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The potential of CAR T cell therapy for prostate cancer

Abstract

Chimeric antigen receptor (CAR) T cell immunotherapy involves the genetic modification of the patient’s own T cells so that they specifically recognize and destroy tumour cells. Considerable clinical success has been achieved using this technique in patients with lymphoid malignancies, but clinical studies that investigated treating solid tumours using this emerging technology have been disappointing. A number of developments might be able to increase the efficacy of CAR T cell therapy for treatment of prostate cancer, including improved trafficking to the tumour, techniques to overcome the immunosuppressive tumour microenvironment, as well as methods to enhance CAR T cell persistence, specificity and safety. Furthermore, CAR T cell therapy has the potential to be combined with other treatment modalities, such as androgen deprivation therapy, radiotherapy or chemotherapy, and could be applied as focal CAR T cell therapy for prostate cancer.

Key points

  • Chimeric antigen receptor (CAR) T cells, based on genetic engineering of the patient’s own T cells for targeted tumour cell lysis, have great potential as immunotherapy for prostate cancer.

  • Current developments focus on optimizing CAR T cells to improve trafficking to the tumour, overcome the immunosuppressive tumour microenvironment, and increase the cells’ persistence, specificity and safety.

  • Preclinical studies show that combination with standard therapies, such as androgen deprivation therapy, radiotherapy or chemotherapy, can be used to enhance the efficacy of CAR T cells against prostate cancer.

  • Intratumoural application of CAR T cells based on optimized imaging modalities could provide an effective and safe new focal therapeutic option for patients with localized prostate cancer.

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Fig. 1: Schematic representation of different CAR generations.
Fig. 2: Obstacles to CAR T cell therapy in the tumour microenvironment of prostate cancer.
Fig. 3: Transperineal injection of CAR T cells for focal therapy of prostate cancer.

References

  1. 1.

    Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    Google Scholar 

  2. 2.

    Moris, L. et al. Benefits and risks of primary treatments for high-risk localized and locally advanced prostate cancer: an international multidisciplinary systematic review. Eur. Urol. 77, 614–627 (2020).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Pascale, M. et al. The outcome of prostate cancer patients treated with curative intent strongly depends on survival after metastatic progression. BMC Cancer 17, 651 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Sathianathen, N. J., Konety, B. R., Crook, J., Saad, F. & Lawrentschuk, N. Landmarks in prostate cancer. Nat. Rev. Urol. 15, 627–642 (2018).

    PubMed  Article  Google Scholar 

  5. 5.

    Cha, H. R., Lee, J. H. & Ponnazhagan, S. Revisiting immunotherapy: a focus on prostate cancer. Cancer Res. 80, 1615–1623 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Bilusic, M., Madan, R. A. & Gulley, J. L. Immunotherapy of prostate cancer: facts and hopes. Clin. Cancer Res. 23, 6764–6770 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Kiessling, A. et al. Tumor-associated antigens for specific immunotherapy of prostate cancer. Cancers 4, 193–217 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Kantoff, P. W. et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 1099–1105 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Kantoff, P. W., Gulley, J. L. & Pico-Navarro, C. Revised overall survival analysis of a phase II, randomized, double-blind, controlled study of PROSTVAC in men with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 35, 124–125 (2017).

    PubMed  Article  Google Scholar 

  10. 10.

    Hansen, A. R. et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann. Oncol. 29, 1807–1813 (2018).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Kwon, E. D. et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 15, 700–712 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Hernandez-Hoyos, G. et al. MOR209/ES414, a novel bispecific antibody targeting PSMA for the treatment of metastatic castration-resistant prostate cancer. Mol. Cancer Ther. 15, 2155–2165 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Tran, B. et al. Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 38, TPS261–TPS261 (2020).

    Article  Google Scholar 

  14. 14.

