. Galetto, R., Chion-Sotinel, I., Gouble, A., and Smith, J. (2015). Bypassing the constraint for chimeric antigen receptor (CAR) development in T-Cells expressing the targeted antigen: improvement of Anti-CS1 CAR activity in allogenic TCRa/CS1 double knockout T-Cells for the treatment of multiple myeloma (MM). Blood 126, 116-116.
  10. Galon, J., Rossi, J., Turcan, S., Danan, C., Locke, F.L., Neelapu, S.S., Miklos, D.B., Bartlett, N.L., Jacobson, C.A., Braunschweig, I., et al. (2017). Characterization of anti-CD19 chimeric antigen receptor (CAR) T cell-mediated tumor microenvironment immune gene profile in a multicenter trial (ZUMA-1) with axicabtagene ciloleucel (axi-cel, KTE-C19). J. Clin. Oncol. 35, 3025-3025. https://doi.org/10.1200/JCO.2017.35.15_suppl.3025
  11. Gogishvili, T., Danhof, S., Prommersberger, S., Rydzek, J., Schreder, M., Brede, C., Einsele, H., and Hudecek, M. (2017). SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7 normal lymphocytes. Blood 130, 2838-2847. https://doi.org/10.1182/blood-2017-04-778423
  12. Haapaniemi, E., Botla, S., Persson, J., Schmierer, B., and Taipale, J. (2018). CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat. Med. 24, 927-930. https://doi.org/10.1038/s41591-018-0049-z
  13. Ihry, R.J., Worringer, K.A., Salick, M.R., Frias, E., Ho, D., Theriault, K., Kommineni, S., Chen, J., Sondey, M., Ye, C., et al. (2018). p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat. Med. 24, 939-946 https://doi.org/10.1038/s41591-018-0050-6
  14. Jenkins, M., Davenport, A., Cross, R., Yong, C., Ritchie, D.S., Trapani, J., Kershaw, M., Darcy, P., and Neeson, P. (2015). CAR-T Cells are serial killers of tumor cells. Blood 126, 3088-3088.
  15. Jung, I.-Y., Kim, Y.-Y., Yu, H.-S., Lee, M., Kim, S., and Lee, J. (2018). CRISPR/Cas9-mediated knockout of DGK improves anti-tumor activities of human T cells. Cancer Res. DOI: 10.1158/0008-5472.CAN-18-0030.
  16. Kim, S., Koo, T., Jee, H.G., Cho, H.Y., Lee, G., Lim, D.G., Shin, H.S., and Kim, J.S. (2018). CRISPR RNAs trigger innate immune responses in human cells. Genome Res. DOI: 10.1101/gr.231936.117.
  17. Klebanoff, C.A., Scott, C.D., Leonardi, A.J., Yamamoto, T.N., Cruz, A.C., Ouyang, C., Ramaswamy, M., Roychoudhuri, R., Ji, Y., Eil, R.L., et al. (2016). Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest. 126, 318-334.
  18. Lee, D.W., Kochenderfer, J.N., Stetler-Stevenson, M., Cui, Y.K., Delbrook, C., Feldman, S.A., Fry, T.J., Orentas, R., Sabatino, M., Shah, N.N., et al. (2015). T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. The Lancet 385, 517-528. https://doi.org/10.1016/S0140-6736(14)61403-3
  19. Levine, B.L., Miskin, J., Wonnacott, K., and Keir, C. (2017). Global manufacturing of CAR T cell therapy. Mol. Ther. Methods Clin. Dev. 4, 92-101. https://doi.org/10.1016/j.omtm.2016.12.006
  20. Liu, S.Y., and Wu, Y.L. (2017). Ongoing clinical trials of PD-1 and PDL1 inhibitors for lung cancer in China. J. Hematol. Oncol. 10, 136. https://doi.org/10.1186/s13045-017-0506-z
  21. Ma, Q., Gonzalo-Daganzo, R.M., and Junghans, R.P. (2002). Genetically engineered T cells as adoptive immunotherapy of cancer. Cancer Chemother. Biol. Response Modif 20, 315-341.
