Skip to main content

Advertisement

SpringerLink
Log in

CAR T cell therapy as a promising approach in cancer immunotherapy: challenges and opportunities

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Background

Chimeric antigen receptor (CAR)-modified T cell therapy has shown great potential in the immunotherapy of patients with hematologic malignancies. In spite of this striking achievement, there are still major challenges to overcome in CAR T cell therapy of solid tumors, including treatment-related toxicity and specificity. Also, other obstacles may be encountered in tackling solid tumors, such as their immunosuppressive microenvironment, the heterogeneous expression of cell surface markers, and the cumbersome arrival of T cells at the tumor site. Although several strategies have been developed to overcome these challenges, aditional research aimed at enhancing its efficacy with minimum side effects, the design of precise yet simplified work flows and the possibility to scale-up production with reduced costs and related risks is still warranted.

Conclusions

Here, we review main strategies to establish a balance between the toxicity and activity of CAR T cells in order to enhance their specificity and surpass immunosuppression. In recent years, many clinical studies have been conducted that eventually led to approved products. To date, the FDA has approved two anti-CD19 CAR T cell products for non-Hodgkin lymphoma therapy, i.e., axicbtagene ciloleucel and tisagenlecleucel. With all the advances that have been made in the field of CAR T cell therapy for hematologic malignancies therapy, ongoing studies are focused on optimizing its efficacy and specificity, as well as reducing the side effects. Also, the efforts are poised to broaden CAR T cell therapeutics for other cancers, especially solid tumors.

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
Fig. 4

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. A. Ribas, J.D. Wolchok, Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. S.A. Rosenberg, N.P. Restifo, Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. L. de la Cruz-Merino, E. Grande-Pulido, A. Albero-Tamarit, M.E, .C.-M. de Villena, Cancer and immune response: old and new evidence for future challenges. Oncologist 13, 1246–1254 (2008)

    PubMed  Google Scholar 

  4. M.E. Dudley, J.R. Wunderlich, P.F. Robbins, J.C. Yang, P. Hwu, D.J. Schwartzentruber, S.L. Topalian, R. Sherry, N.P. Restifo, A.M. Hubicki, Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. L. Ni, J. Lu, Interferon gamma in cancer immunotherapy. Cancer Med. 7, 4509–4516 (2018)

    PubMed  PubMed Central  Google Scholar 

  6. H.J. Jackson, S. Rafiq, R.J. Brentjens, Driving CAR T-cells forward. Nature Rev. Clin. Oncol. 13, 370 (2016)

    CAS  Google Scholar 

  7. G. Lipowska-Bhalla, D.E. Gilham, R.E. Hawkins, D.G. Rothwell, Targeted immunotherapy of cancer with CAR T cells: achievements and challenges. Cancer Immunol. Immunother. 61, 953–962 (2012)

    CAS  PubMed  Google Scholar 

  8. C.H. June, R.S. O’Connor, O.U. Kawalekar, S. Ghassemi, M.C. Milone, CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018)

    CAS  PubMed  Google Scholar 

  9. S. Srivastava, S.R. Riddell, Engineering CAR-T cells: design concepts. Trends Immunol. 36, 494–502 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Z.L. Chang, M.H. Lorenzini, X. Chen, U. Tran, N.J. Bangayan, Y.Y. Chen, Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nature Chem. Biol. 14, 317–324 (2018). https://doi.org/10.1038/nchembio.2565

    Article  CAS  Google Scholar 

  11. B. Savoldo, C.A. Ramos, E. Liu, M.P. Mims, M.J. Keating, G. Carrum, R.T. Kamble, C.M. Bollard, A.P. Gee, Z. Mei, CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822–1826 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. K.S. Kahlon, C. Brown, L.J. Cooper, A. Raubitschek, S.J. Forman, M.C. Jensen, Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 64, 9160–9166 (2004)

    CAS  PubMed  Google Scholar 

  13. C.E. Brown, D. Alizadeh, R. Starr, L. Weng, J.R. Wagner, A. Naranjo, J.R. Ostberg, M.S. Blanchard, J. Kilpatrick, J. Simpson, Regression of glioblastoma after chimeric antigen receptor T-cell therapy. New Engl. J. Med. 375, 2561–2569 (2016). https://doi.org/10.1056/NEJMoa1610497

    Article  CAS  PubMed  Google Scholar 

  14. T. Thayaparan, R.M. Petrovic, D.Y. Achkova, T. Zabinski, D.M. Davies, A. Klampatsa, A.C. Parente-Pereira, L.M. Whilding, S.J. van der Stegen, N. Woodman, CAR T-cell immunotherapy of MET-expressing malignant mesothelioma. Oncoimmunology 6, e1363137 (2017)

    PubMed  PubMed Central  Google Scholar 

  15. K. Kudo, C. Imai, P. Lorenzini, T. Kamiya, K. Kono, A.M. Davidoff, W.J. Chng, D. Campana, T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 74, 93–103 (2014)

    CAS  PubMed  Google Scholar 

  16. Y.J. Xie, M. Dougan, N. Jailkhani, J. Ingram, T. Fang, L. Kummer, N. Momin, N. Pishesha, S. Rickelt, R.O. Hynes, Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc. Natl. Acad. Sci. USA 116, 7624–7631 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. S. De Munter, J. Ingels, G. Goetgeluk, S. Bonte, M. Pille, K. Weening, T. Kerre, H. Abken, B. Vandekerckhove, Nanobody based dual specific CARs. Int. J. Mol. Sci. 19, 403 (2018)

    PubMed Central  Google Scholar 

  18. P. Bannas, J. Hambach, F. Koch-Nolte, Nanobodies and nanobody-based human heavy chain antibodies as antitumor therapeutics. Front. Immunol. 8, 1603 (2017)

    PubMed  PubMed Central  Google Scholar 

  19. C.E. Brown, P.S. Adusumilli, Next frontiers in CAR T-cell therapy. Mol. Ther. Oncolytics 3, 16028 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. C.A. Ramos, G. Dotti, Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Exp. Opin. Biol. Ther. 11, 855–873 (2011)

    CAS  Google Scholar 

  21. Z. Zhao, M. Condomines, S.J.C. van der Stegen, F. Perna, C.C. Kloss, G. Gunset, J. Plotkin, M. Sadelain, Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015). https://doi.org/10.1016/j.ccell.2015.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. O.U. Kawalekar, R.S. O’Connor, J.A. Fraietta, L. Guo, S.E. McGettigan, A.D. Posey Jr., P.R. Patel, S. Guedan, J. Scholler, B. Keith, Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016)

    CAS  PubMed  Google Scholar 

  23. S.J. Van Der Stegen, M. Hamieh, M. Sadelain, The pharmacology of second-generation chimeric antigen receptors. Nature Rev. Drug Disc. 14, 499–509 (2015)

    Google Scholar 

  24. A.H. Long, W.M. Haso, J.F. Shern, K.M. Wanhainen, M. Murgai, M. Ingaramo, J.P. Smith, A.J. Walker, M.E. Kohler, V.R. Venkateshwara, 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nature Med. 21, 581 (2015)

