Engineering advanced cancer therapies with synthetic biology

Abstract

Engineered immune-cell-based cancer therapies have demonstrated robust efficacy in B cell malignancies, but challenges such as the lack of ideal targetable tumour antigens, tumour-mediated immunosuppression and severe toxicity still hinder their therapeutic efficacy and broad applicability. Synthetic biology can be used to overcome these challenges and create more robust, effective adaptive therapies that enable the specific targeting of cancer cells while sparing healthy cells. In this Progress article, we review recently developed gene circuit therapies for cancer using immune cells, nucleic acids and bacteria as chassis. We conclude by discussing outstanding challenges and future directions for realizing these gene circuit therapies in the clinic.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Synthetic biology approaches that increase chimeric antigen receptor T cell antitumour specificity.
Fig. 2: Split receptor designs to regulate T cell responses.
Fig. 3: Nucleic acid-based circuits for targeting cancer cells.

References

  1. 1.

    Kitada, T., DiAndreth, B., Teague, B. & Weiss, R. Programming gene and engineered-cell therapies with synthetic biology. Science 359, eaad1067 (2018).

    PubMed  Google Scholar 

  2. 2.

    Benenson, Y. Biomolecular computing systems: principles, progress and potential. Nat. Rev. Genet. 13, 455–468 (2012).

    CAS  PubMed  Google Scholar 

  3. 3.

    Auslander, S. & Fussenegger, M. From gene switches to mammalian designer cells: present and future prospects. Trends Biotechnol. 31, 155–168 (2013).

    CAS  PubMed  Google Scholar 

  4. 4.

    Kittleson, J. T., Wu, G. C. & Anderson, J. C. Successes and failures in modular genetic engineering. Curr. Opin. Chem. Biol. 16, 329–336 (2012).

    CAS  PubMed  Google Scholar 

  5. 5.

    Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Chakravarti, D., Cho, J. H., Weinberg, B. H., Wong, N. M. & Wong, W. W. Synthetic biology approaches in cancer immunotherapy, genetic network engineering, and genome editing. Integr. Biol. 8, 504–517 (2016).

    Google Scholar 

  13. 13.

    Roybal, K. T. & Lim, W. A. Synthetic immunology: hacking immune cells to expand their therapeutic capabilities. Annu. Rev. Immunol. 35, 229–253 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Klebanoff, C. A., Rosenberg, S. A. & Restifo, N. P. Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat. Med. 22, 26–36 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Tasian, S. K. & Gardner, R. A. CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B cell acute lymphoblastic leukemia (ALL). Ther. Adv. Hematol. 6, 228–241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Morgan, R. A. et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18, 843–851 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Morsut, L. et al. Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 164, 780–791 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kloss, C. C., Condomines, M., Cartellieri, M., Bachmann, M. & Sadelain, M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71–75 (2013).

    CAS  PubMed  Google Scholar 

  20. 20.

    Fedorov, V. D., Themeli, M. & Sadelain, M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl Med. 5, 215ra172 (2013).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Gardner, R. A. et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129, 3322–3331 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).

    CAS  PubMed  Google Scholar 

  23. 23.

    Hegde, M. et al. Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Mol. Ther. 21, 2087–2101 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Grada, Z. et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol. Ther. Nucleic Acids 2, e105 (2013).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Zah, E., Lin, M. Y., Silva-Benedict, A., Jensen, M. C. & Chen, Y. Y. T. Cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 498–508 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Qin, H., Haso, W., Nguyen, S. M. & Fry, T. J. Preclinical development of bispecific chimeric antigen receptor targeting both CD19 and CD22. Blood 126, 4427–4427 (2015).

    Google Scholar 

  27. 27.

    Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438 (2018).

    CAS  PubMed  Google Scholar 

  28. 28.

    Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).

    CAS  PubMed  Google Scholar 

  29. 29.

    Gros, A. et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016).

    CAS  PubMed  Google Scholar 

  30. 30.

    Strønen, E. et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 352, 1337–1341 (2016).

    PubMed  Google Scholar 

  31. 31.

    Ho, P., Ede, C. & Chen, Y. Y. Modularly constructed synthetic granzyme B molecule enables interrogation of intracellular proteases for targeted cytotoxicity. ACS Synth. Biol. 6, 1484–1495 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748 (2018).

    CAS  PubMed  Google Scholar 

  33. 33.

    Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wu, C. Y., Roybal, K. T., Puchner, E. M., Onuffer, J. & Lim, W. A. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350, aab4077 (2015).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Pan, Y. et al. Mechanogenetics for the remote and noninvasive control of cancer immunotherapy. Proc. Natl Acad. Sci. USA 115, 992–997 (2018).

