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Redirecting T cells to treat solid pediatric cancers

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Abstract

The capacity of single-agent therapy with immune checkpoint inhibitors to control solid cancers by unleashing preexisting local antitumor T cell responses has renewed interest in the broader use of T cells as anticancer therapeutics. At the same time, durable responses of refractory B-lineage malignancies to chimeric-receptor engineered T cells illustrate that T cells can be effectively redirected to cancers that lack preexisting tumor antigen-specific T cells, as most typical childhood cancers. This review summarizes strategies by which T cells can be modified to recognize defined antigens, with a focus on chimeric-receptor engineering. We provide an overview of candidate target antigens currently investigated in advanced preclinical and early clinical trials in pediatric malignancies and discuss the prerequisites for an adequate in vivo function of engineered T cells in the microenvironment of solid tumors and intrinsic and extrinsic limitations of current redirected T cell therapies. We further address innovative solutions to recruit therapeutic T cells to tumors, overcome the unreliable and heterogenous expression of most known tumor-associated antigens, and prevent functional inactivation of T cells in the hostile microenvironment of solid childhood tumors.

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References

  1. Rossig, C., Juergens, H., Schrappe, M., Moericke, A., Henze, G., von Stackelberg, A., et al. (2013). Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria. Pediatric Blood & Cancer, 60(10), 1574–1581.

    CAS  Google Scholar 

  2. Stahl, M., Ranft, A., Paulussen, M., Bolling, T., Vieth, V., Bielack, S., et al. (2011). Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatric Blood & Cancer, 57(4), 549–553.

    Google Scholar 

  3. Bielack, S. S., Kempf-Bielack, B., Branscheid, D., Carrle, D., Friedel, G., Helmke, K., et al. (2009). Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. Journal of Clinical Oncology, 27(4), 557–565.

    PubMed  Google Scholar 

  4. Rossig, C., Juergens, H., & Berdel, W. E. (2011). New targets and targeted drugs for the treatment of cancer: an outlook to pediatric oncology. Pediatric Hematology and Oncology, 28(7), 539–555.

    CAS  PubMed  Google Scholar 

  5. Doebele, R. C., Davis, L. E., Vaishnavi, A., Le, A. T., Estrada-Bernal, A., Keysar, S., et al. (2015). An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discovery, 5(10), 1049–1057.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Brahmer, J., Reckamp, K. L., Baas, P., Crino, L., Eberhardt, W. E., Poddubskaya, E., et al. (2015). Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. The New England Journal of Medicine, 373(2), 123–135.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kurtulus, S., Madi, A., Escobar, G., Klapholz, M., Nyman, J., Christian, E., et al. (2019). Checkpoint blockade immunotherapy induces dynamic changes in PD-1(-)CD8(+) tumor-infiltrating T cells. Immunity, 50(1), 181–194 e186.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M. J., Wallweber, H. A., et al. (2017). T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science, 355(6332), 1428–1433.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ott, P. A., Bang, Y. J., Piha-Paul, S. A., Razak, A. R. A., Bennouna, J., Soria, J. C., et al. (2019). T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. Journal of Clinical Oncology, 37(4), 318–327.

    PubMed  Google Scholar 

  10. Grobner, S. N., Worst, B. C., Weischenfeldt, J., Buchhalter, I., Kleinheinz, K., Rudneva, V. A., et al. (2018). The landscape of genomic alterations across childhood cancers. Nature, 555(7696), 321–327.

    PubMed  Google Scholar 

  11. Ma, X., Liu, Y., Liu, Y., Alexandrov, L. B., Edmonson, M. N., Gawad, C., et al. (2018). Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature, 555(7696), 371–376.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Vakkila, J., Jaffe, R., Michelow, M., & Lotze, M. T. (2006). Pediatric cancers are infiltrated predominantly by macrophages and contain a paucity of dendritic cells: a major nosologic difference with adult tumors. Clinical Cancer Research, 12(7 Pt 1), 2049–2054.

    CAS  PubMed  Google Scholar 

  13. Tawbi, H. A., Burgess, M., Bolejack, V., Van Tine, B. A., Schuetze, S. M., Hu, J., et al. (2017). Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. The Lancet Oncology, 18(11), 1493–1501.

    CAS  PubMed  Google Scholar 

  14. Merchant, M. S., Wright, M., Baird, K., Wexler, L. H., Rodriguez-Galindo, C., Bernstein, D., et al. (2016). Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clinical Cancer Research, 22(6), 1364–1370.

    CAS  PubMed  Google Scholar 

  15. Meyer-Wentrup, F., Richter, G., & Burdach, S. (2005). Identification of an immunogenic EWS-FLI1-derived HLA-DR-restricted T helper cell epitope. Pediatric Hematology and Oncology, 22(4), 297–308.

    CAS  PubMed  Google Scholar 

  16. Griffioen, M., Kessler, J. H., Borghi, M., van Soest, R. A., van der Minne, C. E., Nouta, J., et al. (2006). Detection and functional analysis of CD8+ T cells specific for PRAME: a target for T-cell therapy. Clinical Cancer Research, 12(10), 3130–3136.

    CAS  PubMed  Google Scholar 

  17. Schirmer, D., Grunewald, T. G., Klar, R., Schmidt, O., Wohlleber, D., Rubio, R. A., et al. (2016). Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity. Oncoimmunology, 5(6), e1175795.

    PubMed  PubMed Central  Google Scholar 

  18. Quintarelli, C., Dotti, G., De Angelis, B., Hoyos, V., Mims, M., Luciano, L., et al. (2008). Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia. Blood, 112(5), 1876–1885.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gerdemann, U., Katari, U., Christin, A. S., Cruz, C. R., Tripic, T., Rousseau, A., et al. (2011). Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma. Molecular Therapy, 19(12), 2258–2268.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Altvater, B., Kailayangiri, S., Theimann, N., Ahlmann, M., Farwick, N., Chen, C., et al. (2014). Common Ewing sarcoma-associated antigens fail to induce natural T cell responses in both patients and healthy individuals. Cancer Immunology, Immunotherapy, 63(10), 1047–1060.

    CAS  PubMed  Google Scholar 

  21. Morgan, R. A., Dudley, M. E., Wunderlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., et al. (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 314(5796), 126–129.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Robbins, P. F., Li, Y. F., El-Gamil, M., Zhao, Y., Wargo, J. A., Zheng, Z., et al. (2008). Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. Journal of Immunology, 180(9), 6116–6131.

    CAS  Google Scholar 

  23. D'Angelo, S. P., Melchiori, L., Merchant, M. S., Bernstein, D., Glod, J., Kaplan, R., et al. (2018). Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259)T cells in synovial sarcoma. Cancer Discovery, 8(8), 944–957.

    CAS  PubMed  Google Scholar 

  24. Raffaghello, L., Prigione, I., Bocca, P., Morandi, F., Camoriano, M., Gambini, C., et al. (2005). Multiple defects of the antigen-processing machinery components in human neuroblastoma: immunotherapeutic implications. Oncogene, 24(29), 4634–4644.

    CAS  PubMed  Google Scholar 

  25. Linette, G. P., Stadtmauer, E. A., Maus, M. V., Rapoport, A. P., Levine, B. L., Emery, L., et al. (2013). Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood, 122(6), 863–871.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Mastaglio, S., Genovese, P., Magnani, Z., Ruggiero, E., Landoni, E., Camisa, B., et al. (2017). NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. Blood, 130(5), 606–618.

    CAS  PubMed  Google Scholar 

  27. Bargou, R., Leo, E., Zugmaier, G., Klinger, M., Goebeler, M., Knop, S., et al. (2008). Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science, 321(5891), 974–977.

    CAS  PubMed  Google Scholar 

  28. von Stackelberg, A., Locatelli, F., Zugmaier, G., Handgretinger, R., Trippett, T. M., Rizzari, C., et al. (2016). Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Journal of Clinical Oncology, 34(36), 4381–4389.

    Google Scholar 

  29. Ahmed, M., Cheng, M., Cheung, I. Y., & Cheung, N. K. (2015). Human derived dimerization tag enhances tumor killing potency of a T-cell engaging bispecific antibody. Oncoimmunology, 4(4), e989776.

    PubMed  PubMed Central  Google Scholar 

  30. Finney, H. M., Lawson, A. D., Bebbington, C. R., & Weir, A. N. (1998). Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. Journal of Immunology, 161(6), 2791–2797.

    CAS  Google Scholar 

  31. Imai, C., Mihara, K., Andreansky, M., Nicholson, I. C., Pui, C. H., Geiger, T. L., et al. (2004). Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia, 18(4), 676–684.

    CAS  PubMed  Google Scholar 

  32. Eshhar, Z., Waks, T., Gross, G., & Schindler, D. G. (1993). Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proceedings of the National Academy of Sciences of the United States of America, 90(2), 720–724.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pule, M. A., Savoldo, B., Myers, G. D., Rossig, C., Russell, H. V., Dotti, G., et al. (2008). Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nature Medicine, 14(11), 1264–1270.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Turtle, C. J., Hanafi, L. A., Berger, C., Gooley, T. A., Cherian, S., Hudecek, M., et al. (2016). CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. The Journal of Clinical Investigation, 126(6), 2123–2138.

    PubMed  PubMed Central  Google Scholar 

  35. Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., et al. (2018). Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. The New England Journal of Medicine, 378(5), 439–448.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee, D. W., Kochenderfer, J. N., Stetler-Stevenson, M., Cui, Y. K., Delbrook, C., Feldman, S. A., et al. (2015). T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet, 385(9967), 517–528.

    CAS  PubMed  Google Scholar 

  37. Gardner, R. A., Finney, O., Annesley, C., Brakke, H., Summers, C., Leger, K., et al. (2017). Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood, 129(25), 3322–3331.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Neelapu, S. S., Locke, F. L., Bartlett, N. L., Lekakis, L. J., Miklos, D. B., Jacobson, C. A., et al. (2017). Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. The New England Journal of Medicine, 377(26), 2531–2544.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Heczey, A., Louis, C. U., Savoldo, B., Dakhova, O., Durett, A., Grilley, B., et al. (2017). CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Molecular Therapy, 25(9), 2214–2224.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Louis, C. U., Savoldo, B., Dotti, G., Pule, M., Yvon, E., Myers, G. D., et al. (2011). Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood, 118(23), 6050–6056.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Straathof, K., Flutter, B., Wallace, R., Thomas, S., Cheung, G., Collura, A., et al. (2018). A Cancer Research UK phase I trial of anti-GD2 chimeric antigen receptor (CAR) transduced T-cells (1RG-CART) in patients with relapsed or refractory neuroblastoma. Cancer Research, 78(13 Supplement), CT145.

    Google Scholar 

  42. Ahmed, N., Brawley, V. S., Hegde, M., Robertson, C., Ghazi, A., Gerken, C., et al. (2015). Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. Journal of Clinical Oncology, 33(15), 1688–1696.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ahmed, N., Brawley, V., Hegde, M., Bielamowicz, K., Kalra, M., Landi, D., et al. (2017). HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncology, 3(8), 1094–1101.

    PubMed  PubMed Central  Google Scholar 

  44. Sotillo, E., Barrett, D. M., Black, K. L., Bagashev, A., Oldridge, D., Wu, G., et al. (2015). Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discovery, 5(12), 1282–1295.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu, Z. L., Schwartz, E., Seeger, R., & Ladisch, S. (1986). Expression of GD2 ganglioside by untreated primary human neuroblastomas. Cancer Research, 46(1), 440–443.

    CAS  PubMed  Google Scholar 

  46. Schulz, G., Cheresh, D. A., Varki, N. M., Yu, A., Staffileno, L. K., & Reisfeld, R. A. (1984). Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Research, 44(12), 5914–5920.

    CAS  PubMed  Google Scholar 

  47. Rossig, C., Bollard, C. M., Nuchtern, J. G., Rooney, C. M., & Brenner, M. K. (2002). Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy. Blood, 99(6), 2009–2016.

    CAS  PubMed  Google Scholar 

  48. Sorkin, L. S., Otto, M., Baldwin III, W. M., Vail, E., Gillies, S. D., Handgretinger, R., et al. (2010). Anti-GD(2) with an FC point mutation reduces complement fixation and decreases antibody-induced allodynia. Pain, 149(1), 135–142.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Richman, S. A., Nunez-Cruz, S., Moghimi, B., Li, L. Z., Gershenson, Z. T., Mourelatos, Z., et al. (2018). High-affinity GD2-specific CAR T cells induce fatal encephalitis in a preclinical neuroblastoma model. Cancer Immunology Research, 6(1), 36–46.

    CAS  PubMed  Google Scholar 

  50. Andersch, L., Radke, J., Klaus, A., Schwiebert, S., Winkler, A., Schumann, E., et al. (2019). CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing. BMC Cancer, 19(1), 895.

    PubMed  PubMed Central  Google Scholar 

  51. Portoukalian, J., David, M. J., Gain, P., & Richard, M. (1993). Shedding of GD2 ganglioside in patients with retinoblastoma. International Journal of Cancer, 53(6), 948–951.

    CAS  PubMed  Google Scholar 

  52. Mount, C. W., Majzner, R. G., Sundaresh, S., Arnold, E. P., Kadapakkam, M., Haile, S., et al. (2018). Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas. Nature Medicine, 24(5), 572–579.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Dobrenkov, K., Ostrovnaya, I., Gu, J., Cheung, I. Y., & Cheung, N. K. (2016). Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults. Pediatric Blood & Cancer, 63(10), 1780–1785.

    CAS  Google Scholar 

  54. Kailayangiri, S., Altvater, B., Spurny, C., Jamitzky, S., Schelhaas, S., Jacobs, A. H., et al. (2017). Targeting Ewing sarcoma with activated and GD2-specific chimeric antigen receptor-engineered human NK cells induces upregulation of immune-inhibitory HLA-G. Oncoimmunology, 6(1), e1250050.

    PubMed  Google Scholar 

  55. Long, A. H., Highfill, S. L., Cui, Y., Smith, J. P., Walker, A. J., Ramakrishna, S., et al. (2016). Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunology Research, 4(10), 869–880.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Roth, M., Linkowski, M., Tarim, J., Piperdi, S., Sowers, R., Geller, D., et al. (2014). Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. Cancer, 120(4), 548–554.

    CAS  PubMed  Google Scholar 

  57. Modak, S., Gerald, W., & Cheung, N. K. (2002). Disialoganglioside GD2 and a novel tumor antigen: potential targets for immunotherapy of desmoplastic small round cell tumor. Medical and Pediatric Oncology, 39(6), 547–551.

    PubMed  Google Scholar 

  58. Geiser, M., Schultz, D., Le Cardinal, A., Voshol, H., & Garcia-Echeverria, C. (1999). Identification of the human melanoma-associated chondroitin sulfate proteoglycan antigen epitope recognized by the antitumor monoclonal antibody 763.74 from a peptide phage library. Cancer Research, 59(4), 905–910.

    CAS  PubMed  Google Scholar 

  59. Svendsen, A., Verhoeff, J. J., Immervoll, H., Brogger, J. C., Kmiecik, J., Poli, A., et al. (2011). Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. Acta Neuropathologica, 122(4), 495–510.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Pellegatta, S., Savoldo, B., Di Ianni, N., Corbetta, C., Chen, Y., Patane, M., et al. (2018). Constitutive and TNFalpha-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy. Science Translational Medicine, 10(430).

    PubMed  Google Scholar 

  61. Brehm, H., Niesen, J., Mladenov, R., Stein, C., Pardo, A., Fey, G., et al. (2014). A CSPG4-specific immunotoxin kills rhabdomyosarcoma cells and binds to primary tumor tissues. Cancer Letters, 352(2), 228–235.

    CAS  PubMed  Google Scholar 

  62. Wang, X., Katayama, A., Wang, Y., Yu, L., Favoino, E., Sakakura, K., et al. (2011). Functional characterization of an scFv-Fc antibody that immunotherapeutically targets the common cancer cell surface proteoglycan CSPG4. Cancer Research, 71(24), 7410–7422.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Geldres, C., Savoldo, B., Hoyos, V., Caruana, I., Zhang, M., Yvon, E., et al. (2014). T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo. Clinical Cancer Research, 20(4), 962–971.

    CAS  PubMed  Google Scholar 

  64. Wang, J., Svendsen, A., Kmiecik, J., Immervoll, H., Skaftnesmo, K. O., Planaguma, J., et al. (2011). Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma. PLoS One, 6(7), e23062.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Beard, R. E., Zheng, Z., Lagisetty, K. H., Burns, W. R., Tran, E., Hewitt, S. M., et al. (2014). Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells. Journal for Immunotherapy of Cancer, 2, 25.

    PubMed  PubMed Central  Google Scholar 

  66. Prieto, C., Lopez-Millan, B., Roca-Ho, H., Stam, R. W., Romero-Moya, D., Rodriguez-Baena, F. J., et al. (2018). Correction: NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL. Leukemia, 32(10), 2306.

    CAS  PubMed  Google Scholar 

  67. Bosse, K. R., Raman, P., Zhu, Z., Lane, M., Martinez, D., Heitzeneder, S., et al. (2017). Identification of GPC2 as an oncoprotein and candidate immunotherapeutic target in high-risk neuroblastoma. Cancer Cell, 32(3), 295–309 e212.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, N., Fu, H., Hewitt, S. M., Dimitrov, D. S., & Ho, M. (2017). Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma. Proceedings of the National Academy of Sciences of the United States of America, 114(32), E6623–E6631.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Scotlandi, K., Manara, M. C., Hattinger, C. M., Benini, S., Perdichizzi, S., Pasello, M., et al. (2005). Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing’s sarcoma. European Journal of Cancer, 41(9), 1349–1361.

    CAS  PubMed  Google Scholar 

  70. Ahmed, N., Salsman, V. S., Yvon, E., Louis, C. U., Perlaky, L., Wels, W. S., et al. (2009). Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Molecular Therapy, 17(10), 1779–1787.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Gorlick, R., Huvos, A. G., Heller, G., Aledo, A., Beardsley, G. P., Healey, J. H., et al. (1999). Expression of HER2/erbB-2 correlates with survival in osteosarcoma. Journal of Clinical Oncology, 17(9), 2781–2788.

    CAS  PubMed  Google Scholar 

  72. Ganti, R., Skapek, S. X., Zhang, J., Fuller, C. E., Wu, J., Billups, C. A., et al. (2006). Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma. Modern Pathology, 19(9), 1213–1220.

    CAS  PubMed  Google Scholar 

  73. Ahmed, N., Ratnayake, M., Savoldo, B., Perlaky, L., Dotti, G., Wels, W. S., et al. (2007). Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Research, 67(12), 5957–5964.

    CAS  PubMed  Google Scholar 

  74. Morgan, R. A., Yang, J. C., Kitano, M., Dudley, M. E., Laurencot, C. M., & Rosenberg, S. A. (2010). Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular Therapy, 18(4), 843–851.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Navai, S. A., Derenzo, C., Joseph, S. K., Sanber, K., Byrd, T., Zhang, H., et al. (2019). Administration of HER2-CAR T cells after lymphodepletion safely improves T cell expansion and induces clinical responses in patients with advanced sarcomas. Cancer Research, 79(13 Supplement), LB-147.

    Google Scholar 

  76. Padfield, E., Ellis, H. P., & Kurian, K. M. (2015). Current therapeutic advances targeting EGFR and EGFRvIII in glioblastoma. Frontiers in Oncology, 5, 5.

    PubMed  PubMed Central  Google Scholar 

  77. O'Rourke, D. M., Nasrallah, M. P., Desai, A., Melenhorst, J. J., Mansfield, K., Morrissette, J. J. D., et al. (2017). A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Science Translational Medicine, 9(399).

    PubMed  PubMed Central  Google Scholar 

  78. Gan, H. K., Burgess, A. W., Clayton, A. H., & Scott, A. M. (2012). Targeting of a conformationally exposed, tumor-specific epitope of EGFR as a strategy for cancer therapy. Cancer Research, 72(12), 2924–2930.

    CAS  PubMed  Google Scholar 

  79. Goff, S. L., Morgan, R. A., Yang, J. C., Sherry, R. M., Robbins, P. F., Restifo, N. P., et al. (2019). Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. Journal of Immunotherapy, 42(4), 126–135.

    CAS  PubMed  Google Scholar 

  80. Debinski, W., Gibo, D. M., Hulet, S. W., Connor, J. R., & Gillespie, G. Y. (1999). Receptor for interleukin 13 is a marker and therapeutic target for human high-grade gliomas. Clinical Cancer Research, 5(5), 985–990.

    CAS  PubMed  Google Scholar 

  81. Newman, J. P., Wang, G. Y., Arima, K., Guan, S. P., Waters, M. R., Cavenee, W. K., et al. (2017). Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme. Nature Communications, 8(1), 1913.

    PubMed  PubMed Central  Google Scholar 

  82. Loftus, R. W., Koff, M. D., Brown, J. R., Patel, H. M., Jensen, J. T., Reddy, S., et al. (2015). The dynamics of Enterococcus transmission from bacterial reservoirs commonly encountered by anesthesia providers. Anesthesia and Analgesia, 120(4), 827–836.

    CAS  PubMed  Google Scholar 

  83. Keu, K. V., Witney, T. H., Yaghoubi, S., Rosenberg, J., Kurien, A., Magnusson, R., et al. (2017). Reporter gene imaging of targeted T cell immunotherapy in recurrent glioma. Science Translational Medicine, 9(373).

    PubMed  PubMed Central  Google Scholar 

  84. Brown, C. E., Alizadeh, D., Starr, R., Weng, L., Wagner, J. R., Naranjo, A., et al. (2016). Regression of glioblastoma after chimeric antigen receptor T-cell therapy. The New England Journal of Medicine, 375(26), 2561–2569.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Passoni, L., Longo, L., Collini, P., Coluccia, A. M., Bozzi, F., Podda, M., et al. (2009). Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients. Cancer Research, 69(18), 7338–7346.

    CAS  PubMed  Google Scholar 

  86. Mosse, Y. P. (2016). Anaplastic lymphoma kinase as a cancer target in pediatric malignancies. Clinical Cancer Research, 22(3), 546–552.

    CAS  PubMed  Google Scholar 

  87. Walker, A. J., Majzner, R. G., Zhang, L., Wanhainen, K., Long, A. H., Nguyen, S. M., et al. (2017). Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Molecular Therapy, 25(9), 2189–2201.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang, W., Xu, Y., Zhang, L., Wang, S., Yin, B., Zhao, S., et al. (2018). Synergistic effects of TGFbeta2, WNT9a, and FGFR4 signals attenuate satellite cell differentiation during skeletal muscle development. Aging Cell, 17(4), e12788.

    PubMed  PubMed Central  Google Scholar 

  89. Khan, J., Wei, J. S., Ringner, M., Saal, L. H., Ladanyi, M., Westermann, F., et al. (2001). Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nature Medicine, 7(6), 673–679.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Shern, J. F., Chen, L., Chmielecki, J., Wei, J. S., Patidar, R., Rosenberg, M., et al. (2014). Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discovery, 4(2), 216–231.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Taylor, J. G. T., Cheuk, A. T., Tsang, P. S., Chung, J. Y., Song, Y. K., Desai, K., et al. (2009). Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. The Journal of Clinical Investigation, 119(11), 3395–3407.

    CAS  PubMed  Google Scholar 

  92. McKinnon, T., Venier, R., Yohe, M., Sindiri, S., Gryder, B. E., Shern, J. F., et al. (2018). Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma. Oncogene, 37(20), 2630–2644.

    CAS  PubMed  Google Scholar 

  93. Shivaprasad, N., Xiong, Y., Yohe, M., Schneider, D., Shern, J., Baskar, S., et al. (2016). Developing FGFR4 chimeric antigen receptor CAR T cell therapy against rhabdomyosarcoma. Molecular Therapy, 24(1), S257–S258.

    Google Scholar 

  94. Husain, B., Ramani, S.R., Chiang, E., Lehoux, I., Paduchuri, S., Arena, T.A., et al. (2019). A platform for extracellular interactome discovery identifies novel functional binding partners for the immune receptors B7-H3/CD276 and PVR/CD155. Molecular & Cellular Proteomics, Jul 15.

  95. Modak, S., Kramer, K., Gultekin, S. H., Guo, H. F., & Cheung, N. K. (2001). Monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors. Cancer Research, 61(10), 4048–4054.

    CAS  PubMed  Google Scholar 

  96. Ahmed, M., Cheng, M., Zhao, Q., Goldgur, Y., Cheal, S. M., Guo, H. F., et al. (2015). Humanized affinity-matured monoclonal antibody 8H9 has potent antitumor activity and binds to FG loop of tumor antigen B7-H3. The Journal of Biological Chemistry, 290(50), 30018–30029.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Castriconi, R., Dondero, A., Augugliaro, R., Cantoni, C., Carnemolla, B., Sementa, A. R., et al. (2004). Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proceedings of the National Academy of Sciences of the United States of America, 101(34), 12640–12645.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Seaman, S., Zhu, Z., Saha, S., Zhang, X. M., Yang, M. Y., Hilton, M. B., et al. (2017). Eradication of tumors through simultaneous ablation of CD276/B7-H3-positive tumor cells and tumor vasculature. Cancer Cell, 31(4), 501–515 e508.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Majzner, R. G., Theruvath, J. L., Nellan, A., Heitzeneder, S., Cui, Y., Mount, C. W., et al. (2019). CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and prain tumors. Clinical Cancer Research, 25(8), 2560–2574.

    PubMed  Google Scholar 

  100. Zhou, Z., Luther, N., Ibrahim, G. M., Hawkins, C., Vibhakar, R., Handler, M. H., et al. (2013). B7-H3, a potential therapeutic target, is expressed in diffuse intrinsic pontine glioma. Journal of Neuro-Oncology, 111(3), 257–264.

    CAS  PubMed  Google Scholar 

  101. Wang, L., Zhang, Q., Chen, W., Shan, B., Ding, Y., Zhang, G., et al. (2013). B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One, 8(8), e70689.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Loo, D., Alderson, R. F., Chen, F. Z., Huang, L., Zhang, W., Gorlatov, S., et al. (2012). Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Clinical Cancer Research, 18(14), 3834–3845.

    CAS  PubMed  Google Scholar 

  103. Kramer, K., Kushner, B. H., Modak, S., Pandit-Taskar, N., Smith-Jones, P., Zanzonico, P., et al. (2010). Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. Journal of Neuro-Oncology, 97(3), 409–418.

    PubMed  Google Scholar 

  104. Du, H., Hirabayashi, K., Ahn, S., Kren, N. P., Montgomery, S. A., Wang, X., et al. (2019). Antitumor responses in the absence of toxicity in solid tumors by targeting B7-H3 via chimeric antigen receptor T cells. Cancer Cell, 35(2), 221–237 e228.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Nehama, D., Di Ianni, N., Musio, S., Du, H., Patane, M., Pollo, B., et al. (2019). B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres. EBioMedicine, 47, 33–43.

    PubMed  PubMed Central  Google Scholar 

  106. Watanabe, K., Terakura, S., Martens, A. C., van Meerten, T., Uchiyama, S., Imai, M., et al. (2015). Target antigen density governs the efficacy of anti-CD20-CD28-CD3 zeta chimeric antigen receptor-modified effector CD8+ T cells. Journal of Immunology, 194(3), 911–920.

    CAS  Google Scholar 

  107. Hombach, A. A., Gorgens, A., Chmielewski, M., Murke, F., Kimpel, J., Giebel, B., et al. (2016). Superior therapeutic index in lymphoma therapy: CD30(+) CD34(+) hematopoietic stem cells resist a chimeric antigen receptor T-cell attack. Molecular Therapy, 24(8), 1423–1434.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Fry, T. J., Shah, N. N., Orentas, R. J., Stetler-Stevenson, M., Yuan, C. M., Ramakrishna, S., et al. (2018). CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nature Medicine, 24(1), 20–28.

    CAS  PubMed  Google Scholar 

  109. Kailayangiri, S., Altvater, B., Lesch, S., Balbach, S., Gottlich, C., Kuhnemundt, J., et al. (2019). EZH2 inhibition in Ewing sarcoma upregulates GD2 expression for targeting with gene-modified T cells. Molecular Therapy, 27(5), 933–946.

    CAS  PubMed  Google Scholar 

  110. Ramakrishna, S., Highfill, S. L., Walsh, Z., Nguyen, S. M., Lei, H., Shern, J. F., et al. (2019). Modulation of target antigen density improves CAR T-cell functionality and persistence. Clinical Cancer Research, 25(17), 5329–5341.

    PubMed  Google Scholar 

  111. Pont, M.J., Hill, T., Cole, G.O., Abbott, J.J., Kelliher, J., Salter, A.I., et al. (2019). gamma-secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood, Sep 26.

  112. Ruella, M., Barrett, D. M., Kenderian, S. S., Shestova, O., Hofmann, T. J., Perazzelli, J., et al. (2016). Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. The Journal of Clinical Investigation, 126(10), 3814–3826.

    PubMed  PubMed Central  Google Scholar 

  113. Sukumaran, S., Watanabe, N., Bajgain, P., Raja, K., Mohammed, S., Fisher, W. E., et al. (2018). Enhancing the potency and specificity of engineered T cells for cancer treatment. Cancer Discovery, 8(8), 972–987.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Grada, Z., Hegde, M., Byrd, T., Shaffer, D. R., Ghazi, A., Brawley, V. S., et al. (2013). TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Molecular Therapy--Nucleic Acids, 2, e105.

    PubMed  PubMed Central  Google Scholar 

  115. Hegde, M., Mukherjee, M., Grada, Z., Pignata, A., Landi, D., Navai, S. A., et al. (2016). Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. The Journal of Clinical Investigation, 126(8), 3036–3052.

    PubMed  PubMed Central  Google Scholar 

  116. Ahn, S., Li, J., Sun, C., Gao, K., Hirabayashi, K., Li, H., et al. (2019). Cancer immunotherapy with T cells carrying bispecific receptors that mimic antibodies. Cancer Immunology Research, 7(5), 773–783.

    CAS  PubMed  Google Scholar 

  117. Choi, B. D., Yu, X., Castano, A. P., Bouffard, A. A., Schmidts, A., Larson, R. C., et al. (2019). CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nature Biotechnology, 37(9), 1049–1058.

    CAS  PubMed  Google Scholar 

  118. Lee, Y. G., Marks, I., Srinivasarao, M., Kanduluru, A. K., Mahalingam, S. M., Liu, X., et al. (2019). Use of a single CAR T cell and several bispecific adapters facilitates eradication of multiple antigenically different solid tumors. Cancer Research, 79(2), 387–396.

    CAS  PubMed  Google Scholar 

  119. Ma, J. S., Kim, J. Y., Kazane, S. A., Choi, S. H., Yun, H. Y., Kim, M. S., et al. (2016). Versatile strategy for controlling the specificity and activity of engineered T cells. Proceedings of the National Academy of Sciences of the United States of America, 113(4), E450–E458.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Urbanska, K., Lanitis, E., Poussin, M., Lynn, R. C., Gavin, B. P., Kelderman, S., et al. (2012). A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Research, 72(7), 1844–1852.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Cartellieri, M., Feldmann, A., Koristka, S., Arndt, C., Loff, S., Ehninger, A., et al. (2016). Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer Journal, 6(8), e458.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Mitwasi, N., Feldmann, A., Bergmann, R., Berndt, N., Arndt, C., Koristka, S., et al. (2017). Development of novel target modules for retargeting of UniCAR T cells to GD2 positive tumor cells. Oncotarget, 8(65), 108584–108603.

    PubMed  PubMed Central  Google Scholar 

  123. Roybal, K. T., Williams, J. Z., Morsut, L., Rupp, L. J., Kolinko, I., Choe, J. H., et al. (2016). Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell, 167(2), 419–432 e416.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Srivastava, S., Salter, A. I., Liggitt, D., Yechan-Gunja, S., Sarvothama, M., Cooper, K., et al. (2019). Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated roxicity to normal tissues and enables selective tumor targeting. Cancer Cell, 35(3), 489–503 e488.

    CAS  PubMed  Google Scholar 

  125. Caruana, I., Savoldo, B., Hoyos, V., Weber, G., Liu, H., Kim, E. S., et al. (2015). Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nature Medicine, 21(5), 524–529.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., et al. (2018). Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature Medicine, 24(5), 541–550.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Parihar, R., Rivas, C., Huynh, M., Omer, B., Lapteva, N., Metelitsa, L. S., et al. (2019). NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Cancer Immunology Research, 7(3), 363–375.

    PubMed  Google Scholar 

  128. Chang, C. H., Qiu, J., O'Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., et al. (2015). Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell, 162(6), 1229–1241.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Turtle, C. J., Hanafi, L. A., Berger, C., Hudecek, M., Pender, B., Robinson, E., et al. (2016). Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Science Translational Medicine, 8(355), 355ra116.

    PubMed  PubMed Central  Google Scholar 

  130. Chmielewski, M., Kopecky, C., Hombach, A. A., & Abken, H. (2011). 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 Research, 71(17), 5697–5706.

    CAS  PubMed  Google Scholar 

  131. Chinnasamy, D., Yu, Z., Kerkar, S. P., Zhang, L., Morgan, R. A., Restifo, N. P., et al. (2012). Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clinical Cancer Research, 18(6), 1672–1683.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang, L., Morgan, R. A., Beane, J. D., Zheng, Z., Dudley, M. E., Kassim, S. H., et al. (2015). Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clinical Cancer Research, 21(10), 2278–2288.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Robertson, M. J., Kirkwood, J. M., Logan, T. F., Koch, K. M., Kathman, S., Kirby, L. C., et al. (2008). A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clinical Cancer Research, 14(11), 3462–3469.

    CAS  PubMed  Google Scholar 

  134. Chmielewski, M., & Abken, H. (2017). CAR T cells releasing IL-18 convert to T-Bet(high) FoxO1(low) effectors that exhibit augmented activity against advanced solid tumors. Cell Reports, 21(11), 3205–3219.

    CAS  PubMed  Google Scholar 

  135. Hu, B., Ren, J., Luo, Y., Keith, B., Young, R. M., Scholler, J., et al. (2017). Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Reports, 20(13), 3025–3033.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Avanzi, M. P., Yeku, O., Li, X., Wijewarnasuriya, D. P., van Leeuwen, D. G., Cheung, K., et al. (2018). Engineered tumor-targeted T vells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Reports, 23(7), 2130–2141.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Chen, Y., Sun, C., Landoni, E., Metelitsa, L., Dotti, G., & Savoldo, B. (2019). Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clinical Cancer Research, 25(9), 2915–2924.

    PubMed  Google Scholar 

  138. Landmeier, S., Altvater, B., Pscherer, S., Eing, B. R., Kuehn, J., Rooney, C. M., et al. (2007). Gene-engineered varicella-zoster virus reactive CD4+ cytotoxic T cells exert tumor-specific effector function. Cancer Research, 67(17), 8335–8343.

    CAS  PubMed  Google Scholar 

  139. Tanaka, M., Tashiro, H., Omer, B., Lapteva, N., Ando, J., Ngo, M., et al. (2017). Vaccination targeting native receptors to enhance the function and proliferation of chimeric antigen receptor (CAR)-modified T cells. Clinical Cancer Research.

  140. Rossig, C., Pule, M., Altvater, B., Saiagh, S., Wright, G., Ghorashian, S., et al. (2017). Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia. Leukemia, 31(5), 1087–1095.

    CAS  PubMed  Google Scholar 

  141. Ma, L., Dichwalkar, T., Chang, J. Y. H., Cossette, B., Garafola, D., Zhang, A. Q., et al. (2019). Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science, 365(6449), 162–168.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. VanSeggelen, H., Tantalo, D. G., Afsahi, A., Hammill, J. A., & Bramson, J. L. (2015). Chimeric antigen receptor-engineered T cells as oncolytic virus carriers. Molecular Therapy–Oncolytics, 2, 15014.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Tanoue, K., Rosewell Shaw, A., Watanabe, N., Porter, C., Rana, B., Gottschalk, S., et al. (2017). Armed oncolytic adenovirus-expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors. Cancer Research, 77(8), 2040–2051.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Jacoby, E., Bielorai, B., Avigdor, A., Itzhaki, O., Hutt, D., Nussboim, V., et al. (2018). Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. American Journal of Hematology, 93(12), 1485–1492.

    CAS  PubMed  Google Scholar 

  145. Schuster, S. J., Svoboda, J., Chong, E. A., Nasta, S. D., Mato, A. R., Anak, O., et al. (2017). Chimeric antigen receptor T cells in refractory B-cell lymphomas. The New England Journal of Medicine, 377(26), 2545–2554.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kawalekar, O. U., O'Connor, R. S., Fraietta, J. A., Guo, L., McGettigan, S. E., Posey Jr., A. D., et al. (2016). Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity, 44(2), 380–390.

    CAS  PubMed  Google Scholar 

  147. Shum, T., Omer, B., Tashiro, H., Kruse, R. L., Wagner, D. L., Parikh, K., et al. (2017). Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discovery, 7(11), 1238–1247.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Davenport, A. J., Cross, R. S., Watson, K. A., Liao, Y., Shi, W., Prince, H. M., et al. (2018). Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 115(9), E2068–E2076.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Long, A. H., Haso, W. M., Shern, J. F., Wanhainen, K. M., Murgai, M., Ingaramo, M., et al. (2015). 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nature Medicine, 21(6), 581–590.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Gomes-Silva, D., Mukherjee, M., Srinivasan, M., Krenciute, G., Dakhova, O., Zheng, Y., et al. (2017). Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Reports, 21(1), 17–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Fisher, J., Sharma, R., Don, D. W., Barisa, M., Hurtado, M. O., Abramowski, P., et al. (2019). Engineering gammadeltaT cells limits tonic signaling associated with chimeric antigen receptors. Science Signaling, 12(598).

    CAS  PubMed  Google Scholar 

  152. Watanabe, N., Bajgain, P., Sukumaran, S., Ansari, S., Heslop, H. E., Rooney, C. M., et al. (2016). Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology, 5(12), e1253656.

    PubMed  PubMed Central  Google Scholar 

  153. Feucht, J., Sun, J., Eyquem, J., Ho, Y. J., Zhao, Z., Leibold, J., et al. (2019). Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nature Medicine, 25(1), 82–88.

    CAS  PubMed  Google Scholar 

  154. Sakemura, R., Terakura, S., Watanabe, K., Julamanee, J., Takagi, E., Miyao, K., et al. (2016). A Tet-On inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunology Research, 4(8), 658–668.

    CAS  PubMed  Google Scholar 

  155. Mestermann, K., Giavridis, T., Weber, J., Rydzek, J., Frenz, S., Nerreter, T., et al. (2019). The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Science Translational Medicine, 11(499).

    PubMed  Google Scholar 

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Acknowledgments

The authors thank Kinderkrebshilfe Münster e.V. for the continuous support of CAR T cell research at our institution.

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  1. Department of Pediatric Hematology and Oncology Albert-Schweitzer Campus 1, University Children’s Hospital Muenster, 48149, Münster, Germany

    Kerstin K. Rauwolf & Claudia Rossig

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  1. Kerstin K. Rauwolf
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Rauwolf, K.K., Rossig, C. Redirecting T cells to treat solid pediatric cancers. Cancer Metastasis Rev 38, 611–624 (2019). https://doi.org/10.1007/s10555-019-09821-5

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