    CAS  PubMed  Google Scholar 

  25. C.J. Turtle, D.G. Maloney, Clinical trials of CD19-targeted CAR-modified T cell therapy; a complex and varied landscape. Exp. Rev. Hematol. 9, 719–721 (2016). https://doi.org/10.1080/17474086.2016.1203251

    Article  CAS  Google Scholar 

  26. A.E. Foster, A. Mahendravada, N.P. Shinners, W.-C. Chang, J. Crisostomo, A. Lu, M. Khalil, E. Morschl, J.L. Shaw, S. Saha, Regulated expansion and survival of chimeric antigen receptor-modified T cells using small molecule-dependent inducible MyD88/CD40. Mol. Ther. 25, 2176–2188 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. M. Mata, C. Gerken, P. Nguyen, G. Krenciute, D.M. Spencer, S. Gottschalk, Inducible activation of MyD88 and CD40 in CAR T cells results in controllable and potent antitumor activity in preclinical solid tumor models. Cancer Discov. 7, 1306–1319 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. D.-G. Song, Q. Ye, M. Poussin, G.M. Harms, M. Figini, D.J. Powell, CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood 119, 696–706 (2012)

    CAS  PubMed  Google Scholar 

  29. M.A. Pulè, K.C. Straathof, G. Dotti, H.E. Heslop, C.M. Rooney, M.K. Brenner, A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol. Ther. 12, 933–941 (2005)

    PubMed  Google Scholar 

  30. A.A. Hombach, J. Heiders, M. Foppe, M. Chmielewski, H. Abken, OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4 + T cells. Oncoimmunology 1, 458–466 (2012)

    PubMed  PubMed Central  Google Scholar 

  31. H.M. Finney, A.N. Akbar, A.D. Lawson, Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCRζ chain. J. Immunol. 172, 104–113 (2004)

    CAS  PubMed  Google Scholar 

  32. S. Guedan, X. Chen, A. Madar, C. Carpenito, S.E. McGettigan, M.J. Frigault, J. Lee, A.D. Posey, J. Scholler, N. Scholler, ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124, 1070–1080 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. E. Wang, L.C. Wang, C.Y. Tsai, V. Bhoj, Z. Gershenson, E. Moon, K. Newick, J. Sun, A. Lo, T. Baradet, M.D. Feldman, D. Barrett, E. Pure, S. Albelda, M.C. Milone, Generation of potent T-cell immunotherapy for cancer using DAP12-based, multichain, chimeric immunoreceptors. Cancer Immunol. Res. 3, 815–826 (2015). https://doi.org/10.1158/2326-6066.CIR-15-0054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. S. Rafiq, C.S. Hackett, R.J. Brentjens, Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nature Rev. Clin. Oncol. 17, 147–167 (2020). https://doi.org/10.1038/s41571-019-0297-y

    Article  Google Scholar 

  35. J.S. Bridgeman, R.E. Hawkins, S. Bagley, M. Blaylock, M. Holland, D.E. Gilham, The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J. Immunol. 184, 6938–6949 (2010). https://doi.org/10.4049/jimmunol.0901766

    Article  CAS  PubMed  Google Scholar 

  36. D. Abate-Daga, M.L. Davila, CAR models: next-generation CAR modifications for enhanced T-cell function. Mol. Ther. Oncolyt. 3, 16014 (2016)

    CAS  Google Scholar 

  37. G. Dotti, S. Gottschalk, B. Savoldo, M.K. Brenner, Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol. Rev. 257, 107–126 (2014)

    CAS  PubMed  Google Scholar 

  38. S.E. James, P.D. Greenberg, M.C. Jensen, Y. Lin, J. Wang, B.G. Till, A.A. Raubitschek, S.J. Forman, O.W. Press, Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J. Immunol. 180, 7028–7038 (2008)

    CAS  PubMed  Google Scholar 

  39. W. Haso, D.W. Lee, N.N. Shah, M. Stetler-Stevenson, C.M. Yuan, I.H. Pastan, D.S. Dimitrov, R.A. Morgan, D.J. FitzGerald, D.M. Barrett, Anti-CD22–chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165–1174 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. R.D. Guest, R.E. Hawkins, N. Kirillova, E.J. Cheadle, J. Arnold, A. O’Neill, J. Irlam, K.A. Chester, J.T. Kemshead, D.M. Shaw, The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J. Immunother. 28, 203–211 (2005)

    CAS  PubMed  Google Scholar 

  41. M.H. Kershaw, J.A. Westwood, L.L. Parker, G. Wang, Z. Eshhar, S.A. Mavroukakis, D.E. White, J.R. Wunderlich, S. Canevari, L. Rogers-Freezer, A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  42. M.C. Jensen, L. Popplewell, L.J. Cooper, D. DiGiusto, M. Kalos, J.R. Ostberg, S.J. Forman, Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol. Blood Marrow Transpl. 16, 1245–1256 (2010)

    CAS  Google Scholar 

  43. S.L. Maude, N. Frey, P.A. Shaw, R. Aplenc, D.M. Barrett, N.J. Bunin, A. Chew, V.E. Gonzalez, Z. Zheng, S.F. Lacey, Chimeric antigen receptor T cells for sustained remissions in leukemia. New Engl. J. Med. 371, 1507–1517 (2014)

    PubMed  Google Scholar 

  44. R.J. Brentjens, M.L. Davila, I. Riviere, J. Park, X. Wang, L.G. Cowell, S. Bartido, J. Stefanski, C. Taylor, M. Olszewska, CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra138 (2013)

  45. J.N. Kochenderfer, W.H. Wilson, J.E. Janik, M.E. Dudley, M. Stetler-Stevenson, S.A. Feldman, I. Maric, M. Raffeld, D.-A.N. Nathan, B.J. Lanier, Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116, 4099–4102 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. M. Chmielewski, C. Kopecky, A.A. Hombach, H. Abken, 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. 71, 5697–5706 (2011)

    CAS  PubMed  Google Scholar 

  47. M.L. Schubert, J.M. Hoffmann, P. Dreger, C. Müller-Tidow, M. Schmitt, Chimeric antigen receptor transduced T cells: tuning up for the next generation. Int. J. Cancer 142, 1738–1747 (2018)

    CAS  PubMed  Google Scholar 

  48. P. Chang, Interleukin 12-secreting chimeric antigen receptor T cells and cancer immunotherapy. Ph.D. Dissertation. Weill Cornell Medicine. 1–110 (2016)

  49. B. Hu, J. Ren, Y. Luo, B. Keith, R.M. Young, J. Scholler, Y. Zhao, C.H. June, Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep. 20, 3025–3033 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. G. Gross, Z. Eshhar, Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: Counteracting off-tumor toxicities for safe CAR T cell therapy. Ann. Rev. Pharmacol. Toxicol. 56, 59–83 (2016). https://doi.org/10.1146/annurev-pharmtox-010814-124844

    Article  CAS  Google Scholar 

  51. T. Giavridis, S.J. van der Stegen, J. Eyquem, M. Hamieh, M. Sadelain, CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nature Med. 24, 731–738 (2018) https://doi.org/10.1038/s41591-018-0041-7

    Article  CAS  PubMed  Google Scholar 

  52. J. Gust, A. Taraseviciute, C.J. Turtle, Neurotoxicity associated with CD19-targeted CAR-T cell therapies. CNS Drugs 32, 1091–1101 (2018)

    PubMed  PubMed Central  Google Scholar 

  53. M. Namuduri, R.J. Brentjens, Medical management of side effects related to CAR T cell therapy in hematologic malignancies. Exp. Rev. Hematol. 9, 511–513 (2016)

    CAS  Google Scholar 

  54. K. Minagawa, A. Di Stasi, Novel toxicology challenges in the era of chimeric antigen receptor T-cells therapies. Transl Cancer Res. 5, S444–S449 (2016). https://doi.org/10.21037/tcr.2016.09.06

  55. D.W. Lee, B.D. Santomasso, F.L. Locke, A. Ghobadi, C.J. Turtle, J.N. Brudno, M.V. Maus, J.H. Park, E. Mead, S. Pavletic, W.Y. Go, L. Eldjerou, R.A. Gardner, N. Frey, K.J. Curran, K. Peggs, M. Pasquini, J.F. DiPersio, M.R.M. van den Brink, K.V. Komanduri, S.A. Grupp, S.S. Neelapu, ASTCT Consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transpl. 25, 625–638 (2019). https://doi.org/10.1016/j.bbmt.2018.12.758

    Article  CAS  Google Scholar 

  56. K.M. Mahadeo, S.J. Khazal, H. Abdel-Azim, J.C. Fitzgerald, A. Taraseviciute, C.M. Bollard, P. Tewari, C. Duncan, C. Traube, D. McCall, M.E. Steiner, I.M. Cheifetz, L.E. Lehmann, R. Mejia, J.M. Slopis, R. Bajwa, P. Kebriaei, P.L. Martin, J. Moffet, J. McArthur, D. Petropoulos, J. O’Hanlon Curry, S. Featherston, J. Foglesong, B. Shoberu, A. Gulbis, M.E. Mireles, L. Hafemeister, C. Nguyen, N. Kapoor, K. Rezvani, S.S. Neelapu, E.J. Shpall, Pediatric acute lung and N. sepsis investigators, management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nature Rev. Clin. Oncol. 16, 45–63 (2019). https://doi.org/10.1038/s41571-018-0075-2

    Article  CAS  Google Scholar 

  57. D.W. Lee, R. Gardner, D.L. Porter, C.U. Louis, N. Ahmed, M. Jensen, S.A. Grupp, C.L. Mackall, Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  58. M. Sachdeva, P. Duchateau, S. Depil, L. Poirot, J. Valton, Granulocyte–macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators. J. Biol. Chem. 294, 5430–5437 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  59. J. Gust, K.A. Hay, L.-A. Hanafi, D. Li, D. Myerson, L.F. Gonzalez-Cuyar, C. Yeung, W.C. Liles, M. Wurfel, J.A. Lopez, Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 7, 1404–1419 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  60. C.K. Chou, C.J. Turtle, Insight into mechanisms associated with cytokine release syndrome and neurotoxicity after CD19 CAR-T cell immunotherapy. Bone Marrow Transpl. 54, 780–784 (2019). https://doi.org/10.1038/s41409-019-0602-5

    Article  Google Scholar 

  61. C. Perrinjaquet, N. Desbaillets, A.F. Hottinger, Neurotoxicity associated with cancer immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy. Curr. Opin. Neurol. 32, 500–510 (2019)

    CAS  PubMed  Google Scholar 

  62. U.H. Acharya, T. Dhawale, S. Yun, C.A. Jacobson, J.C. Chavez, J.D. Ramos, J. Appelbaum, D.G. Maloney, Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy. Expert Rev. Hematol. 12, 195–205 (2019)

    CAS  PubMed  Google Scholar 

  63. H.J. Jackson, R.J. Brentjens, Overcoming antigen escape with CAR T-cell therapy. Cancer Discov. 5, 1238–1240 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. E. Sotillo, D.M. Barrett, K.L. Black, A. Bagashev, D. Oldridge, G. Wu, R. Sussman, C. Lanauze, M. Ruella, M.R. Gazzara, Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  65. F. Braig, A. Brandt, M. Goebeler, H.-P. Tony, A.-K. Kurze, P. Nollau, T. Bumm, S. Böttcher, R.C. Bargou, M. Binder, Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood 129, 100–104 (2017)

    CAS  PubMed  Google Scholar 

  66. S. Rafiq, R.J. Brentjens, Tumors evading CARs—the chase is on. Nature Med. 24, 1492–1493 (2018)

    CAS  PubMed  Google Scholar 

  67. J. Fischer, C. Paret, K. El Malki, F. Alt, A. Wingerter, M.A. Neu, B. Kron, A. Russo, N. Lehmann, L. Roth, CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in B-ALL patients at initial diagnosis. J. Immunother. 40, 187 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  68. R. Gardner, D. Wu, S. Cherian, M. Fang, L.-A. Hanafi, O. Finney, H. Smithers, M.C. Jensen, S.R. Riddell, D.G. Maloney, Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127, 2406–2410 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  69. E.J. Orlando, X. Han, C. Tribouley, P.A. Wood, R.J. Leary, M. Riester, J.E. Levine, M. Qayed, S.A. Grupp, M. Boyer, Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nature Med. 24, 1504–1506 (2018)

    CAS  PubMed  Google Scholar 

  70. B. Heyman, Y. Yang, Chimeric antigen receptor T cell therapy for solid tumors: current status, obstacles and future strategies. Cancers 11, 191 (2019)

    CAS  PubMed Central  Google Scholar 

  71. R.J. Brentjens, I. Riviere, J.H. Park, M.L. Davila, X. Wang, J. Stefanski, C. Taylor, R. Yeh, S. Bartido, O. Borquez-Ojeda, Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  72. I. Diaconu, B. Ballard, M. Zhang, Y. Chen, J. West, G. Dotti, B. Savoldo, Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells. Mol. Ther. 25, 580–592 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  73. A. Di Stasi, S.-K. Tey, G. Dotti, Y. Fujita, A. Kennedy-Nasser, C. Martinez, K. Straathof, E. Liu, A.G. Durett, B. Grilley, Inducible apoptosis as a safety switch for adoptive cell therapy. New Engl. J. Med. 365, 1673–1683 (2011)

    PubMed  Google Scholar 

  74. R. Sakemura, S. Terakura, K. Watanabe, J. Julamanee, E. Takagi, K. Miyao, D. Koyama, T. Goto, R. Hanajiri, T. Nishida, A Tet-On inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol. Res. 4, 658–668 (2016)

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  76. J.H. Cho, J.J. Collins, W.W. Wong, Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438.e1411 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  77. J. Zhao, Q. Lin, Y. Song, D. Liu, Universal CARs, universal T cells, and universal CAR T cells. J. Hematol. Oncol. 11, 132 (2018)

  78. K.T. Roybal, L.J. Rupp, L. Morsut, W.J. Walker, K.A. McNally, J.S. Park, W.A. Lim, Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. M. Themeli, M. Sadelain, Combinatorial antigen targeting: ideal T-cell sensing and anti-tumor response. Trends Mol. Med. 22, 271–273 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  80. S. Srivastava, A.I. Salter, D. Liggitt, S. Yechan-Gunja, M. Sarvothama, K. Cooper, K.S. Smythe, J.A. Dudakov, R.H. Pierce, C. Rader, 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.e488 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  81. S. Wilkie, M.C. van Schalkwyk, S. Hobbs, D.M. Davies, S.J. van der Stegen, A.C.P. Pereira, S.E. Burbridge, C. Box, S.A. Eccles, J. Maher, 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)