    CAS  PubMed  Google Scholar 

  36. 36.

    Park, J. S. et al. Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal. Proc. Natl Acad. Sci. USA 111, 5896–5901 (2014).

    CAS  PubMed  Google Scholar 

  37. 37.

    Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Yeku, O. O. & Brentjens, R. J. Armored CAR T cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T cell anti-tumour efficacy. Biochem. Soc. Trans. 44, 412–418 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167, 419–432.e16 (2016).

  41. 41.

    Chang, Z. L. et al. Rewiring T cell responses to soluble factors with chimeric antigen receptors. Nat. Chem. Biol. 14, 317–324 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Prosser, M. E., Brown, C. E., Shami, A. F., Forman, S. J. & Jensen, M. C. Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol. Immunol. 51, 263–272 (2012).

    CAS  PubMed  Google Scholar 

  43. 43.

    Ankri, C., Shamalov, K., Horovitz-Fried, M., Mauer, S. & Cohen, C. J. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J. Immunol. 191, 4121–4129 (2013).

    CAS  PubMed  Google Scholar 

  44. 44.

    Anderson, K. G., Stromnes, I. M. & Greenberg, P. D. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31, 311–325 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kojima, R., Scheller, L. & Fussenegger, M. Nonimmune cells equipped with T cell-receptor-like signaling for cancer cell ablation. Nat. Chem. Biol. 14, 42–49 (2018).

    CAS  PubMed  Google Scholar 

  46. 46.

    Nissim, L. & Bar-Ziv, R. H. A tunable dual-promoter integrator for targeting of cancer cells. Mol. Syst. Biol. 6, 444 (2010).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Xie, Z., Wroblewska, L., Prochazka, L., Weiss, R. & Benenson, Y. Multi-input RNAi-based logic circuit for identification of specific cancer cells. Science 333, 1307–1311 (2011).

    CAS  PubMed  Google Scholar 

  48. 48.

    Wroblewska, L. et al. Mammalian synthetic circuits with RNA binding proteins for RNA-only delivery. Nat. Biotechnol. 33, 839–841 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Baudrimont, A. et al. Multiplexed gene control reveals rapid mRNA turnover. Sci. Adv. 3, e1700006 (2017).

    Google Scholar 

  50. 50.

    Mircetic, J., Dietrich, A., Paszkowski-Rogacz, M., Krause, M. & Buchholz, F. Development of a genetic sensor that eliminates p53 deficient cells. Nat. Commun. 8, 1463 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Liu, Y. et al. Directing cellular information flow via CRISPR signal conductors. Nat. Methods 13, 938–944 (2016).

    CAS  PubMed  Google Scholar 

  52. 52.

    Liu, Y., Li, J., Chen, Z., Huang, W. & Cai, Z. Synthesizing artificial devices that redirect cellular information at will. eLife 7, e31936 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Dastor, M. et al. A workflow for in vivo evaluation of candidate inputs and outputs for cell classifier gene circuits. ACS Synth. Biol. 7, 474–489 (2018).

    CAS  PubMed  Google Scholar 

  54. 54.

    Nissim, L. et al. Synthetic RNA-based immunomodulatory gene circuits for cancer immunotherapy. Cell 171, 1138–1150 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Nakazawa, Y. et al. Optimization of the PiggyBac transposon system for the sustained genetic modification of human T lymphocytes. J. Immunother. 32, 826–836 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Ivics, Z. & Izsvak, Z. The expanding universe of transposon technologies for gene and cell engineering. Mob. DNA 1, 25 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    MacLeod, D. T. et al. Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol. Ther. 25, 949–961 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

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

    Google Scholar 

  60. 60.

    Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).

    CAS  PubMed  Google Scholar 

  61. 61.

    Fang, F., Xiao, W. & Tian, Z. NK cell-based immunotherapy for cancer. Semin. Immunol. 31, 37–54 (2017).

    CAS  PubMed  Google Scholar 

  62. 62.

    Krueger, T. E. G., Thorek, D. L. J., Denmeade, S. R., Isaacs, J. T. & Brennen, W. N. Concise review: mesenchymal stem cell-based drug delivery: the good, the bad, the ugly, and the promise. Stem Cells Transl Med. 7, 651–663 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Ando, M. & Nakauchi, H. ‘Off-the-shelf’ immunotherapy with iPSC-derived rejuvenated cytotoxic T lymphocytes. Exp. Hematol. 47, 2–12 (2017).

    CAS  PubMed  Google Scholar 

  64. 64.

    Ibraheem, D., Elaissari, A. & Fessi, H. Gene therapy and DNA delivery systems. Int. J. Pharm. 459, 70–83 (2014).

    CAS  PubMed  Google Scholar 

  65. 65.

    Lundstrom, K. Viral vectors in gene therapy. Diseases 6, E42 (2018).

    PubMed  Google Scholar 

  66. 66.

    Lawler, S. E., Speranza, M. C., Cho, C. F. & Chiocca, E. A. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 3, 841–849 (2017).

    PubMed  Google Scholar 

  67. 67.

    Shi, B. et al. Challenges in DNA delivery and recent advances in multifunctional polymeric DNA delivery systems. Biomacromolecules 18, 2231–2246 (2017).

    CAS  PubMed  Google Scholar 

  68. 68.

    Yin, H. et al. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 15, 541–555 (2014).

    CAS  PubMed  Google Scholar 

  69. 69.

    Wagner, T. E. et al. Small-molecule-based regulation of RNA-delivered circuits in mammalian cells. Nat. Chem. Biol. 14, 1043–1050 (2018).

    CAS  PubMed  Google Scholar 

  70. 70.

    Schreiber, J., Arter, M., Lapique, N., Haefliger, B. & Benenson, Y. Model-guided combinatorial optimization of complex synthetic gene networks. Mol. Syst. Biol. 12, 899 (2016).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Kramer, M. G., Masner, M., Ferreira, F. A. & Hoffman, R. M. Bacterial therapy of cancer: promises, limitations, and insights for future directions. Front. Microbiol. 9, 16 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Anderson, J. C., Clarke, E. J., Arkin, A. P. & Voigt, C. A. Environmentally controlled invasion of cancer cells by engineered bacteria. J. Mol. Biol. 355, 619–627 (2006).

    CAS  PubMed  Google Scholar 

  73. 73.

    Swofford, C. A., Van Dessel, N. & Forbes, N. S. Quorum-sensing Salmonella selectively trigger protein expression within tumors. Proc. Natl Acad. Sci. USA 112, 3457–3462 (2015).

    CAS  PubMed  Google Scholar 

  74. 74.

    Din, M. O. et al. Synchronized cycles of bacterial lysis for in vivo delivery. Nature 536, 81–85 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Huh, J. H., Kittleson, J. T., Arkin, A. P. & Anderson, J. C. Modular design of a synthetic payload delivery device. ACS Synth. Biol. 2, 418–424 (2013).

    CAS  PubMed  Google Scholar 

  76. 76.

    Shi, L., Yu, B., Cai, C. H. & Huang, J. D. Angiogenic inhibitors delivered by the type III secretion system of tumor-targeting Salmonella typhimurium safely shrink tumors in mice. AMB Express 6, 56 (2016).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Xu, X. et al. Effective cancer vaccine platform based on attenuated salmonella and a type III secretion system. Cancer Res. 74, 6260–6270 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    West, K. A. et al. Abstract 2920: Metabolic modulation of the tumor microenvironment using Synthetic Biotic™ Medicines. Cancer Res. 78, 2920 (2018).

    Google Scholar 

  79. 79.

    Siska, P. J. & Rathmell, J. C. T cell metabolic fitness in antitumor immunity. Trends Immunol. 36, 257–264 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Leventhal, D. et al. Activation of innate and adaptive immunity via combinatorial immunotherapy using Synthetic Biotic™ Medicines. Cancer Res. 78, LB-131 (2018).

    Google Scholar 

  81. 81.

    Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142 (2016).

    CAS  PubMed  Google Scholar 

  82. 82.

    Grushkin, D. The new drug circuit. Nat. Med. 18, 1452 (2012).

    CAS  PubMed  Google Scholar 

  83. 83.

    Sadelain, M., Brentjens, R. & Riviere, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

T.K.L. is supported by the Department of Defense (W81XWH-16-1-0565 and W81XWH-18-1-0513) and the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology Bridge Project. M.-R.W. is supported by the Department of Defense (W81XWH-16-1-0452).

Author information

Affiliations

Authors

Contributions

M.-R.W. and B.J. contributed equally. All authors discussed the contents and wrote the article.

Corresponding author

Correspondence to Timothy K. Lu.

Ethics declarations

Competing interests

M.-R.W. and T.K.L. have filed patent applications on part of work discussed in this article. T.K.L. is a co-founder of BiomX, Corvium, Eligo Biosciences, Engine Biosciences, Senti Biosciences, Synlogic and Tango Therapeutics. T.K.L. also holds financial interests in AmpliPhi, IndieBio and Nest.Bio. B.J. declares no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, MR., Jusiak, B. & Lu, T. Engineering advanced cancer therapies with synthetic biology. Nat Rev Cancer 19, 187–195 (2019). https://doi.org/10.1038/s41568-019-0121-0

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing