Skip to main content

Advertisement

SpringerLink
Log in

Overcome tumor relapse in CAR T cell therapy

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Chimeric antigen receptor (CAR) T cell therapy is a novel therapeutic approach that uses gene editing techniques and lentiviral transduction to engineer T cells so that they can effectively kill tumors. However, CAR T cell therapy still has some drawbacks: many patients who received CAR T cell therapy and achieve remission, still had tumor relapse and treatment resistance, which may be due to tumor immune escape and CAR T cell dysfunction. To overcome tumor relapse, more researches are being done to optimize CAR T cell therapy to make it more precise and personalized, including screening for more specific tumor antigens, developing novel CAR T cells, and combinatorial treatment approaches. In this review, we will discuss the mechanisms as well as the progress of research on overcoming plans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Schubert ML, Schmitt M, Wang L, Ramos CA, Jordan K, Müller-Tidow C, Dreger P. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Ann Oncol. 2021;32:34–48.

    Article  CAS  PubMed  Google Scholar 

  2. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.

    Article  CAS  PubMed  Google Scholar 

  3. Cui X, Liu R, Duan L, Cao D, Zhang Q, Zhang A. CAR-T therapy: prospects in targeting cancer stem cells. J Cell Mol Med. 2021;25:9891–904.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, Roshal M, Maslak P, Davila M, Brentjens RJ, Sadelain M. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ruella M, Maus MV. Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies. Comput Struct Biotechnol J. 2016;14:357–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Poorebrahim M, Melief J, Pico de Coaña Y, Wickström SL, Cid-Arregui A, Kiessling R. Counteracting CAR T cell dysfunction. Oncogene. 2021;40:421–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Majzner RG, Heitzeneder S, Mackall CL. Harnessing the immunotherapy revolution for the treatment of childhood cancers. Cancer Cell. 2017;31:476–85.

    Article  CAS  PubMed  Google Scholar 

  9. Asnani M, Hayer KE, Naqvi AS, Zheng S, Yang SY, Oldridge D, Ibrahim F, Maragkakis M, Gazzara MR, Black KL, Bagashev A, Taylor D, Mourelatos Z, Grupp SA, Barrett D, Maris JM, Sotillo E, Barash Y, Thomas-Tikhonenko A. Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia. 2020;34:1202–7.

    Article  PubMed  Google Scholar 

  10. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, Sussman R, Lanauze C, Ruella M, Gazzara MR, Martinez NM, Harrington CT, Chung EY, Perazzelli J, Hofmann TJ, Maude SL, Raman P, Barrera A, Gill S, Lacey SF, Melenhorst JJ, Allman D, Jacoby E, Fry T, Mackall C, Barash Y, Lynch KW, Maris JM, Grupp SA, Thomas-Tikhonenko A. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015;5:1282–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fischer J, Paret C, El Malki K, Alt F, Wingerter A, Neu MA, Kron B, Russo A, Lehmann N, Roth L, Fehr EM, Attig S, Hohberger A, Kindler T, Faber J. CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in b-all patients at initial diagnosis. J immunotherapy (Hagerstown MD). 1997;40(2017):187–95.

    Google Scholar 

  12. Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, Levine JE, Qayed M, Grupp SA, Boyer M, De Moerloose B, Nemecek ER, Bittencourt H, Hiramatsu H, Buechner J, Davies SM, Verneris MR, Nguyen K, Brogdon JL, Bitter H, Morrissey M, Pierog P, Pantano S, Engelman JA, Winckler W. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med. 2018;24:1504–6.

    Article  CAS  PubMed  Google Scholar 

  13. Braig F, Brandt A, Goebeler M, Tony H-P, Kurze A-K, Nollau P, Bumm T, Böttcher S, Bargou RC, Binder M. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood. 2017;129:100–4.

    Article  CAS  PubMed  Google Scholar 

  14. Song MK, Park BB, Uhm JE Resistance mechanisms to CAR T-cell therapy and overcoming strategy in B-cell hematologic malignancies. Int J Mol Sci 20 (2019).

  15. Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, Smithers H, Jensen MC, Riddell SR, Maloney DG, Turtle CJ. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127:2406–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rayes A, McMasters RL, O’Brien MM. Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy. Pediatr Blood Cancer. 2016;63:1113–5.

    Article  CAS  PubMed  Google Scholar 

  17. Evans AG, Rothberg PG, Burack WR, Huntington SF, Porter DL, Friedberg JW, Liesveld JL. Evolution to plasmablastic lymphoma evades CD19-directed chimeric antigen receptor T cells. Br J Haematol. 2015;171:205–9.

    Article  CAS  PubMed  Google Scholar 

  18. Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Investig. 2016;126:2123–38.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, Qin H, Yang Y, Chien CD, Seif AE, Lei H, Song YK, Khan J, Lee DW, Mackall CL, Gardner RA, Jensen MC, Shern JF, Fry TJ. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun. 2016;7:12320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Frank SJ, Niklinska BB, Orloff DG, Merćep M, Ashwell JD, Klausner RD. Structural mutations of the T cell receptor zeta chain and its role in T cell activation. Science. 1990;249:174–7.

    Article  CAS  PubMed  Google Scholar 

  22. Valitutti S, Lanzavecchia A. Serial triggering of TCRs: a basis for the sensitivity and specificity of antigen recognition. Immunol Today. 1997;18:299–304.

    Article  CAS  PubMed  Google Scholar 

  23. Harris DT, Hager MV, Smith SN, Cai Q, Stone JD, Kruger P, Lever M, Dushek O, Schmitt TM, Greenberg PD, Kranz DM. Comparison of T cell activities mediated by human TCRs and CARs that use the same recognition domains. J Immunol (Baltimore MD: 1950). 2018;200:1088–100.

    Article  CAS  Google Scholar 

  24. Walker AJ, Majzner RG, Zhang L, Wanhainen K, Long AH, Nguyen SM, Lopomo P, Vigny M, Fry TJ, Orentas RJ, Mackall CL. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther. 2017;25:2189–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hombach AA, Görgens A, Chmielewski M, Murke F, Kimpel J, Giebel B, Abken H. Superior therapeutic index in lymphoma therapy: CD30(+) CD34(+) hematopoietic stem cells resist a chimeric antigen receptor T-cell attack. Mol Therapy. 2016;24:1423–34.

    Article  CAS  Google Scholar 

  26. Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, Sakemura R, Goto T, Hanajiri R, Imahashi N, Shimada K, Tomita A, Kiyoi H, Nishida T, Naoe T, Murata M. Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8+ T cells. J Immunol (Baltimore MD: 1950). 2015;194:911–20.

    Article  CAS  Google Scholar 

  27. Hamieh M, Dobrin A, Cabriolu A, van der Stegen SJC, Giavridis T, Mansilla-Soto J, Eyquem J, Zhao Z, Whitlock BM, Miele MM, Li Z, Cunanan KM, Huse M, Hendrickson RC, Wang X, Rivière I, Sadelain M. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature. 2019;568:112–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. K. Miyake, H. Karasuyama, The Role of Trogocytosis in the Modulation of Immune Cell Functions, Cells. 10 (2021).

  29. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, Shalabi H, Fountaine TJ, Shern JF, Majzner RG, Stroncek DF, Sabatino M, Feng Y, Dimitrov DS, Zhang L, Nguyen S, Qin H, Dropulic B, Lee DW, Mackall CL. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24:20–8.

    Article  CAS  PubMed  Google Scholar 

  30. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541–7.

    Article  CAS  PubMed  Google Scholar 

  31. Morvan MG, Lanier LL, NK cells and cancer: you can teach innate cells new tricks, Nat Rev Cancer. 16 (2016).

  32. Xuyang X, Xiaochun W, Wei H. Advances in research on tumor immunotherapy and its drug development. J China Pharmaceut Univ. 2021;52:10–9.

    Google Scholar 

  33. Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology. 2014;143:512–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cheong JE, Ekkati A, Sun L. A patent review of IDO1 inhibitors for cancer. Expert Opin Ther Pat. 2018;28:317–30.

    Article  CAS  PubMed  Google Scholar 

  35. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–37.

    Article  CAS  PubMed  Google Scholar 

  36. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, Xia H, Man Q, Zhong W, Antelo LF, Wu B, Xiong X, Liu X, Guan L, Li T, Liu S, Yang R, Lu Y, Dong L, McGettigan S, Somasundaram R, Radhakrishnan R, Mills G, Lu Y, Kim J, Chen YH, Dong H, Zhao Y, Karakousis GC, Mitchell TC, Schuchter LM, Herlyn M, Wherry EJ, Xu X, Guo W. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Whiteside TL. Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem Soc Trans. 2013;41:245–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mulé J, Kerr WG, Jove R, Pardoll D, Yu H. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005;11:1314–21.

    Article  CAS  PubMed  Google Scholar 

  39. J. Cong, X. Wang, X. Zheng, D. Wang, B. Fu, R. Sun, Z. Tian, H. Wei, Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression, Cell Metab. 28 (2018).

  40. Singh N, Lee YG, Shestova O, Ravikumar P, Hayer KE, Hong SJ, Lu XM, Pajarillo R, Agarwal S, Kuramitsu S, Orlando EJ, Mueller KT, Good CR, Berger SL, Shalem O, Weitzman MD, Frey NV, Maude SL, Grupp SA, June CH, Gill S, Ruella M. Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction. Cancer Discov. 2020;10:552–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia; Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia; Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia, New Engl J Med. 374 (2016) 998.

  42. Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118:4817–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kochenderfer JN, Somerville R, Lu L, Iwamoto A, Yang JC, Klebanoff C, Kammula U, Sherry RM, Victoria S, Yuan C, Feldman S, Feldman T, Goy A, Morton KE, Toomey MA, Rosenberg SA. Anti-CD19 CAR T Cells administered after low-dose chemotherapy can induce remissions of chemotherapy-refractory diffuse large B-Cell lymphoma. Blood. 2014;124:550–550.

    Article  Google Scholar 

  44. Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, Dengel K, Kerr ND, Bagg A, Levine BL, June CH, Stadtmauer EA. Chimeric antigen receptor T cells against CD19 for MULTIPLE MYELoma. N Engl J Med. 2015;373:1040–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress RE, Hakim FT, Kochenderfer JN. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19:2048–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Roberts AW, He S, Ritchie D, Hertzberg MS, Durrant ST A phase I study of anti-CD123 monoclonal antibody (mAb) CSL360 targeting leukemia stem cells (LSC) in AML, J Clin Oncol 28 (2010).

  47. Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Hönemann D, Gambell P, Westerman DA, Haurat J, Westwood JA, Scott AM, Kravets L, Dickinson M, Trapani JA, Smyth MJ, Darcy PK, Kershaw MH, Prince HM. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Therapy. 2013;21:2122–9.

    Article  CAS  Google Scholar 

  48. Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 2016;6:133–46.

    Article  CAS  PubMed  Google Scholar 

  49. Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM, Kalos M, June CH. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res. 2014;2:112–20.

    Article  CAS  PubMed  Google Scholar 

  50. Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013;1:26–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Haffner MC, Kronberger IE, Ross JS, Sheehan CE, Zitt M, Mühlmann G, Ofner D, Zelger B, Ensinger C, Yang XJ, Geley S, Margreiter R, Bander NH. Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers. Hum Pathol. 2009;40:1754–61.

    Article  CAS  PubMed  Google Scholar 

  52. Chang SS. Overview of prostate-specific membrane antigen. Rev Urol. 2004;6(Suppl 10):S13-18.

    PubMed  PubMed Central  Google Scholar 

  53. Slovin SF, Wang X, Hullings M, Arauz G, Riviere I. Chimeric antigen receptor (CAR + ) modified T cells targeting prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC). J Clin Oncol Off J Am Soc Clin Oncol. 2013;31:72–72.

    Article  Google Scholar 

  54. Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist. 2002;7(Suppl 4):31–9.

    Article  CAS  PubMed  Google Scholar 

  55. Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N, Kuan CT, Song H, Zhang W, Fine HA, Rosenberg SA. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther. 2012;23:1043–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward, Nature reviews. Clin Oncol. 2016;13:370–83.

    CAS  Google Scholar 

  57. Katz SC, Burga RA, McCormack E, Wang LJ, Mooring W, Point GR, Khare PD, Thorn M, Ma Q, Stainken BF, Assanah EO, Davies R, Espat NJ, Junghans RP. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin Cancer Res. 2015;21:3149–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hong H, Stastny M, Brown C, Chang WC, Ostberg JR, Forman SJ, Jensen MC. Diverse solid tumors expressing a restricted epitope of L1-CAM can be targeted by chimeric antigen receptor redirected T lymphocytes. J Immunother. 2014;37:93–104.

    Article  CAS  PubMed  Google Scholar 

  59. Gargett T, Brown MP. Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy. 2015;17:487–95.

    Article  CAS  PubMed  Google Scholar 

  60. Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, Wakefield A, Fousek K, Bielamowicz K, Chow KK, Brawley VS, Byrd TT, Krebs S, Gottschalk S, Wels WS, Baker ML, Dotti G, Mamonkin M, Brenner MK, Orange JS, Ahmed N. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest. 2016;126:3036–52.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Charan M, Dravid P, Cam M, Audino A, Gross AC, Arnold MA, Roberts RD, Cripe TP, Pertsemlidis A, Houghton PJ, Cam H. GD2-directed CAR-T cells in combination with HGF-targeted neutralizing antibody (AMG102) prevent primary tumor growth and metastasis in Ewing sarcoma. Int J Cancer. 2020;146:3184–95.

    Article  CAS  PubMed  Google Scholar 

  62. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18:843–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yu M, Scherwitzl I, Opp S, Tsirigos A, Meruelo D. Molecular and metabolic pathways mediating curative treatment of a non-Hodgkin B cell lymphoma by Sindbis viral vectors and anti-4-1BB monoclonal antibody. J Immunother Cancer. 2019;7:185.

    Article  PubMed  PubMed Central  Google Scholar 

  64. MacKay M, Afshinnekoo E, Rub J, Hassan C, Khunte M, Baskaran N, Owens B, Liu L, Roboz GJ, Guzman ML, Melnick AM, Wu S, Mason CE. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat Biotechnol. 2020;38:233–44.

    Article  CAS  PubMed  Google Scholar 

  65. Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 2018;8:1219–26.

    Article  CAS  PubMed  Google Scholar 

  66. Ruella M, Barrett DM, Kenderian SS, Shestova O, Hofmann TJ, Perazzelli J, Klichinsky M, Aikawa V, Nazimuddin F, Kozlowski M, Scholler J, Lacey SF, Melenhorst JJ, Morrissette JJ, Christian DA, Hunter CA, Kalos M, Porter DL, June CH, Grupp SA, Gill S. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest. 2016;126:3814–26.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Schneider D, Xiong Y, Wu D, Nӧlle V, Schmitz S, Haso W, Kaiser A, Dropulic B, Orentas RJ. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J Immunother Cancer. 2017;5:42.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Zah E, Lin MY, Silva-Benedict A, Jensen MC, Chen YY. T Cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res. 2016;4:498–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, Wu MF, Orange JS, Sumazin P, Man TK, Joseph SK, Hegde M, Ahmed N. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro Oncol. 2018;20:506–18.

    Article  CAS  PubMed  Google Scholar 

  70. Gill S, Tasian SK, Ruella M, Shestova O, Li Y, Porter DL, Carroll M, Danet-Desnoyers G, Scholler J, Grupp SA, June CH, Kalos M. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood. 2014;123:2343–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nguyen S, Lacan C, Roos-Weil D. Allogeneic CAR-NK cells: a promising alternative to autologous CAR-T cells—State of the art, sources of NK cells, limits and perspectives]. Bull Cancer. 2021;108:S81-s91.

    Article  PubMed  Google Scholar 

  72. Wei J, Long L, Zheng W, Dhungana Y, Lim SA, Guy C, Wang Y, Wang Y-D, Qian C, Xu B, Kc A, Saravia J, Huang H, Yu J, Doench JG, Geiger TL, Chi H, Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy, Nature. (2019).

  73. Coon ME, Stephan SB, Gupta V, Kealey CP, Stephan MT, Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours, Nat Biomed Eng. (2019).

  74. Choi BD, Yu X, Castano AP, Bouffard AA, Schmidts A, Larson RC, Bailey SR, Boroughs AC, Frigault MJ, Leick MB, Scarfò I, Cetrulo CL, Demehri S, Nahed BV, Cahill DP, Wakimoto H, Curry WT, Carter BS, Maus MV. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat Biotechnol. 2019;37:1049–58.

    Article  CAS  PubMed  Google Scholar 

  75. Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L 'Off-the-shelf' allogeneic CAR T cells: development and challenges, Nat Rev Drug Discov. (2020).

  76. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013;210:1695–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yousef S, Marvin J, Steinbach M, Langemo A, Kovacsovics T, Binder M, Kröger N, Luetkens T, Atanackovic D. Immunomodulatory molecule PD-L1 is expressed on malignant plasma cells and myeloma-propagating pre-plasma cells in the bone marrow of multiple myeloma patients. Blood Cancer J. 2015;5: e285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39:98–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang J, Yuan R, Song W, Sun J, Liu D, Li Z. PD-1, PD-L1 (B7–H1) and tumor-site immune modulation therapy: the historical perspective. J Hematol Oncol. 2017;10:34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I, Rosenberg SA. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunotherapy (Hagerstown MD: 1997). 2010;33:828–33.

    CAS  Google Scholar 

  81. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunotherapy (Hagerstown MD: 1997). 2013;36:382–9.

    CAS  PubMed Central  Google Scholar 

  82. Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, DiGiacomo AM, Danielli R, Altomonte M, Mutti L, Maio M. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14:1104–11.

    Article  PubMed  CAS  Google Scholar 

  83. Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113:1581–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy, Nature reviews. Clin Oncol. 2019;16:372–85.

    CAS  Google Scholar 

  85. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126:3130–44.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Liu G, Zhang Q, Li D, Zhang L, Gu Z, Liu J, Liu G, Yang M, Gu J, Cui X, Pan Y, Tian X. PD-1 silencing improves anti-tumor activities of human mesothelin-targeted CAR T cells. Hum Immunol. 2021;82:130–8.

    Article  CAS  PubMed  Google Scholar 

  87. Ping Y, Li F, Nan S, Zhang D, Shi X, Shan J, Zhang Y. Augmenting the effectiveness of CAR-T cells by enhanced self-delivery of PD-1-neutralizing scFv. Front Cell Dev Biol. 2020;8:803.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Dong E, Yue X-Z, Shui L, Liu B-R, Li Q-Q, Yang Y, Luo H, Wang W, Yang H-S. IFN-γ surmounts PD-L1/PD1 inhibition to CAR-T cell therapy by upregulating ICAM-1 on tumor cells. Signal Transduct Target Ther. 2021;6:20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Serganova I, Moroz E, Cohen I, Moroz M, Mane M, Zurita J, Shenker L, Ponomarev V, Blasberg R. Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade. Mol Therapy Oncolytics. 2017;4:41–54.

    Article  CAS  Google Scholar 

  90. Rafiq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes DJ, Song M, Miele MM, Li Z, Wang P, Yan S, Xiang J, Ma X, Seshan VE, Hendrickson RC, Liu C, Brentjens RJ. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018;36:847–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kalinin RS, Ukrainskaya VM, Chumakov SP, Moysenovich AM, Tereshchuk VM, Volkov DV, Pershin DS, Maksimov EG, Zhang H, Maschan MA, Rubtsov YP, Stepanov AV. Engineered removal of PD-1 from the surface of CD19 CAR-T cells results in increased activation and diminished survival. Front Mol Biosci. 2021;8: 745286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hauth F, Ho AY, Ferrone S, Duda DG. Radiotherapy to enhance chimeric antigen receptor T-cell therapeutic efficacy in solid tumors: a narrative review. JAMA Oncol. 2021;7:1051–9.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Minn I, Rowe SP, Pomper MG. Enhancing CAR T-cell therapy through cellular imaging and radiotherapy. Lancet Oncol. 2019;20:e443–51.

    Article  CAS  PubMed  Google Scholar 

  94. Qin VM, Haynes NM, D’Souza C, Neeson PJ, Zhu JJ. CAR-T plus radiotherapy: a promising combination for immunosuppressive tumors. Front Immunol. 2021;12: 813832.

    Article  CAS  PubMed  Google Scholar 

  95. DeSelm C, Palomba ML, Yahalom J, Hamieh M, Eyquem J, Rajasekhar VK, Sadelain M. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther. 2018;26:2542–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Weiss T, Weller M, Guckenberger M, Sentman CL, Roth P. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. Cancer Res. 2018;78:1031–43.

    Article  CAS  PubMed  Google Scholar 

  97. Qu C, Ping N, Kang L, Liu H, Qin S, Wu Q, Chen X, Zhou M, Xia F, Ye A, Kong D, Li C, Yu L, Wu D, Jin Z. Radiation priming chimeric antigen receptor T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma with high tumor burden. J Immunother. 2020;43:32–7.

    Article  CAS  PubMed  Google Scholar 

  98. Jin H, Lee JS, Kim DC, Ko YS, Lee GW, Kim HJ Increased extracellular adenosine in radiotherapy-resistant breast cancer cells enhances tumor progression through A2AR-Akt-β-catenin signaling, Cancers 13 (2021).

  99. Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy, Nature reviews. Clin Oncol. 2021;18:9–34.

    Google Scholar 

  100. Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, Maus MV, Fraietta JA, Zhao Y, June CH. Dominant-negative TGF-β receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther. 2018;26:1855–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Narayan V, Barber-Rotenberg J, Fraietta J, Hwang W-T, Lacey SF, Plesa G, Carpenter EL, Maude SL, Lal P, Vapiwala N, Melenhorst JJ, Sebro R, Farwell M, Moniak M, Gilmore J, Lledo L, Dengel K, June CH, Haas NB A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer, 39; 2021, 125–125.

  102. Johnson LR, Lee DY, Eacret JS, Ye D, June CH, Minn AJ. The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function. Cell. 2021;184:4981-4995.e4914.

    Article  CAS  PubMed  Google Scholar 

  103. Tanaka M, Tashiro H, Omer B, Lapteva N, Ando J, Ngo M, Mehta B, Dotti G, Kinchington PR, Leen AM, Rossig C, Rooney CM. Vaccination targeting native receptors to enhance the function and proliferation of chimeric antigen receptor (CAR)-modified T cells. Clin Cancer Res. 2017;23:3499–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lynn RC, Poussin M, Kalota A, Feng Y, Low PS, Dimitrov DS, Powell DJ. Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells. Blood. 2015;125:3466–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Biberacher V, Decker T, Oelsner M, Wagner M, Bogner C, Schmidt B, Kreitman RJ, Peschel C, Pastan I, Meyer C Zum Büschenfelde, I. Ringshausen, The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-βII depletion, Haematologica 97; 2012, 771–779.

  107. Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, Mi T, Switzer K, Singh H, Huls H, Lee DA, Heimberger AB, Champlin RE, Cooper LJ. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 2015;75:3505–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernandez-Mateos J, Khan K, Lampis A, Eason K, Huntingford I, Burke R, Rata M, Koh DM, Tunariu N, Collins D, Hulkki-Wilson S, Ragulan C, Spiteri I, Moorcraft SY, Chau I, Rao S, Watkins D, Fotiadis N, Bali M, Darvish-Damavandi M, Lote H, Eltahir Z, Smyth EC, Begum R, Clarke PA, Hahne JC, Dowsett M, de Bono J, Workman P, Sadanandam A, Fassan M, Sansom OJ, Eccles S, Starling N, Braconi C, Sottoriva A, Robinson SP, Cunningham D, Valeri N. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018;359:920–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bar-Ephraim YE, Kretzschmar K, Clevers H. Organoids in immunological research. Nat Rev Immunol 2020;20(5):279–293. https://doi.org/10.1038/s41577-019-0248-y.

  110. Tchou J, Zhao Y, Levine BL, Zhang PJ, Davis MM, Melenhorst JJ, Kulikovskaya I, Brennan AL, Liu X, Lacey SF, Posey AD Jr, Williams AD, So A, Conejo-Garcia JR, Plesa G, Young RM, McGettigan S, Campbell J, Pierce RH, Matro JM, DeMichele AM, Clark AS, Cooper LJ, Schuchter LM, Vonderheide RH, June CH. Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer. Cancer Immunol Res. 2017;5:1152–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Thanks to all the authors who participated in the design and data analysis of this paper, Key Laboratory of Digestive System Oncology of Gansu Province and Lanzhou University Second Hospital for providing convenience.

Funding

This work was supported by Special Research Project of Lanzhou University Serving the Economic and Social Development of Gansu Province (054000282), Lanzhou Talent Innovation and Entrepreneurship Project (2020-RC-38), Fundamental Research Funds for the Central Universities (lzujbky-2020-kb14) and Ministry of Economic Development and Trade, Government of Alberta.

Author information

Authors and Affiliations

  1. The Second Clinical Medical School of Lanzhou University, The Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China

    Cheng-Dong Huo, Yan-Mei Gu, Dai-Jun Wang & Yu-Min Li

  2. Gansu Provincial Hospital, Lanzhou, Gansu, China

    Jie Yang

Authors
  1. Cheng-Dong Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan-Mei Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dai-Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Xia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Min Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Min Li.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval and Informed consent

Not available.

Additional information

Publisher's Note

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

Jie Yang is the co-first author.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huo, CD., Yang, J., Gu, YM. et al. Overcome tumor relapse in CAR T cell therapy. Clin Transl Oncol 24, 1833–1843 (2022). https://doi.org/10.1007/s12094-022-02847-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-022-02847-2

Keywords

Search

Navigation