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  83. D. Xu, G. Jin, D. Chai, X. Zhou, W. Gu, Y. Chong, J. Song, J. Zheng, The development of CAR design for tumor CAR-T cell therapy. Oncotarget 9, 13991 (2018)

    PubMed  PubMed Central  Google Scholar 

  84. M. Hegde, M. Mukherjee, Z. Grada, A. Pignata, D. Landi, S.A. Navai, A. Wakefield, K. Fousek, K. Bielamowicz, K.K. Chow, Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Invest. 126, 3036–3052 (2016)

    PubMed  PubMed Central  Google Scholar 

  85. M.A. Rosenthal, C. Balana, M.E. van Linde, C. Sayehli, W.M. Fiedler, M. Wermke, C. Massard, I.K. Mellinghoff, M. Khasraw, A. Ang, ATIM-49 (LTBK-01). AMG 596, a novel anti-EGFRvIII bispecific T cell engager (BiTE®) molecule for the treatment of glioblastoma (GBM): planned interim analysis in recurrent GBM (rGBM). Neuro-Oncology 21, vi283 (2019)

    PubMed Central  Google Scholar 

  86. D.M. O’Rourke, M.P. Nasrallah, A. Desai, J.J. Melenhorst, K. Mansfield, J.J. Morrissette, M. Martinez-Lage, S. Brem, E. Maloney, A. Shen, 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, 399 (2017)

    Google Scholar 

  87. D.M. O’Rourke, M. Nasrallah, J.J. Morrissette, J.J. Melenhorst, S.F. Lacey, K. Mansfield, M. Martinez-Lage, A.S. Desai, S. Brem, E. Maloney, Pilot study of T cells redirected to EGFRvIII with a chimeric antigen receptor in patients with EGFRvIII + glioblastoma. J Clin Oncol. 2067 (2016)

  88. M. Chen, R. Sun, B. Shi, Y. Wang, S. Di, H. Luo, Y. Sun, Z. Li, M. Zhou, H. Jiang, Antitumor efficacy of chimeric antigen receptor T cells against EGFRvIII-expressing glioblastoma in C57BL/6 mice. Biomed. Pharmacother. 113, 108734 (2019)

    CAS  PubMed  Google Scholar 

  89. M. Ruella, B.L. Levine, C.A.R.S. Smart, optimized development of a chimeric antigen receptor (CAR) T cell targeting epidermal growth factor receptor variant III (EGFRvIII) for glioblastoma. Ann. Transl. Med. 4, 13 (2016)

    PubMed  PubMed Central  Google Scholar 

  90. H.G. Caruso, A.B. Heimberger, L.J. Cooper, Steering CAR T cells to distinguish friend from foe. Oncoimmunol. 8, e1271857 (2019)

    Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  92. V.D. Fedorov, M. Sadelain, C.C. Kloss, Novel approaches to enhance the specificity and safety of engineered T cells. Cancer J. 20, 160–165 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  93. K. Feng, Y. Guo, H. Dai, Y. Wang, X. Li, H. Jia, W. Han, 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. 59, 468–479 (2016)

    CAS  PubMed  Google Scholar 

  94. E. Drent, M. Themeli, R. Poels, R. de Jong-Korlaar, H. Yuan, J. de Bruijn, A.C. Martens, S. Zweegman, N.W. van de Donk, R.W. Groen, A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol. Ther. 25, 1946–1958 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Y. Liu, X. Chen, W. Han, Y. Zhang, Tisagenlecleucel, an approved anti-CD19 chimeric antigen receptor T-cell therapy for the treatment of leukemia. Drugs Today 53, 597–608 (2017)

    CAS  Google Scholar 

  96. A.L. Garfall, M.V. Maus, W.-T. Hwang, S.F. Lacey, Y.D. Mahnke, J.J. Melenhorst, Z. Zheng, D.T. Vogl, A.D. Cohen, B.M. Weiss, Chimeric antigen receptor T cells against CD19 for multiple myeloma. New Engl. J. Med. 373, 1040–1047 (2015)

    CAS  PubMed  Google Scholar 

  97. S.A. Grupp, M. Kalos, D. Barrett, R. Aplenc, D.L. Porter, S.R. Rheingold, D.T. Teachey, A. Chew, B. Hauck, J.F. Wright, Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. New Engl. J. Med. 368, 1509–1518 (2013)

    CAS  PubMed  Google Scholar 

  98. D.W. Lee, J.N. Kochenderfer, M. Stetler-Stevenson, Y.K. Cui, C. Delbrook, S.A. Feldman, T.J. Fry, R. Orentas, M. Sabatino, N.N. Shah, T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015)

    CAS  PubMed  Google Scholar 

  99. E. Zhang, J. Gu, H. Xu, Prospects for chimeric antigen receptor-modified T cell therapy for solid tumors. Mol. Cancer 17, 7 (2018)

    PubMed  PubMed Central  Google Scholar 

  100. A. Holzinger, H. Abken, CAR T cells targeting solid tumors: carcinoembryonic antigen (CEA) proves to be a safe target. Cancer Immunol. Immunother. 66, 1505–1507 (2017)

    PubMed  Google Scholar 

  101. P. Bocca, E. Di Carlo, I. Caruana, L. Emionite, M. Cilli, B. De Angelis, C. Quintarelli, A. Pezzolo, L. Raffaghello, F. Morandi, Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model. Oncoimmunology 7, e1378843 (2018)

    Google Scholar 

  102. A. Morello, M. Sadelain, P.S. Adusumilli, Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 6, 133–146 (2016)

    CAS  PubMed  Google Scholar 

  103. H. Abken, Driving CARs on the highway to solid cancer: some considerations on the adoptive therapy with CAR T cells. Human Gene Ther. 28, 1047–1060 (2017)

    CAS  Google Scholar 

  104. N. Ahmed, V.S. Brawley, M. Hegde, C. Robertson, A. Ghazi, C. Gerken, E. Liu, O. Dakhova, A. Ashoori, A. Corder, Human epidermal growth factor receptor 2 (HER2)–specific chimeric antigen receptor–modified T cells for the immunotherapy of HER2-positive sarcoma. J. Cin. Oncol. 33, 1688 (2015)

    CAS  Google Scholar 

  105. E. Lanitis, M. Irving, G. Coukos, Targeting the tumor vasculature to enhance T cell activity. Curr. Opin. Immunol. 33, 55–63 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  106. A. Schmidts, M.V. Maus, Making CAR T cells a solid option for solid tumors. Front. Immunol. 9, 2593 (2018)

    PubMed  PubMed Central  Google Scholar 

  107. U. Sahin, E. Derhovanessian, M. Miller, B.-P. Kloke, P. Simon, M. Löwer, V. Bukur, A.D. Tadmor, U. Luxemburger, B. Schrörs, Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017)

    CAS  PubMed  Google Scholar 

  108. P.A. Ott, Z. Hu, D.B. Keskin, S.A. Shukla, J. Sun, D.J. Bozym, W. Zhang, A. Luoma, A. Giobbie-Hurder, L. Peter, An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  109. S. Stevanović, A. Pasetto, S.R. Helman, J.J. Gartner, T.D. Prickett, B. Howie, H.S. Robins, P.F. Robbins, C.A. Klebanoff, S.A. Rosenberg, Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205 (2017)

    PubMed  PubMed Central  Google Scholar 

  110. J. Zhou, M.E. Dudley, S.A. Rosenberg, P.F. Robbins, Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. J. Immunother. 28, 53 (2005)

    PubMed  PubMed Central  Google Scholar 

  111. K.C. Pituch, J. Miska, G. Krenciute, W.K. Panek, G. Li, T. Rodriguez-Cruz, M. Wu, Y. Han, M.S. Lesniak, S. Gottschalk, Adoptive transfer of IL13Rα2-specific chimeric antigen receptor T cells creates a pro-inflammatory environment in glioblastoma. Mol. Ther. 26, 986–995 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  112. K. Bielamowicz, K. Fousek, T.T. Byrd, H. Samaha, M. Mukherjee, N. Aware, M.-F. Wu, J.S. Orange, P. Sumazin, T.-K. Man, Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology 20, 506–518 (2018)

    CAS  PubMed  Google Scholar 

  113. S. Van Schandevyl, T. Kerre, Chimeric antigen receptor T-cell therapy: design improvements and therapeutic strategies in cancer treatment. Acta Clin. Belg. 75, 26–32 (2020)

    PubMed  Google Scholar 

  114. A.K. Park, S. Priceman, E. Gerdts, W.-C. Chang, S. Wright, S.J. Forman, C.E. Brown, Development of chimeric antigen receptor (CAR) T-cell immunotherapy for glioblastoma targeting epidermal growth factor receptor variant III (EGFRvIII). J. Immunother. Cancer 3, P119 (2015)

    PubMed Central  Google Scholar 

  115. A. Sahin, C. Sanchez, S. Bullain, P. Waterman, R. Weissleder, B.S. Carter, Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma. PloS One 13, e0199414 (2018)

    PubMed  PubMed Central  Google Scholar 

  116. J. Wei, X. Han, J. Bo, W. Han, Target selection for CAR-T therapy. J. Hematol. Oncol. 12, 1–9 (2019)

    Google Scholar 

  117. G. Xie, N.A. Ivica, B. Jia, Y. Li, H. Dong, Y. Liang, D. Brown, R. Rizwan, J. Chen, Author Correction: CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia. Nat. Biomed. Eng. 5, 124 (2021)

    PubMed  Google Scholar 

  118. I. Scarfò, M.V. Maus, Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment. J. Immunother. Cancer 5, 1–8 (2017)

    Google Scholar 

  119. B. Liu, L. Yan, M. Zhou, Target selection of CAR T cell therapy in accordance with the TME for solid tumors. Am. J. Cancer Res. 9, 228 (2019)

  120. A. Lo, L.-C.S. Wang, J. Scholler, J. Monslow, D. Avery, K. Newick, S. O’Brien, R.A. Evans, D.J. Bajor, C. Clendenin, Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75, 2800–2810 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  121. L.-C.S. Wang, A. Lo, J. Scholler, J. Sun, R.S. Majumdar, V. Kapoor, M. Antzis, C.E. Cotner, L.A. Johnson, A.C. Durham, Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2, 154–166 (2014)

    CAS  PubMed  Google Scholar 

  122. R. Sackstein, T. Schatton, S.R. Barthel, T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab. Invest. 97, 669 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  123. E.K. Moon, C. Carpenito, J. Sun, L.-C.S. Wang, V. Kapoor, J. Predina, D.J. Powell, J.L. Riley, C.H. June, S.M. Albelda, Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin. Cancer Res. 17, 4719–4730 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  124. J.A. Craddock, A. Lu, A. Bear, M. Pule, M.K. Brenner, C.M. Rooney, A.E. Foster, Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 33, 780 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  125. A. Di Stasi, B. De Angelis, C.M. Rooney, L. Zhang, A. Mahendravada, A.E. Foster, H.E. Heslop, M.K. Brenner, G. Dotti, B. Savoldo, T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009)

    PubMed  PubMed Central  Google Scholar 

  126. I. Siddiqui, M. Erreni, M. Van Brakel, R. Debets, P. Allavena, Enhanced recruitment of genetically modified CX3CR1-positive human T cells into Fractalkine/CX3CL1 expressing tumors: importance of the chemokine gradient. J. Immunother. Cancer 4, 21 (2016)

    PubMed  PubMed Central  Google Scholar 

  127. W. Peng, Y. Ye, B.A. Rabinovich, C. Liu, Y. Lou, M. Zhang, M. Whittington, Y. Yang, W.W. Overwijk, G. Lizée, Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin. Cancer Res. 16, 5458–5468 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  128. P. Spear, A. Barber, C.L. Sentman, Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors. Oncoimmunology 2, e23564 (2013)

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  130. M.M. D’Aloia, I.G. Zizzari, B. Sacchetti, L. Pierelli, M. Alimandi, CAR-T cells: the long and winding road to solid tumors. Cell Death Dis. 9, 282 (2018). https://doi.org/10.1038/s41419-018-0278-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. N. Kanagawa, M. Niwa, Y. Hatanaka, Y. Tani, S. Nakagawa, T. Fujita, A. Yamamoto, N. Okada, CC-chemokine ligand 17 gene therapy induces tumor regression through augmentation of tumor-infiltrating immune cells in a murine model of preexisting CT26 colon carcinoma. Int. J. Cancer 121, 2013–2022 (2007). https://doi.org/10.1002/ijc.22908

    Article  CAS  PubMed  Google Scholar 

  132. E. Lavergne, C. Combadiere, M. Iga, A. Boissonnas, O. Bonduelle, M. Maho, P. Debre, B. Combadiere, Intratumoral CC chemokine ligand 5 overexpression delays tumor growth and increases tumor cell infiltration. J. Immunol. 173, 3755–3762 (2004). https://doi.org/10.4049/jimmunol.173.6.3755

    Article  CAS  PubMed  Google Scholar 

  133. S.J. Priceman, D. Tilakawardane, B. Jeang, B. Aguilar, J.P. Murad, A.K. Park, W.-C. Chang, J.R. Ostberg, J. Neman, R. Jandial, Regional delivery of chimeric antigen receptor–engineered T cells effectively targets HER2 + breast Cancer metastasis to the brain. Clin. Cancer Res. 24, 95–105 (2018)

    CAS  PubMed  Google Scholar 

  134. A. Louveau, T.H. Harris, J. Kipnis, Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36, 569–577 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  135. B.D. Choi, C.M. Suryadevara, P.C. Gedeon, J.E. Herndon, I.I.L. Sanchez-Perez, D.D. Bigner, J.H. Sampson, Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma. J. Clin. Neurosci. 21, 189–190 (2014)

    PubMed  Google Scholar 

  136. J. Tchou, Y. Zhao, B.L. Levine, P.J. Zhang, M.M. Davis, J.J. Melenhorst, I. Kulikovskaya, A.L. Brennan, X. Liu, S.F. Lacey, A.D. Posey Jr., A.D. Williams, A. So, J.R. Conejo-Garcia, G. Plesa, R.M. Young, S. McGettigan, J. Campbell, R.H. Pierce, J.M. Matro, A.M. DeMichele, A.S. Clark, L.J. Cooper, L.M. Schuchter, R.H. Vonderheide, C.H. June, Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol. Res. 5, 1152–1161 (2017). https://doi.org/10.1158/2326-6066.CIR-17-0189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. S.C. Katz, R.A. Burga, E. McCormack, L.J. Wang, W. Mooring, G.R. Point, P.D. Khare, M. Thorn, Q. Ma, B.F. Stainken, E.O. Assanah, R. Davies, N.J. Espat, R.P. Junghans, Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA + liver metastases. Clin. Cancer Res. 21, 3149–3159 (2015). https://doi.org/10.1158/1078-0432.CCR-14-1421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. D.H. Yoon, M.J. Osborn, J. Tolar, C.J. Kim, Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR-Ts): Combination or built-in CAR-T. Int. J. Mol. Sci. 19, 340 (2018). https://doi.org/10.3390/ijms19020340

    Article  CAS  PubMed Central  Google Scholar 

  139. B.T. Aftab, R.R. Shen, C.D. Pham, M. Wu, D.J. Munson, P.S. Adusumilli, M. Zauderer, V. Rusch, R. O’Cearbhaill, A. Zhu, A Phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. 79(13 Suppl) (2019). https://doi.org/10.1158/1538-7445.AM2019-CT036

  140. I. Caruana, B. Savoldo, V. Hoyos, G. Weber, H. Liu, E.S. Kim, M.M. Ittmann, D. Marchetti, G. Dotti, Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  141. M. Binnewies, E.W. Roberts, K. Kersten, V. Chan, D.F. Fearon, M. Merad, L.M. Coussens, D.I. Gabrilovich, S. Ostrand-Rosenberg, C.C. Hedrick, Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  142. M. Overchuk, G. Zheng, Overcoming obstacles in the tumor microenvironment: Recent advancements in nanoparticle delivery for cancer theranostics. Biomaterials 156, 217–237 (2018)

    CAS  PubMed  Google Scholar 

  143. A.H. Long, S.L. Highfill, Y. Cui, J.P. Smith, A.J. Walker, S. Ramakrishna, R. El-Etriby, S. Galli, M.G. Tsokos, R.J. Orentas, Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol. Res. 4, 869–880 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  144. V. Kumar, S. Patel, E. Tcyganov, D.I. Gabrilovich, The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  145. L.J. Rupp, K. Schumann, K.T. Roybal, R.E. Gate, J.Y. Chun, W.A. Lim, A. Marson, CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 1–10 (2017)

    CAS  Google Scholar 

  146. J. Ren, X. Zhang, X. Liu, C. Fang, S. Jiang, C.H. June, Y. Zhao, A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8, 17002 (2017)

    PubMed  PubMed Central  Google Scholar 

  147. Y. Zhang, X. Zhang, C. Cheng, W. Mu, X. Liu, N. Li, X. Wei, X. Liu, C. Xia, H. Wang, CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. Front. Med. 11, 554–562 (2017)

    PubMed  Google Scholar 

  148. S. Rafiq, O.O. Yeku, H.J. Jackson, T.J. Purdon, D.G. van Leeuwen, D.J. Drakes, M. Song, M.M. Miele, Z. Li, P. Wang, Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  149. X. Liu, R. Ranganathan, S. Jiang, C. Fang, J. Sun, S. Kim, K. Newick, A. Lo, C.H. June, Y. Zhao, A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 76, 1578–1590 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  150. A.M. Leen, S. Sukumaran, N. Watanabe, S. Mohammed, J. Keirnan, R. Yanagisawa, U. Anurathapan, D. Rendon, H.E. Heslop, C.M. Rooney, Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol. Ther. 22, 1211–1220 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  151. K. Adachi, Y. Kano, T. Nagai, N. Okuyama, Y. Sakoda, K. Tamada, IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat. Biotechnol. 36, 346 (2018)

    CAS  PubMed  Google Scholar 

  152. C.S. Hinrichs, R. Spolski, C.M. Paulos, L. Gattinoni, K.W. Kerstann, D.C. Palmer, C.A. Klebanoff, S.A. Rosenberg, W.J. Leonard, N.P. Restifo, IL-2 and IL-21 confer opposing differentiation programs to CD8 + T cells for adoptive immunotherapy. Blood 111, 5326–5333 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  153. M. Koneru, T.J. Purdon, D. Spriggs, S. Koneru, R.J. Brentjens, IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015)

    PubMed  PubMed Central  Google Scholar 

  154. O.O. Yeku, T.J. Purdon, M. Koneru, D. Spriggs, R.J. Brentjens, Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci. Rep. 7, 1–14 (2017)

    CAS  Google Scholar 

  155. M. Koneru, R. O’Cearbhaill, S. Pendharkar, D.R. Spriggs, R.J. Brentjens, A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16 ecto directed chimeric antigen receptors for recurrent ovarian cancer. J. Transl. Med. 13, 102 (2015)

    PubMed  PubMed Central  Google Scholar 

  156. M. Chmielewski, H. Abken, CAR T cells releasing IL-18 convert to T-Bethigh FoxO1low effectors that exhibit augmented activity against advanced solid tumors. Cell Rep. 21, 3205–3219 (2017)

    CAS  PubMed  Google Scholar 

  157. M.C. Schmid, C.J. Avraamides, H.C. Dippold, I. Franco, P. Foubert, L.G. Ellies, L.M. Acevedo, J.R. Manglicmot, X. Song, W. Wrasidlo, Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715–727 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  158. P. Vormittag, R. Gunn, S. Ghorashian, F.S. Veraitch, A guide to manufacturing CAR T cell therapies. Curr. Opin. Biotechnol. 53, 164–181 (2018)

    CAS  PubMed  Google Scholar 

  159. M.L. Davila, I. Riviere, X. Wang, S. Bartido, J. Park, K. Curran, S.S. Chung, J. Stefanski, O. Borquez-Ojeda, M. Olszewska, Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra225 (2014)

  160. D. Sommermeyer, M. Hudecek, P.L. Kosasih, T. Gogishvili, D.G. Maloney, C.J. Turtle, S.R. Riddell, Chimeric antigen receptor-modified T cells derived from defined CD8 + and CD4 + subsets confer superior antitumor reactivity in vivo. Leukemia 30, 492–500 (2016)

    CAS  PubMed  Google Scholar 

  161. C. Berger, M.C. Jensen, P.M. Lansdorp, M. Gough, C. Elliott, S.R. Riddell, Adoptive transfer of effector CD8 + T cells derived from central memory cells establishes persistent T cell memory in primates. J. Clin. Invest. 118, 294–305 (2008)

    CAS  PubMed  Google Scholar 

  162. X. Wang, I. Rivière, Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol. Ther. Oncolytics 3, 16015 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  163. M.C. Jensen, P. Clarke, G. Tan, C. Wright, W. Chung-Chang, T.N. Clark, F. Zhang, M.L. Slovak, A.M. Wu, S.J. Forman, Human T lymphocyte genetic modification with naked DNA. Mol. Ther. 1, 49–55 (2000)

    CAS  PubMed  Google Scholar 

  164. S. Ghassemi, F. Bedoya, S. Nunez-Cruz, C. June, J. Melenhorst, M. Milone, Shortened T cell culture with IL-7 and IL-15 provides the most potent chimeric antigen receptor (CAR)-modified T cells for adoptive immunotherapy. J. Immunol. 196, 214–223 (2016)

    Google Scholar 

  165. J.N. Kochenderfer, S.A. Feldman, Y. Zhao, H. Xu, M.A. Black, R.A. Morgan, W.H. Wilson, S.A. Rosenberg, Construction and pre-clinical evaluation of an anti-CD19 chimeric antigen receptor. J. Immunother. 32, 689 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  166. H. Singh, J. Moyes, M. Huls, L. Cooper, Manufacture of T cells using the Sleeping Beauty system to enforce expression of a CD19-specific chimeric antigen receptor. Cancer Gene Ther. 22, 95–100 (2015)

    CAS  PubMed  Google Scholar 

  167. P. Kebriaei, H. Huls, H. Singh, S. Olivares, M. Figliola, S. Maiti, S. Shihuang, P.R. Kumar, B. Jena, M.A. Forget, Adoptive therapy using sleeping beauty gene transfer system and artificial antigen presenting cells to manufacture T cells expressing CD19-specific chimeric antigen receptor. Blood 124, 311–311 (2014)

    Google Scholar 

  168. M. Kalos, B.L. Levine, D.L. Porter, S. Katz, S.A. Grupp, A. Bagg, C.H. June, T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011)

  169. B.L. Levine, J. Miskin, K. Wonnacott, C. Keir, Global manufacturing of CAR T cell therapy. Mol. Ther. Meth. Clin. Dev. 4, 92–101 (2017)

    CAS  Google Scholar 

  170. S. Ramanayake, I. Bilmon, D. Bishop, M.-C. Dubosq, E. Blyth, L. Clancy, D. Gottlieb, K. Micklethwaite, Low-cost generation of Good Manufacturing Practice–grade CD19-specific chimeric antigen receptor–expressing T cells using piggyBac gene transfer and patient-derived materials. Cytotherapy 17, 1251–1267 (2015)

    CAS  PubMed  Google Scholar 

  171. G.L. Beatty, A.R. Haas, M.V. Maus, D.A. Torigian, M.C. Soulen, G. Plesa, A. Chew, Y. Zhao, B.L. Levine, S.M. Albelda, Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies. Cancer Immunol Res. 2, 112–120 (2014)

    CAS  PubMed  Google Scholar 

  172. J.R. Park, D.L. DiGiusto, M. Slovak, C. Wright, A. Naranjo, J. Wagner, H.B. Meechoovet, C. Bautista, W.-C. Chang, J.R. Ostberg, Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol. Ther. 15, 825–833 (2007)

    CAS  PubMed  Google Scholar 

  173. C.U. Louis, B. Savoldo, G. Dotti, M. Pule, E. Yvon, G.D. Myers, C. Rossig, H.V. Russell, O. Diouf, E. Liu, Antitumor activity and long-term fate of chimeric antigen receptor–positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  174. C.E. Brown, B. Badie, M.E. Barish, L. Weng, J.R. Ostberg, W.-C. Chang, A. Naranjo, R. Starr, J. Wagner, CJCcr. Wright, Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8 + T cells in patients with recurrent glioblastoma. Clin. Cancer Res. 21, 4062–4072 (2015)

  175. R.P. Junghans, Q. Ma, R. Rathore, E.M. Gomes, A.J. Bais, A.S. Lo, M. Abedi, R.A. Davies, H.J. Cabral, A.S.J.T.P. Al-Homsi, Phase I trial of anti‐PSMA designer CAR‐T cells in prostate cancer: possible role for interacting interleukin 2‐T cell pharmacodynamics as a determinant of clinical response. Prostate 76, 1257–1270 (2016)

    CAS  PubMed  Google Scholar 

  176. R.A. Morgan, J.C. Yang, M. Kitano, M.E. Dudley, C.M. Laurencot, S.A.J.M.T. Rosenberg, Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18, 843–851 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  177. F.C. Thistlethwaite, D.E. Gilham, R.D. Guest, D.G. Rothwell, M. Pillai, D.J. Burt, A.J. Byatte, N. Kirillova, J.W. Valle, S.K.J.C.I. Sharma, 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. 66, 1425–1436 (2017)

    CAS  Google Scholar 

  178. C.H. Lamers, S. Sleijfer, S. Van Steenbergen, P. Van Elzakker, B. Van Krimpen, C. Groot, A. Vulto, M. Den Bakker, E. Oosterwijk, R.JMt. Debets, Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21, 904–912 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  179. E. Van Cutsem, J. Machiels, M. Van den Eynde, H. Prenen, A. Hendlisz, L. Shaza, J. Carrasco, J. Canon, P. Sotiropoulou, E.JAo.O. Breman, Phase 1 studies assessing the safety and clinical activity of autologous and allogeneic NKG2D-based CAR-T therapy in metastatic colorectal cancer. Ann. Oncol. 30, iv124–iv125 (2019)

    Google Scholar 

  180. G.L. Beatty, M.H. O’Hara, S.F. Lacey, D.A. Torigian, F. Nazimuddin, F. Chen, I.M. Kulikovskaya, M.C. Soulen, M. McGarvey, A.M.J.G. Nelson, Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155, 29–32 (2018)

    CAS  PubMed  Google Scholar 

  181. D.M. O’Rourke, M.P. Nasrallah, A. Desai, J.J. Melenhorst, K. Mansfield, J.J. Morrissette, M. Martinez-Lage, S. Brem, E. Maloney, AJStm. Shen, 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)

  182. S.L. Goff, R.A. Morgan, J.C. Yang, R.M. Sherry, P.F. Robbins, N.P. Restifo, S.A. Feldman, Y.-C. Lu, L. Lu, Z.JJo.I. Zheng, Pilot trial of adoptive transfer of chimeric antigen receptor–transduced T cells targeting EGFRvIII in patients with glioblastoma. J. Immunother. 42, 126–135 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  183. N. Ahmed, V. Brawley, M. Hegde, K. Bielamowicz, M. Kalra, D. Landi, C. Robertson, T.L. Gray, O. Diouf, A.JJo. Wakefield, Her2-specific chimeric antigen receptor–modified virus-specific t cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncology 3, 1094–1101 (2017)

    PubMed  PubMed Central  Google Scholar 

  184. P.S. Adusumilli, M.G. Zauderer, V.W. Rusch, R. O’Cearbhaill, A. Zhu, D. Ngai, E. McGee, N. Chintala, J. Messinger and W. Cheema, Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent. J. Clin. Oncol. 37, 2511–2511 (2019)

    Google Scholar 

  185. C. Zhang, Z. Wang, Z. Yang, M. Wang, S. Li, Y. Li, R. Zhang, Z. Xiong, Z. Wei, J. Shen, Phase I escalating-dose trial of CAR-T therapy targeting CEA + metastatic colorectal cancers. Mol. Ther. 25, 1248–1258 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  186. B.G. Till, M.C. Jensen, J. Wang, E.Y. Chen, B.L. Wood, H.A. Greisman, X. Qian, S.E. James, A. Raubitschek, S.J.J.B. Forman, Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. J. Am. Soc. Hematol. 112, 2261–2271 (2008)

    CAS  Google Scholar 

  187. Q. Wang, Y. Wang, H. Lv, Q. Han, H. Fan, B. Guo, L.I. Wang, W.-dJMt. Han, Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol. Ther. 23, 184–191 (2015)

    CAS  PubMed  Google Scholar 

  188. J.S. Abramson, L. Palomba, L.I. Gordon, M. Lunning, J. Arnason, A. Forero-Torres, T.M. Albertson, V.S. Exton, C. Sutherland, B. Xie, Transcend NHL 001: immunotherapy with the CD19-directed CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Blood 128, 4192–4192 (2016)

    Google Scholar 

  189. J.S. Abramson, M.L. Palomba, L.I. Gordon, M.A. Lunning, M.L. Wang, J.E. Arnason, A. Mehta, E. Purev, D.G. Maloney, C. Andreadis, Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Blood 134, 241–241 (2019)

    Google Scholar 

  190. F.L. Locke, S.S. Neelapu, N.L. Bartlett, T. Siddiqi, J.C. Chavez, C.M. Hosing, A. Ghobadi, L.E. Budde, A. Bot, J.M.J.M.T., Rossi, Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol. Ther. 25, 285–295 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  191. S.S. Neelapu, F.L. Locke, N.L. Bartlett, L.J. Lekakis, D.B. Miklos, C.A. Jacobson, I. Braunschweig, O.O. Oluwole, T. Siddiqi, Y.J.N.EJo.M. Lin, Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. New Engl. J. Med. 377, 2531–2544 (2017)

    CAS  PubMed  Google Scholar 

  192. J. Buechner, S.A. Grupp, S.L. Maude, M. Boyer, H. Bittencourt, T.W. Laetsch, P. Bader, M.R. Verneris, H. Stefanski, G.D.J.C.L. Myers, Myeloma and leukemia, global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): update to the interim analysis. Clin. Lymph. Myel. Leukemia 17, S263–S264 (2017)

    Google Scholar 

  193. S.J. Schuster, M.R. Bishop, C.S. Tam, E.K. Waller, P. Borchmann, J.P. McGuirk, U. Jaeger, S. Jaglowski, C. Andreadis, J.R.J.B. Westin, Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood 130, 577–577 (2017)

    Google Scholar 

  194. J.N. Kochenderfer, R.P. Somerville, T. Lu, V. Shi, A. Bot, J. Rossi, A. Xue, S.L. Goff, J.C. Yang, R.M.J.J.o.CO. Sherry, Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J. Clin. Oncol. 35, 1803 (2017)

  195. M. Wang, J. Munoz, A. Goy, F.L. Locke, C.A. Jacobson, B.T. Hill, J.M. Timmerman, H. Holmes, S. Jaglowski, I.W. Flinn, KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. New Engl. J. Med. 382, 1331–1342 (2020)

    CAS  PubMed  Google Scholar 

  196. W.G. Wierda, M.R. Bishop, O. Oluwole, A.C. Logan, M.R. Baer, W.B. Donnellan, K.M. O’Dwyer, J.E. Castro, G.J. Schiller, H.J.B.o.B. Holmes and M, Updated phase 1 results of Zuma-3: Kte-X19, an anti-CD19 chimeric a antigen receptorT Cell therapy, in adult patients with relapsed/refractory acute lymphoblastic leukemia. Transplantation 25, S185 (2019)

  197. B. Shah, M. Bishop, O. Oluwole, A. Logan, M. Baer, W. Donnellan, K. O’Dwyer, H. Holmes, M. Arellano, A.J.H. Ghobadi, KTE-X19, An anti-CD19 Chimeric antigen receptor t cell therapy, in adult patients with relapsed/refractory acute lymphoblastic leukemia: End of phase 1 results of Zuma-3. HemaSphere 3, 426 (2019)

    Google Scholar 

  198. A. Wayne, V. Huynh, N. Hijiya, R. Rouce, P. Brown, J. Krueger, M. Rytting, C. Kitko, E.D. Ziga, M.J.H. Hermiston, Phase 1 results of zuma-4: KTE-X19, an anti-CD19 Chimeric antigen receptor t cell therapy, in pediatric and adolescent patients with relapsed/refractory b cell acute lymphoblastic leukemia. HemaSphere 3, 433 (2019)

    Google Scholar 

  199. L.J. Nastoupil, M.D. Jain, L. Feng, J.Y. Spiegel, A. Ghobadi, Y. Lin, S. Dahiya, M. Lunning, L. Lekakis, P.JJo.C.O. Reagan, Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: Results from the US lymphoma CAR T consortium. J. Clin. Oncol. 19, 3119–3128 (2020)

    Google Scholar 

  200. M.-L. Schuber, S. Dietrich, S. Stilgenbauer, A. Schmitt, P. Pavel, A. Kunz, A. Bondong, M. Wegner, P. Stadtherr, S.JBo.B.M. Jung, Feasibility and safety of CD19 CAR T cell treatment for B-cell lymphoma relapse after allogeneic hematopoietic stem cell transplantation. Biol. Blood Bone Marrow Transpl. 26, 1575–1580 (2020)

    Google Scholar 

  201. P.-P. Zheng, J.M. Kros, J. Li, Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts. Drug Discov. Today 23, 1175–1182 (2018)

    PubMed  Google Scholar 

  202. L.J. Nastoupil, M.D. Jain, J.Y. Spiegel, A. Ghobadi, Y. Lin, S. Dahiya, M.A. Lunning, L.J. Lekakis, P.M. Reagan, O.O. Oluwole, Axicabtagene ciloleucel (axi-cel) CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: real world experience. Blood 132, 91–91 (2018)

    Google Scholar 

  203. V. Prasad, Tisagenlecleucel—the first approved CAR-T-cell therapy: implications for payers and policy makers. Nat. Rev. Clin. Oncol. 15, 11–12 (2018)

    PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Maryam Akhoundi and Mahsa Mohammadi contributed equally to this work.

Authors and Affiliations

  1. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Maryam Akhoundi & Mahsa Mohammadi

  2. Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

    Mohsen Sheykhhasan & Nashmin Fayazi

  3. Department of Reproductive Biology, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran

    Seyedeh Saeideh Sahraei

  4. Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran

    Seyedeh Saeideh Sahraei & Mohsen Sheykhhasan

Authors
  1. Maryam Akhoundi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahsa Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seyedeh Saeideh Sahraei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohsen Sheykhhasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nashmin Fayazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MA and MM were the major contributors to the writing and revision of the manuscript. SSS and NF collected the related references and participated in discussions. MA and MM revised this article critically for important intellectual content. MS gave approval for the final version of the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Mohsen Sheykhhasan.

Ethics declarations

Conflicts of interest/Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akhoundi, M., Mohammadi, M., Sahraei, S.S. et al. CAR T cell therapy as a promising approach in cancer immunotherapy: challenges and opportunities. Cell Oncol. 44, 495–523 (2021). https://doi.org/10.1007/s13402-021-00593-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-021-00593-1

Keywords

Search

Navigation