  22. Magklara, A., and Lomvardas, S. (2013). Stochastic gene expression in mammals: lessons from olfaction. Trends Cell Biol. 23, 449-456. https://doi.org/10.1016/j.tcb.2013.04.005
  23. Menger, L., Sledzinska, A., Bergerhoff, K., Vargas, F.A., Smith, J., Poirot, L., Pule, M., Herrero, J., Peggs, K.S., and Quezada, S.A. (2016). TALEN-mediated inactivation of PD-1 in tumor-reactive lymphocytes promotes intratumoral T-cell persistence and rejection of established tumors. Cancer Res. 76, 2087-2093. https://doi.org/10.1158/0008-5472.CAN-15-3352
  24. Moeller, M., Haynes, N.M., Trapani, J.A., Teng, M.W., Jackson, J.T., Tanner, J.E., Cerutti, L., Jane, S.M., Kershaw, M.H., Smyth, M.J., et al. (2004). A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells. Cancer Gene Ther. 11, 371-379. https://doi.org/10.1038/sj.cgt.7700710
  25. Naidoo, J., Page, D.B., Li, B.T., Connell, L.C., Schindler, K., Lacouture, M.E., Postow, M.A., and Wolchok, J.D. (2015). Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann. Oncol. 26, 2375-2391.
  26. Nguyen, L.T., and Ohashi, P.S. (2014). Clinical blockade of PD1 and LAG3 - potential mechanisms of action. Nat. Rev. Immunol. 15, 45. https://doi.org/10.1038/ni.2769
  27. Odorizzi, P.M., Pauken, K.E., Paley, M.A., Sharpe, A., and Wherry, E.J. (2015). Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8 T cells. J. Exp. Med. 212, 1125-1137. https://doi.org/10.1084/jem.20142237
  28. Osborn, M.J., Webber, B.R., Knipping, F., Lonetree, C.-l., Tennis, N., DeFeo, A.P., McElroy, A.N., Starker, C.G., Lee, C., Merkel, S., et al. (2016). Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol. Ther. 24, 570-581. https://doi.org/10.1038/mt.2015.197
  29. Park, J.R., Digiusto, D.L., Slovak, M., Wright, C., Naranjo, A., Wagner, J., Meechoovet, H.B., Bautista, C., Chang, W.C., Ostberg, J.R., et al. (2007). Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol. Ther. 15, 825-833. https://doi.org/10.1038/sj.mt.6300104
  30. Park, J.H., Geyer, M.B., and Brentjens, R.J. (2016). CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 127, 3312-3320. https://doi.org/10.1182/blood-2016-02-629063
  31. Pauken, K.E., Sammons, M.A., Odorizzi, P.M., Manne, S., Godec, J., Khan, O., Drake, A.M., Chen, Z., Sen, D.R., Kurachi, M., et al. (2016). Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160-1165. https://doi.org/10.1126/science.aaf2807
  32. Peter, M.E., Hadji, A., Murmann, A.E., Brockway, S., Putzbach, W., Pattanayak, A., and Ceppi, P. (2015). The role of CD95 and CD95 ligand in cancer. Cell Death Differ. 22, 549. https://doi.org/10.1038/cdd.2015.3
  33. Pinz, K., Liu, H., Golightly, M., Jares, A., Lan, F., Zieve, G.W., Hagag, N., Schuster, M., Firor, A.E., Jiang, X., et al. (2016). Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Leukemia 30, 701-707. https://doi.org/10.1038/leu.2015.311
  34. Poirot, L., Philip, B., Schiffer-Mannioui, C., Le Clerre, D., Chion-Sotinel, I., Derniame, S., Bas, C., Potrel, P., Lemaire, L., Duclert, A., et al. (2015). Multiplex genome edited T-cell manufacturing platform for "off-the-shelf" adoptive T-cell immunotherapies. Cancer Res. 75, 3853-3864. https://doi.org/10.1158/0008-5472.CAN-14-3321
  35. Porter, D.L., Hwang, W.-T., Frey, N.V., Lacey, S.F., Shaw, P.A., Loren, A.W., Bagg, A., Marcucci, K.T., Shen, A., Gonzalez, V., et al. (2015). Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139-303ra139. https://doi.org/10.1126/scitranslmed.aac5415
  36. Qasim, W., Zhan, H., Samarasinghe, S., Adams, S., Amrolia, P., Stafford, S., Butler, K., Rivat, C., Wright, G., Somana, K., et al. (2017). Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, pii: eaaj2013.
  37. Ren, J., Liu, X., Fang, C., Jiang, S., June, C.H., and Zhao, Y. (2017a). Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition. Clin. Cancer Res. 23, 2255-2266. https://doi.org/10.1158/1078-0432.CCR-16-1300
  38. Ren, J., Zhang, X., Liu, X., Fang, C., Jiang, S., June, C.H., and Zhao, Y. (2017b). A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8, 17002-17011.
  39. Riese, M.J., Wang, L.C., Moon, E.K., Joshi, R.P., Ranganathan, A., June, C.H., Koretzky, G.A., and Albelda, S.M. (2013). Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res. 73, 3566-3577. https://doi.org/10.1158/0008-5472.CAN-12-3874
  40. Rupp, L.J., Schumann, K., Roybal, K.T., Gate, R.E., Ye, C.J., Lim, W.A., and Marson, A. (2017). CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 737. https://doi.org/10.1038/s41598-017-00462-8
  41. Sander, J.D., and Joung, J.K. (2014). CRISPR-Cas systems for editing, regulating and targeting genomes. Nat. Biotechnol. 32, 347. https://doi.org/10.1038/nbt.2842
  42. Sather, B.D., Romano Ibarra, G.S., Sommer, K., Curinga, G., Hale, M., Khan, I.F., Singh, S., Song, Y., Gwiazda, K., Sahni, J., et al. (2015). Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template. Sci. Transl. Med. 7, 307ra156. https://doi.org/10.1126/scitranslmed.aac5530
  43. Savoldo, B., Ramos, C.A., Liu, E., Mims, M.P., Keating, M.J., Carrum, G., Kamble, R.T., Bollard, C.M., Gee, A.P., Mei, Z., et al. (2011). CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822-1826. https://doi.org/10.1172/JCI46110
  44. Schadendorf, D., Hodi, F.S., Robert, C., Weber, J.S., Margolin, K., Hamid, O., Patt, D., Chen, T.-T., Berman, D.M., and Wolchok, J.D. (2015). Pooled analysis of long-term survival data from phase II and phase III trials of Ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889-1894. https://doi.org/10.1200/JCO.2014.56.2736
  45. Schietinger, A., Philip, M., Krisnawan, V.E., Chiu, E.Y., Delrow, J.J., Basom, R.S., Lauer, P., Brockstedt, D.G., Knoblaugh, S.E., Hammerling, G.J., et al. (2016). Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389-401. https://doi.org/10.1016/j.immuni.2016.07.011
  46. Singh, N., Perazzelli, J., Grupp, S.A., and Barrett, D.M. (2016). Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci. Transl. Med. 8, 320ra323-320ra323.
  47. Slaymaker, I.M., Gao, L., Zetsche, B., Scott, D.A., Yan, W.X., and Zhang, F. (2016). Rationally engineered Cas9 nucleases with improved specificity. Science 351, 84-88. https://doi.org/10.1126/science.aad5227
  48. Su, S., Hu, B., Shao, J., Shen, B., Du, J., Du, Y., Zhou, J., Yu, L., Zhang, L., Chen, F., et al. (2016). CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients. Sci. Rep. 6, 20070. https://doi.org/10.1038/srep20070
  49. Tsai, S.Q., Zheng, Z., Nguyen, N.T., Liebers, M., Topkar, V.V., Thapar, V., Wyvekens, N., Khayter, C., Iafrate, A.J., Le, L.P., et al. (2014). GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat.Biotechnol. 33, 187.
  50. Valton, J., Guyot, V., Marechal, A., Filhol, J.-M., Juillerat, A., Duclert, A., Duchateau, P., and Poirot, L. (2015). A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy. Mol. Ther. 23, 1507-1518. https://doi.org/10.1038/mt.2015.104
  51. Zhang, Y., Zhang, X., Cheng, C., Mu, W., Liu, X., Li, N., Wei, X., Liu, X., Xia, C., and Wang, H. (2017). CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. Front. Med. 11, 554-562. https://doi.org/10.1007/s11684-017-0543-6

Cited by

  1. CRISPR and Target-Specific DNA Endonucleases for Efficient DNA Knock-in in Eukaryotic Genomes vol.41, pp.11, 2018, https://doi.org/10.14348/molcells.2018.0408
  2. When CAR Meets Stem Cells vol.20, pp.8, 2018, https://doi.org/10.3390/ijms20081825
  3. Therapeutic application of the CRISPR system: current issues and new prospects vol.138, pp.6, 2019, https://doi.org/10.1007/s00439-019-02028-2
  4. Mechanisms of resistance to CAR T cell therapy vol.16, pp.6, 2019, https://doi.org/10.1038/s41571-019-0184-6
  5. Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma vol.11, pp.7, 2018, https://doi.org/10.3390/cancers11070971
  6. CRISPR/Cas9 guided genome and epigenome engineering and its therapeutic applications in immune mediated diseases vol.96, pp.None, 2019, https://doi.org/10.1016/j.semcdb.2019.05.007
  7. Vectofusin-1 Improves Transduction of Primary Human Cells with Diverse Retroviral and Lentiviral Pseudotypes, Enabling Robust, Automated Closed-System Manufacturing vol.30, pp.12, 2019, https://doi.org/10.1089/hum.2019.157
  8. Public Acceptability of Gene Therapy and Gene Editing for Human Use: A Systematic Review vol.31, pp.1, 2018, https://doi.org/10.1089/hum.2019.197
  9. Adeno‐Associated Viral Vectors for Homology‐Directed Generation of CAR‐T Cells vol.15, pp.1, 2018, https://doi.org/10.1002/biot.201900286
  10. CRISPR/Cas9 technology: towards a new generation of improved CAR-T cells for anticancer therapies vol.19, pp.3, 2020, https://doi.org/10.1093/bfgp/elz039
  11. Nanotechnology and immunoengineering: How nanotechnology can boost CAR-T therapy vol.109, pp.None, 2018, https://doi.org/10.1016/j.actbio.2020.04.015
  12. CRISPR/Cas9 based genome editing for targeted transcriptional control in triple-negative breast cancer vol.19, pp.None, 2021, https://doi.org/10.1016/j.csbj.2021.04.036
  13. Delivery technologies for T cell gene editing: Applications in cancer immunotherapy vol.67, pp.None, 2018, https://doi.org/10.1016/j.ebiom.2021.103354
  14. Targeted multi-epitope switching enables straightforward positive/negative selection of CAR T cells vol.28, pp.9, 2018, https://doi.org/10.1038/s41434-021-00220-6
  15. Strengthening the CAR‐T cell therapeutic application using CRISPR/Cas9 technology vol.118, pp.10, 2018, https://doi.org/10.1002/bit.27882
  16. CRISPR-Cas9 cytidine and adenosine base editing of splice-sites mediates highly-efficient disruption of proteins in primary and immortalized cells vol.12, pp.1, 2021, https://doi.org/10.1038/s41467-021-22009-2