Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Rethinking cancer targeting strategies in the era of smart cell therapeutics

Nature Reviews Cancer volume 22, pages 693–702 (2022)Cite this article

Subjects

Abstract

In the past several decades, the development of cancer therapeutics has largely focused on precision targeting of single cancer-associated molecules. Despite great advances, such targeted therapies still show incomplete precision and the eventual development of resistance due to target heterogeneity or mutation. However, the recent development of cell-based therapies such as chimeric antigen receptor (CAR) T cells presents a revolutionary opportunity to reframe strategies for targeting cancers. Immune cells equipped with synthetic circuits are essentially living computers that can be programmed to recognize tumours based on multiple signals, including both tumour cell-intrinsic and microenvironmental. Moreover, cells can be programmed to launch broad but highly localized therapeutic responses that can limit the potential for escape while still maintaining high precision. Although these emerging smart cell engineering capabilities have yet to be fully implemented in the clinic, we argue here that they will become much more powerful when combined with machine learning analysis of genomic data, which can guide the design of therapeutic recognition programs that are the most discriminatory and actionable. The merging of cancer analytics and synthetic biology could lead to nuanced paradigms of tumour recognition, more akin to facial recognition, that have the ability to more effectively address the complex challenges of treating cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Facial recognition as inspiration for smarter tumour recognition.
Fig. 2: Emerging capabilities of engineering multi-antigen recognition circuits in CAR T cells.
Fig. 3: Computational analysis of tumour profiling data to identify optimal tumour versus normal tissue discrimination circuits.
Fig. 4: Navigating precision and robustness to escape using nuanced combinatorial recognition circuits.

Similar content being viewed by others

References

  1. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Petrelli, F. et al. Different toxicity of cetuximab and panitumumab in metastatic colorectal cancer treatment: a systematic review and meta-analysis. Oncology 94, 191–199 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Soria, J.-C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504–1506 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Raje, N. et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N. Engl. J. Med. 380, 1726–1737 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer 13, 525–541 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Sukumaran, S. et al. Enhancing the potency and specificity of engineered T cells for cancer treatment. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-17-1298 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wilkie, S. et al. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J. Clin. Immunol. 32, 1059–1070 (2012).

    Article  CAS  PubMed  Google Scholar 

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

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Srivastava, S. et al. Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell 35, 489–503 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Williams, J. Z. et al. Precise T cell recognition programs designed by transcriptionally linking multiple receptors. Science 370, 1099–1104 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Richards, R. M. et al. NOT-gated CD93 CAR T cells effectively target AML with minimized endothelial cross-reactivity. Blood Cancer Discov. 2, 648–665 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hamburger, A. E. et al. Engineered T cells directed at tumors with defined allelic loss. Mol. Immunol. 128, 298–310 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Mazor, Y. et al. Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence. Sci. Rep. 7, 40098 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Runcie, K., Budman, D. R., John, V. & Seetharamu, N. Bi-specific and tri-specific antibodies — the next big thing in solid tumor therapeutics. Mol. Med. Camb. Mass. 24, 50 (2018).

    PubMed  PubMed Central  Google Scholar 

  23. Neijssen, J. et al. Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET. J. Biol. Chem. 296, 100641 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Park, K. et al. Amivantamab in EGFR Exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J. Clin. Oncol. 39, 3391–3402 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gunnoo, S. B. et al. Creation of a gated antibody as a conditionally functional synthetic protein. Nat. Commun. 5, 4388 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Lajoie, M. J. et al. Designed protein logic to target cells with precise combinations of surface antigens. Science https://doi.org/10.1126/science.aba6527 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhao, W. & Sher, X. Systematically benchmarking peptide–MHC binding predictors: from synthetic to naturally processed epitopes. PLoS Comput. Biol. 14, e1006457 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kalaora, S. et al. Combined analysis of antigen presentation and T-cell recognition reveals restricted immune responses in melanoma. Cancer Discov. 8, 1366–1375 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Douglass, J. et al. Bispecific antibodies targeting mutant RAS neoantigens. Sci. Immunol. 6, eabd5515 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hsiue, E. H.-C. et al. Targeting a neoantigen derived from a common TP53 mutation. Science 371, eabc8697 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cancer Genome Atlas Research Network. et al. The Cancer Genome Atlas pan-cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).

    Article  PubMed Central  Google Scholar 

  32. Uhlén, M. et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol. Cell. Proteom. MCP 4, 1920–1932 (2005).

    Article  Google Scholar 

  33. Bausch-Fluck, D. et al. A mass spectrometric-derived cell surface protein atlas. PLoS ONE 10, e0121314 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Aguet, F. et al. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    Article  Google Scholar 

  35. Fagerberg, L. et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell. Proteom. MCP 13, 397–406 (2014).

    Article  CAS  Google Scholar 

  36. Tabula Muris Consortium. et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018).

    Article  Google Scholar 

  37. He, S. et al. Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs. Genome Biol. 21, 294 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. The Tabula Sapiens Consortium. The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896 (2022).

    Article  Google Scholar 

  39. Hummel, H.-D. et al. Pasotuxizumab, a BiTE® immune therapy for castration-resistant prostate cancer: phase I, dose-escalation study findings. Immunotherapy 13, 125–141 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Narayan, V. et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. https://doi.org/10.1038/s41591-022-01726-1 (2022).

    Article  PubMed  Google Scholar 

  41. Uhlen, M. et al. A pathology atlas of the human cancer transcriptome. Science 357, eaan2507 (2017).

    Article  PubMed  Google Scholar 

  42. Thistlethwaite, F. C. et al. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol. Immunother. 66, 1425–1436 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Perna, F. et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell 32, 506–519 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hu, Z. et al. The Cancer Surfaceome Atlas integrates genomic, functional and drug response data to identify actionable targets. Nat. Cancer 2, 1406–1422 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Dannenfelser, R. et al. Discriminatory power of combinatorial antigen recognition in cancer T cell therapies. Cell Syst. 11, 215–228.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Baslan, T. & Hicks, J. Unravelling biology and shifting paradigms in cancer with single-cell sequencing. Nat. Rev. Cancer 17, 557–569 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Turke, A. B. et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tsai, P.-C., Hernandez-Ilizaliturri, F. J., Bangia, N., Olejniczak, S. H. & Czuczman, M. S. Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma. Clin. Cancer Res. 18, 1039–1050 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Turtle, C. J. et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Schram, A. M. et al. A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors. J. Clin. Oncol. 38, TPS3654 (2020).

    Article  Google Scholar 

  52. Ruella, M. et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Invest. https://doi.org/10.1172/JCI87366 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Fousek, K. et al. CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Leukemia 35, 75–89 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Schneider, D. et al. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J. Immunother. Cancer 5, 42 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hegde, M. et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Invest. 126, 3036–3052 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Spiegel, J. Y. et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat. Med. 27, 1419–1431 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ajina, A. & Maher, J. Strategies to address chimeric antigen receptor tonic signaling. Mol. Cancer Ther. 17, 1795–1815 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhang, Y. et al. Long-term activity of tandem CD19/CD20 CAR therapy in refractory/relapsed B-cell lymphoma: a single-arm, phase 1–2 trial. Leukemia 36, 189–196 (2022).

    Article  CAS  PubMed  Google Scholar 

  60. Shalabi, H. et al. CD19/22 CAR T-cells in children and young adults with B-ALL: phase I results and development of a novel bicistronic CAR. Blood https://doi.org/10.1182/blood.2022015795 (2022).

    Article  PubMed  Google Scholar 

  61. Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell https://doi.org/10.1016/j.cell.2018.03.038 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Shin, S. H. et al. An elaborate new linker system significantly enhances the efficacy of an HER2–antibody–drug conjugate against refractory HER2-positive cancers. Adv. Sci. 8, 2102414 (2021).

    Article  CAS  Google Scholar 

  63. Wikstrand, C. J., McLendon, R. E., Friedman, A. H. & Bigner, D. D. Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res. 57, 4130–4140 (1997).

    CAS  PubMed  Google Scholar 

  64. O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl Med. 9, eaaa0984 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 37, 1049–1058 (2019).

    Article  CAS  PubMed  Google Scholar 

  66. Choe, J. H. et al. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci. Transl Med. 13, eabe7378 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hernandez-Lopez, R. A. et al. T cell circuits that sense antigen density with an ultrasensitive threshold. Science 371, 1166–1171 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Campbell, J. D. et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet. 48, 607–616 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Milone, M. C. & O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 32, 1529–1541 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wu, S. C.-Y. et al. piggyBac is a flexible and highly active transposon as compared to sleeping beauty, Tol2, and Mos1 in mammalian cells. Proc. Natl Acad. Sci. USA 103, 15008–15013 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dupuy, A. J., Akagi, K., Largaespada, D. A., Copeland, N. G. & Jenkins, N. A. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436, 221–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Huang, X. et al. Sleeping Beauty transposon-mediated engineering of human primary T cells for therapy of CD19+ lymphoid malignancies. Mol. Ther. J. Am. Soc. Gene Ther. 16, 580–589 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Roth, T. L. et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559, 405–409 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shy, B. R. et al. High-yield genome engineering in primary cells using a hybrid ssDNA repair template and small-molecule cocktails. Nat Biotechnol. https://doi.org/10.1038/s41587-022-01418-8 (2022).

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge O. Troyanskaya and H. Okada (and their groups) who have played key roles in the development of ideas presented in this manuscript. They also thank current and past members of the Lim Lab and the UCSF Cell Design Institute. The work in the authors’ laboratories is supported by the following grants: NIH/NCI U54CA244438 (W.A.L.), NIH/NCI R01CA258789 (W.A.L.), NIH/NCI R01CA249018 (W.A.L.) and NIH/NCI K08CA259610 (G.M.A.). Research by the authors reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under the aformentioned award numbers. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Greg M. Allen

  2. Cell Design Institute, University of California San Francisco, San Francisco, CA, USA

    Greg M. Allen & Wendell A. Lim

  3. Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA

    Wendell A. Lim

Authors
  1. Greg M. Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wendell A. Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Wendell A. Lim.

Ethics declarations

Competing interests

W.A.L holds equity in Gilead and Intellia, is an adviser for Allogene Therapeutics and has filed patents related to this work. G.M.A. declares no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note

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

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Allen, G.M., Lim, W.A. Rethinking cancer targeting strategies in the era of smart cell therapeutics. Nat Rev Cancer 22, 693–702 (2022). https://doi.org/10.1038/s41568-022-00505-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-022-00505-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer