SpringerLink
Log in

Current Challenges and Potential Strategies for Designing a New Generation of Chimeric Antigen Receptor-T cells with High Anti-tumor Activity in Solid Tumors

  • Published:
Current Tissue Microenvironment Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Cancer immunotherapy is a treatment made by activating and strengthening the effects of immune system cells that destroy atypical cells like cancer in the body, such as natural killer cells and cytotoxic T lymphocytes. Solid tumors are abnormal tissue masses that usually do not contain areas of cyst or fluid. The cytotoxicity effect of chimeric antigen receptor encoding T (CAR-T) cell on solid tumors needs to be investigated considering the tumor microenvironment, signaling, and cytokine/chemokine release and working mechanism of CAR-T cells of each cancer type. This review aims to discuss new generations of CAR that can be targeted against solid tumors.

Recent Findings

Considering the findings, this review reports that the mechanism of action that inhibits CAR-T cells includes tumor microenvironment, differentiation efficiency of cells, and tumor antigen heterogeneity, causing impaired anti-cancer action for solid tumors. In this review, the literature was reviewed to propose new-generation CAR-T cells that may show an improved anti-tumor effect against 14 solid tumor types.

Summary

This review suggests different CAR-T cell approaches against solid tumors. Here, we proposed that there are many different CAR-T cell approaches that are yet to be investigated against solid tumors to show promising anti-tumor capacity.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lanitis E, Poussin M, Hagemann IS, Coukos G, Sandaltzopoulos R, Scholler N, Powell DJ. Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. Mol Ther. 2012;20:633–43. https://doi.org/10.1038/mt.2011.256.

    Article  CAS  PubMed  Google Scholar 

  2. •• Karlsson H, Svensson E, Gigg C, Jarvius M, Olsson-Strömberg U, Savoldo B, Dotti G, Loskog A. Evaluation of intracellular signaling downstream chimeric antigen receptors. PLoS ONE. 2015; https://doi.org/10.1371/journal.pone.0144787. Review suggesting other signaling pathways be considered while designing the next-generation CAR.

  3. Oluwole OO, Davila ML. At The Bedside: Clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies. J Leukoc Biol. 2016;100:1265–72. https://doi.org/10.1189/jlb.5bt1115-524r.

    Article  CAS  PubMed  Google Scholar 

  4. •• Zabel M, Tauber PA, Pickl WF. The making and function of CAR cells. Immunol Lett. 2019; https://doi.org/10.1016/j.imlet.2019.06.002. It gives detailed information about the construction and function of CAR cells.

  5. Bao F, Wan W, He T, Qi F, Liu G, Hu K, Lu XA, Yang P, Dong F, Wang J, **g H. Autologous CD19-directed chimeric antigen receptor-T cell is an effective and safe treatment to refractory or relapsed diffuse large B-cell lymphoma. Cancer Gene Ther. 2019;26:248–55. https://doi.org/10.1038/s41417-018-0073-7.

    Article  CAS  PubMed  Google Scholar 

  6. •• Gauthier J, Yakoub-Agha I. Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: clinical data to date, current limitations and perspectives. Curr Res Transl Med. 2017; https://doi.org/10.1016/j.retram.2017.08.003. In the clinical practice of CAR-T cell therapy, the effect of CD19-targeted CAR-T cells on hematological and solid tumors has been demonstrated.

  7. Ghobadi A. Chimeric antigen receptor T cell therapy for non-Hodgkin lymphoma. Curr Res Transl Med. 2018;66:43–9. https://doi.org/10.1016/j.retram.2018.03.005.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zhylko A, Winiarska M, Graczyk-Jarzynka A. The great war of today: modifications of car-t cells to effectively combat malignancies. Cancers. 2020; https://doi.org/10.3390/cancers12082030.

  9. Rossig C. CAR T cell immunotherapy in hematology and beyond. Clin Immunol. 2018;186:54–8. https://doi.org/10.1016/j.clim.2017.09.016.

    Article  CAS  PubMed  Google Scholar 

  10. Grupp S. Beginning the CAR T cell therapy revolution in the US and EU. Curr Res Transl Med. 2018;66:62–4. https://doi.org/10.1016/j.retram.2018.03.004.

    Article  PubMed  Google Scholar 

  11. Yassine F, Iqbal M, Murthy H, Kharfan-Dabaja MA, Chavez JC. Real world experience of approved chimeric antigen receptor T-cell therapies outside of clinical trials. Curr Res Transl Med. 2020;68:159–70. https://doi.org/10.1016/j.retram.2020.05.005.

    Article  PubMed  Google Scholar 

  12. • Kiesgen S, Chicaybam L, Chintala NK, Adusumilli PS. Chimeric antigen receptor (CAR) T-cell therapy for thoracic malignancies. J Thorac Oncol. 2018; https://doi.org/10.1016/j.jtho.2017.10.001. Experimental stages of CAR-T cell therapy for CD19-targeted thoracic malignancies are shown.

  13. Mollanoori H, Shahraki H, Rahmati Y, Teimourian S. CRISPR/Cas9 and CAR-T cell, collaboration of two revolutionary technologies in cancer immunotherapy, an instruction for successful cancer treatment. Hum Immunol. 2018;79:876–82. https://doi.org/10.1016/j.humimm.2018.09.007.

    Article  CAS  PubMed  Google Scholar 

  14. •• Baybutt TR, Flickinger JC, Caparosa EM, Snook AE. Advances in chimeric antigen receptor T-cell therapies for solid tumors. Clin Pharmacol Ther. 2019; https://doi.org/10.1002/cpt.1280. Recent advances in CAR-T cell therapy for solid tumors are noted.

  15. Boyiadzis MM, Dhodapkar MV, Brentjens RJ, Kochenderfer JN, Neelapu SS, Maus MV, Porter DL, Maloney DG, Grupp SA, Mackall CL, June CH, Bishop MR. Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. J Immunother Cancer. 2018;6:137. https://doi.org/10.1186/s40425-018-0460-5.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Siddiqi HF, Staser KW, Nambudiri VE. Research techniques made simple: CAR T-cell therapy. J Investig Dermatol. 2018;138:2501–2504.e1. https://doi.org/10.1016/j.jid.2018.09.002.

    Article  CAS  PubMed  Google Scholar 

  17. Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, Kobold S. Teaching an old dog new tricks: next-generation CAR T cells. Br J Cancer. 2019;120:26–37. https://doi.org/10.1038/s41416-018-0325-1.

    Article  CAS  PubMed  Google Scholar 

  18. Ramachandran M, Dimberg A, Essand M. The cancer-immunity cycle as rational design for synthetic cancer drugs: novel DC vaccines and CAR T-cells. Semin Cancer Biol. 2017;45:23–35. https://doi.org/10.1016/j.semcancer.2017.02.010.

    Article  CAS  PubMed  Google Scholar 

  19. • Mirzaei HR, Rodriguez A, Shepphird J, Brown CE, Badie B. Chimeric antigen receptors T cell therapy in solid tumor: challenges and clinical applications. Front Immunol. 2017; https://doi.org/10.3389/fimmu.2017.01850. The review states that the modifications to be developed in designing CAR-T cells in solid tumors are essential in clinical applications.

  20. Hinrichs CS, Restifo NP. Reassessing target antigens for adoptive T-cell therapy. Nat Biotechnol. 2013;31:999–1008. https://doi.org/10.1038/nbt.2725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. •• Yu S, Li A, Liu Q, Li T, Yuan X, Han X, Wu K. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017; https://doi.org/10.1186/s13045-017-0444-9. The activities of CAR-T cells developed in new-generation designs were evaluated.

  22. •• Ma S, Li X, Wang X, Cheng L, Li Z, Zhang C, et al. Current progress in car-t cell therapy for solid tumors. Int J Biol Sci. 2019; https://doi.org/10.7150/ijbs.34213. The review focused on improving CAR-T cell design and removing the negative effects of the tumor microenvironment on solid tumors.

  23. Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21:177–84. https://doi.org/10.1016/j.ceb.2008.12.010.

    Article  CAS  PubMed  Google Scholar 

  24. Olayioye MA. NEW EMBO MEMBERS’ REVIEW: The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67. https://doi.org/10.1093/emboj/19.13.3159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sasada T, Azuma K, Ohtake J, Fujimoto Y. Immune responses to epidermal growth factor receptor (EGFR) and their application for cancer treatment. Front Pharmacol. 2016; https://doi.org/10.3389/fphar.2016.00405.

  26. Yano S, Kondo K, Yamaguchi M, Richmond G, Hutchison M, Wakeling A, Averbuch S, Wadsworth P. Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase ınhibition. Anticancer Res. 2003;23:3639–50.

    CAS  PubMed  Google Scholar 

  27. Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist. 2002;7:31–9. https://doi.org/10.1634/theoncologist.7-suppl_4-31.

    Article  CAS  PubMed  Google Scholar 

  28. Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, Makino K, Saya H, Hirano H, Kuratsu J, Oka K, Ishimaru Y, Ushio Y. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003;63:6962–70.

    CAS  PubMed  Google Scholar 

  29. Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60(5):1383–7.

    CAS  PubMed  Google Scholar 

  30. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA. 1992;89:2965–9. https://doi.org/10.1073/pnas.89.7.2965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bigner DD. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA. 1990;87:4207–11. https://doi.org/10.1073/pnas.87.11.4207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, Nace AK, Dentchev T, Thekkat P, Loew A, Boesteanu AC, Cogdill AP, Chen T, Fraietta JA, Kloss CC, Posey AD Jr, Engels B, Singh R, Ezell T, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015;7:275ra22. https://doi.org/10.1126/scitranslmed.aaa4963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Thaci B, Brown CE, Binello E, Werbaneth K, Sampath P, Sengupta S. Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy. Neuro-Oncol. 2014;16:1304–12. https://doi.org/10.1093/neuonc/nou045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. • Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016; https://doi.org/10.1056/nejmoa1610497. The research provides excellent insight into the targeted design of CAR-T on multifocal glioblastoma.

  35. Ahmed N, Ratnayake M, Savoldo B, Perlaky L, Dotti G, Wels WS, Bhattacharjee MB, Gilbertson RJ, Shine HD, Weiss HL, Rooney CM, Heslop HE, Gottschalk S. Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. 2007;67:5957–64. https://doi.org/10.1158/0008-5472.CAN-06-4309.

    Article  CAS  PubMed  Google Scholar 

  36. Ho M, Bera TK, Willingham MC, Onda M, Hassan R, FitzGerald D, Pastan I. Mesothelin expression in human lung cancer. Clin Cancer Res. 2007;13:1571–5. https://doi.org/10.1158/1078-0432.CCR-06-2161.

    Article  CAS  PubMed  Google Scholar 

  37. Li M, Bharadwaj U, Zhang R, Zhang S, Mu H, Fisher WE, Brunicardi FC, Chen C, Yao Q. Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer. Mol Cancer Ther. 2008;7:286–96. https://doi.org/10.1158/1535-7163.MCT-07-0483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen L, Linsley PS, Hellström KE. Costimulation of T cells for tumor immunity. Immunol Today. 1993;14:483–6. https://doi.org/10.1016/0167-5699(93)90262-J.

    Article  CAS  PubMed  Google Scholar 

  39. Su Y, Huang X, Raskovalova T, Zacharia L, Lokshin A, Jackson E, Gorelik E. Cooperation of adenosine and prostaglandin E2 (PGE2) in amplification of cAMP-PKA signaling and immunosuppression. Cancer Immunol, Immunother. 2008;57:1611–23. https://doi.org/10.1007/s00262-008-0494-5.

    Article  CAS  PubMed  Google Scholar 

  40. •• Yu S, Li A, Liu Q, Li T, Yuan X, Han X, Wu K. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017; https://doi.org/10.1186/s13045-017-0444-9. The development and outcomes of new strategies against the recurrence of antigen loss for B cell acute lymphoblastic leukemia (B-ALL) have been well evaluated.

  41. John LB, Devaud C, Duong CPM, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, Darcy PK. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013;19:5636–46. https://doi.org/10.1158/1078-0432.CCR-13-0458.

    Article  CAS  PubMed  Google Scholar 

  42. Newick K, O’brien S, Sun J, Kapoor V, Maceyko S, Lo A, et al. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase a localization. Cancer Immunol Res. 2016;4:541–51. https://doi.org/10.1158/2326-6066.CIR-15-0263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. • Chmielewski M, Hombach AA, Abken H. Of CARs and TRUCKs: Chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev. 2014; https://doi.org/10.1111/imr.12125. Clinical evaluation was performed against solid tumors with cancer cell phenotypes.

  44. Chmielewski M, Kopecky C, Hombach AA, Abken H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 2011;71:5697–706. https://doi.org/10.1158/0008-5472.CAN-11-0103.

    Article  CAS  PubMed  Google Scholar 

  45. • Mohammed S, Sukumaran S, Bajgain P, Watanabe N, Heslop HE, Rooney CM, et al. Improving chimeric antigen receptor-modified T cell function by reversing the ımmunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther. 2017; https://doi.org/10.1016/j.ymthe.2016.10.016. The research demonstrates the effects of a PSCA-expressing tumor characterized by an immunosuppressive environment for IL-4 in the treatment of pancreatic cancer.

  46. Yang S, Ji Y, Gattinoni L, Zhang L, Yu Z, Restifo NP, Rosenberg SA, Morgan RA. Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails. Cancer Immunol Immunother. 2013;62:727–36. https://doi.org/10.1007/s00262-012-1378-2.

    Article  CAS  PubMed  Google Scholar 

  47. • Koneru M, Purdon TJ, Spriggs D, Koneru S, Brentjens RJ. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. OncoImmunology. 2015; https://doi.org/10.4161/2162402X.2014.994446. The development and results of a new generation of chimeric antigen receptor targeting for ovarian cancer therapy have been well covered.

  48. Brown CE, Vishwanath RP, Aguilar B, Starr R, Najbauer J, Aboody KS, Jensen MC. Tumor-derived chemokine MCP-1/CCL2 ıs sufficient for mediating tumor tropism of adoptively transferred T cells. J Immunol. 2007;179:3332–41. https://doi.org/10.4049/jimmunol.179.5.3332.

    Article  CAS  PubMed  Google Scholar 

  49. Pedersen MW, Meltorn M, Damstrup L, Poulsen HS. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol. 2001;12:745–60. https://doi.org/10.1023/A:1011177318162.

    Article  CAS  PubMed  Google Scholar 

  50. • Singh N, Perazzelli J, Grupp SA, Barrett DM. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci Transl Med. 2016; https://doi.org/10.1126/scitranslmed.aad5222. The efficacy of selected T cells enriched with interleukin-7 (IL-7) and IL-15 has been demonstrated by cyclophosphamide and cytarabine chemotherapy.

  51. Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, Rossig C, Russell HV, Diouf O, Liu E, Liu H, Wu MF, Gee AP, Mei Z, Rooney CM, Heslop HE, Brenner MK. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011;118:6050–6. https://doi.org/10.1182/blood-2011-05-354449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, Yvon E, Weiss HL, Liu H, Rooney CM, Heslop HE, Brenner MK. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14:1264–70. https://doi.org/10.1038/nm.1882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, ınterleukin-2, and ısotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–34. https://doi.org/10.1056/nejmoa0911123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schönfeld K, Koch J, Dotti G, Heslop HE, Gottschalk S, Wels WS, Baker ML, Ahmed N. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucl Acids. 2013;2:e105. https://doi.org/10.1038/mtna.2013.32.

    Article  CAS  Google Scholar 

  55. 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. https://doi.org/10.1038/mt.2010.24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Park JR, DiGiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther. 2007;15:825–33. https://doi.org/10.1038/sj.mt.6300104.

    Article  CAS  PubMed  Google Scholar 

  57. Tanyi JL, Haas AR, Beatty GL, Morgan MA, Stashwick CJ, O’Hara MH, … June CH. Abstract CT105: safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CART-meso) in patients with mesothelin expressing cancers 2015. https://doi.org/10.1158/1538-7445.am2015-ct105

  58. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2015;21:687–92. https://doi.org/10.1158/1078-0432.CCR-14-1860.

    Article  CAS  PubMed  Google Scholar 

  59. Palazón A, Aragonés J, Morales-Kastresana A, Ortiz De Landázuri M, Melero I. Molecular pathways: hypoxia response in immune cells fighting or promoting cancer. Clin Cancer Res. 2012;18:1207–13. https://doi.org/10.1158/1078-0432.CCR-11-1591.

    Article  CAS  PubMed  Google Scholar 

  60. Bonecchi R, Locati M, Mantovani A. Chemokines and cancer: a fatal attraction. Cancer Cell. 2011;19:434–5. https://doi.org/10.1016/j.ccr.2011.03.017.

    Article  CAS  PubMed  Google Scholar 

  61. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475:222–5. https://doi.org/10.1038/nature10138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. •• Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015; https://doi.org/10.1038/nm.3833. The capacity to degrade the extracellular matrix by increasing heparanase enzyme deprivation in CAR-T cells was investigated in detail.

  63. •• Moon EK, Wang LC, Dolfi DV, Wilson CB, Ranganathan R, Sun J, et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res. 2014; https://doi.org/10.1158/1078-0432.CCR-13-2627. The research has evaluated the inhibition of similar tumor effects in genetically engineered cytotoxic T cells expressing tumor-related CAR.

  64. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. https://doi.org/10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. •• Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 2016; https://doi.org/10.1158/0008-5472.CAN-15-2524. The potential of PD1-CD28 administration on solid tumors to increase CAR-T cell activity has been evaluated.

  66. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Investig. 2007;117:1147–54. https://doi.org/10.1172/JCI31178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Beatty GL, O’Hara M. Chimeric antigen receptor-modified T cells for the treatment of solid tumors: defining the challenges and next steps. Pharmacol Ther. 2016;166:30–9. https://doi.org/10.1016/j.pharmthera.2016.06.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Feng K, Guo Y, Dai H, Wang Y, Li X, Jia H, Han W. Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. Sci China Life Sci. 2016;59:468–79. https://doi.org/10.1007/s11427-016-5023-8.

    Article  CAS  PubMed  Google Scholar 

  69. Rafiq S, Purdon TJ, Daniyan AF, Koneru M, Dao T, Liu C, Scheinberg DA, Brentjens RJ. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms tumor 1 antigen. Leukemia. 2017;31:1788–97. https://doi.org/10.1038/leu.2016.373.

    Article  CAS  PubMed  Google Scholar 

  70. Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, Lim WA. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell. 2016;164:770–9. https://doi.org/10.1016/j.cell.2016.01.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Di Stasi A, Tey S-K, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011;365:1673–83. https://doi.org/10.1056/nejmoa1106152.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Stavrou M, Philip B, Traynor-White C, Davis CG, Onuoha S, Cordoba S, Thomas S, Pule M. A rapamycin-activated caspase 9-based suicide gene. Mol Ther. 2018;26:1266–76. https://doi.org/10.1016/j.ymthe.2018.03.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. D’Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M. CAR-T cells: The long and winding road to solid tumors review-article. Cell Death Dis. 2018;9:282. https://doi.org/10.1038/s41419-018-0278-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011. https://doi.org/10.1038/mto.2016.11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Curran KJ, Pegram HJ, Brentjens RJ. Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med. 2012;14:405–15. https://doi.org/10.1002/jgm.2604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. • Lamers CHJ, Sleijfer S, Van Steenbergen S, Van Elzakker P, Van Krimpen B, Groot C, et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013; https://doi.org/10.1038/mt.2013.17. Carboxy-anhydrase – IX (CAIX) has been shown to express CAR in clinical practice and evaluation in patients with renal cell carcinoma.

  77. Thistlethwaite FC, Gilham DE, Guest RD, Rothwell DG, Pillai M, Burt DJ, Byatte AJ, Kirillova N, Valle JW, Sharma SK, Chester KA, Westwood NB, Halford SER, Nabarro S, Wan S, Austin E, Hawkins RE. 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. 2017;66:1425–36. https://doi.org/10.1007/s00262-017-2034-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ruella M, Maus MV. Catch me if you can: leukemia escape after CD19-directed T cell ımmunotherapies. Comput Struct Biotechnol J. 2016;14:357–62. https://doi.org/10.1016/j.csbj.2016.09.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, 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. 2017; https://doi.org/10.1126/scitranslmed.aaa0984.

  80. Lamers CHJ, Gratama JW, Pouw NMC, Langeveld SCL, Van Krimpen BA, Kraan J, et al. Parallel detection of transduced T lymphocytes after immunogene therapy of renal cell cancer by flow cytometry and real-time polymerase chain reaction: ımplications for loss of transgene expression. Human Gene Ther. 2005;16:1452–62. https://doi.org/10.1089/hum.2005.16.1452.

    Article  CAS  Google Scholar 

  81. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82. https://doi.org/10.1200/JCO.2014.59.4358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Han D, Xu Z, Zhuang Y, Ye Z, Qian Q. Current progress in CAR-T cell therapy for hematological malignancies. J Cancer. 2021;12:326–34. https://doi.org/10.7150/JCA.48976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Stephan MT, Ponomarev V, Brentjens RJ, Chang AH, Dobrenkov KV, Heller G, Sadelain M. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med. 2007;13:1440–9. https://doi.org/10.1038/nm1676.

    Article  CAS  PubMed  Google Scholar 

  84. Krause A, Guo HF, Latouche JB, Tan C, Cheung NKV, Sadelain M. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med. 1998;188:619–26. https://doi.org/10.1084/jem.188.4.619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Celik H, Sciandra M, Flashner B, Gelmez E, Kayraklloǧlu N, Allegakoen DV, et al. Clofarabine inhibits Ewing sarcoma growth through a novel molecular mechanism involving direct binding to CD99. Oncogene. 2018;37:2181–96. https://doi.org/10.1038/s41388-017-0080-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhou R, Yazdanifar M, Roy LD, Whilding LM, Gavrill A, Maher J, Mukherjee P. CAR T cells targeting the tumor MUC1 glycoprotein reduce triple-negative breast cancer growth. Front Immunol. 2019; https://doi.org/10.3389/fimmu.2019.01149.

  87. Nath S, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20:332–42. https://doi.org/10.1016/j.molmed.2014.02.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Schroten H, Hanisch FG, Plogmann R, Hacker J, Uhlenbruck G, Nobis-Bosch R, Wahn V. Inhibition of adhesion of S-fimbriated Escherichia coli to buccal epithelial cells by human milk fat globule membrane components: a novel aspect of the protective function of mucins in the nonimmunoglobulin fraction. Infect Immun. 1992;60:2893–9. https://doi.org/10.1128/iai.60.7.2893-2899.1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yolken RH, Peterson JA, Vonderfecht SL, Fouts ET, Midthun K, Newburg DS. Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis. J Clin Investig. 1992;90:1984–91. https://doi.org/10.1172/JCI116078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dalziel M, Whitehouse C, McFarlane I, Brockhausen I, Gschmeissner S, Schwientek T, Clausen H, Burchell JM, Taylor-Papadimitriou J. The relative activities of the C2GnT1 and ST3Gal-I glycosyltransferases determine O-glycan structure and expression of a tumor-associated epitope on MUC1. J Biol Chem. 2001;276:11007–15. https://doi.org/10.1074/jbc.M006523200.

    Article  CAS  PubMed  Google Scholar 

  91. Roy LD, Dillon LM, Zhou R, Moore LJ, Livasy C, El-Khoury JM, et al. A tumor specific antibody to aid breast cancer screening in women with dense breast tissue. Genes Cancer. 2017; https://doi.org/10.18632/genesandcancer.134.

  92. **g X, Liang H, Hao C, Yang X, Cui X. Overexpression of MUC1 predicts poor prognosis in patients with breast cancer. Oncol Rep. 2019;41:801–10. https://doi.org/10.3892/or.2018.6887.

    Article  CAS  PubMed  Google Scholar 

  93. Sivaganesh V, Promi N, Maher S, Peethambaran B. Emerging immunotherapies against novel molecular targets in breast cancer. Int J Mol Sci. 2021; https://doi.org/10.3390/ijms22052433.

  94. Bębnowska D, Grywalska E, Niedźwiedzka-Rystwej P, Sosnowska-Pasiarska B, Smok-Kalwat J, Pasiarski M, Góźdź S, Roliński J, Polkowski W. CAR-T cell therapy-an overview of targets in gastric cancer. J Clin Med. 2020;9(6):1894. https://doi.org/10.3390/jcm9061894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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. https://doi.org/10.1158/1078-0432.CCR-14-1421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen N, Morello A, Tano Z, Adusumilli PS. CAR T-cell intrinsic PD-1 checkpoint blockade: a two-in-one approach for solid tumor immunotherapy. OncoImmunology. 2017;6:e1273302. https://doi.org/10.1080/2162402X.2016.1273302.

    Article  CAS  PubMed  Google Scholar 

  97. Dannenfelser R, Allen GM, VanderSluis B, Koegel AK, Levinson S, Stark SR, Yao V, Tadych A, Troyanskaya OG, Lim WA. Discriminatory power of combinatorial antigen recognition in cancer T cell therapies. Cell Syst. 2020;11:215–228.e5. https://doi.org/10.1016/j.cels.2020.08.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA. 2012;109:17561–6. https://doi.org/10.1073/pnas.1215397109.

    Article  PubMed  PubMed Central  Google Scholar 

  99. •• Gulden G, Sert B, Teymur T, Ay Y, Tiryaki NN, Mishra AK, et al. CAR-T cells with phytohemagglutinin (PHA) provide anti-cancer capacity with better proliferation, rejuvenated effector memory, and reduced exhausted T cell frequencies. Vaccines. 2023;11(2):313. The first paper of PHA with CAR-T cell shows anti-cancer capacity, strengthening effector memory, and reduced exhaustion of CAR-T cell.

Download references

Acknowledgements

I would like to thank my dear husband, Dr. Royal Khankishiyev, who supported me in this study.

Author information

Authors and Affiliations

  1. Molecular Biology, Institute of Science and Technology, Üsküdar University, Istanbul, Turkey

    Dilara Sahan Khankishiyev, Gamze Gulden & Berranur Sert

  2. Transgenic Cell Technologies and Epigenetic Application and Research Center (TRGENMER), Üsküdar University, Istanbul, Turkey

    Dilara Sahan Khankishiyev, Gamze Gulden, Berranur Sert & Cihan Tastan

  3. Molecular Biology and Genetics Department, Faculty of Engineering and Natural Science, Üsküdar University, Istanbul, Turkey

    Cihan Tastan

Authors
  1. Dilara Sahan Khankishiyev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gamze Gulden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Berranur Sert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cihan Tastan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cihan Tastan.

Ethics declarations

Conflict of Interest

The authors declare 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

Springer Nature or its licensor (e.g. a society or other partner) 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

Sahan Khankishiyev, D., Gulden, G., Sert, B. et al. Current Challenges and Potential Strategies for Designing a New Generation of Chimeric Antigen Receptor-T cells with High Anti-tumor Activity in Solid Tumors. Curr. Tissue Microenviron. Rep. 4, 1–16 (2023). https://doi.org/10.1007/s43152-023-00043-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43152-023-00043-0

Keywords

Search

Navigation