    Elsallab, M., Levine, B. L., Wayne, A. S. & Abou-El-Enein, M. CAR T-cell product performance in haematological malignancies before and after marketing authorisation. Lancet Oncol. 21, e104–e116 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Frigault, M. J. & Maus, M. V. State of the art in CAR T cell therapy for CD19+ B cell malignancies. J. Clin. Invest. 130, 1586–1594 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Patel, P. H. & Kockler, D. R. Sipuleucel-T: a vaccine for metastatic, asymptomatic, androgen-independent prostate cancer. Ann. Pharmacother. 42, 91–98 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Schellhammer, P. F. et al. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology 81, 1297–1302 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Gulley, J. L. et al. Phase III Trial of PROSTVAC in asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. J. Clin. Oncol. 37, 1051–1061 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Salmaninejad, A. et al. PD-1/PD-L1 pathway: basic biology and role in cancer immunotherapy. J. Cell Physiol. 234, 16824–16837 (2019).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Buchbinder, E. I. & Desai, A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 39, 98–106 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Dermani, F. K., Samadi, P., Rahmani, G., Kohlan, A. K. & Najafi, R. PD-1/PD-L1 immune checkpoint: potential target for cancer therapy. J. Cell Physiol. 234, 1313–1325 (2019).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Claps, M. et al. Immune-checkpoint inhibitors and metastatic prostate cancer therapy: learning by making mistakes. Cancer Treat. Rev. 88, 102057 (2020).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Elia, A. R., Caputo, S. & Bellone, M. Immune checkpoint-mediated interactions between cancer and immune cells in prostate adenocarcinoma and melanoma. Front. Immunol. 9, 1786 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Thomsen, L. C. V. et al. A prospective phase I trial of dendritic cell-based cryoimmunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 38, 3029 (2020).

    Article  Google Scholar 

  27. 27.

    Klinger, M., Benjamin, J., Kischel, R., Stienen, S. & Zugmaier, G. Harnessing T cells to fight cancer with BiTE(R) antibody constructs — past developments and future directions. Immunol. Rev. 270, 193–208 (2016).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Campagne, O. et al. Integrated pharmacokinetic/pharmacodynamic model of a bispecific CD3xCD123 DART molecule in nonhuman primates: evaluation of activity and impact of immunogenicity. Clin. Cancer Res. 24, 2631–2641 (2018).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Li, H., Er Saw, P. & Song, E. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. Cell Mol. Immunol. 17, 451–461 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Liu, D. CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy. J. Hematol. Oncol. 12, 113 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Knochelmann, H. M. et al. CAR T cells in solid tumors: blueprints for building effective therapies. Front. Immunol. 9, 1740 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).

    PubMed  Article  Google Scholar 

  35. 35.

    Jayaraman, J. et al. CAR-T design: elements and their synergistic function. EBioMedicine 58, 102931 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Fujiwara, K. et al. Hinge and transmembrane domains of chimeric antigen receptor regulate receptor expression and signaling threshold. Cells 9, 1182 (2020).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  37. 37.

    Holzinger, A. & Abken, H. CAR T cells: a snapshot on the growing options to design a CAR. HemaSphere 3, e172 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Guedan, S., Calderon, H., Posey, A. D. Jr. & Maus, M. V. Engineering and design of chimeric antigen receptors. Mol. Therapy. Methods Clin. Dev. 12, 145–156 (2019).

    CAS  Article  Google Scholar 

  39. 39.

    Hudecek, M. et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19, 3153–3164 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Andersch, L. et al. CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing. BMC Cancer 19, 895 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Guest, R. D. et al. 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  Article  PubMed Central  Google Scholar 

  42. 42.

    Ying, Z. et al. A safe and potent anti-CD19 CAR T cell therapy. Nat. Med. 25, 947–953 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Feucht, J. et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat. Med. 25, 82–88 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Isakov, N. ITAMs: immunoregulatory scaffolds that link immunoreceptors to their intracellular signaling pathways. Recept. Channels 5, 243–253 (1998).

    CAS  PubMed  Google Scholar 

  45. 45.

    Guedan, S. et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124, 1070–1080 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Guedan, S. et al. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight 3, e96976 (2018).

    PubMed Central  Article  Google Scholar 

  47. 47.

    Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Maher, J., Brentjens, R. J., Gunset, G., Riviere, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Pule, M. A. et al. 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).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Weinkove, R., George, P., Dasyam, N. & McLellan, A. D. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin. Transl Immunol. 8, e1049 (2019).

    Article  Google Scholar 

  51. 51.

    van der Stegen, S. J., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Hartmann, J., Schussler-Lenz, M., Bondanza, A. & Buchholz, C. J. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol. Med. 9, 1183–1197 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T Cells. Immunity 44, 380–390 (2016).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T Cells. Cancer Cell 28, 415–428 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Alzubi, J. et al. PSMA-Directed CAR T cells combined with low-dose docetaxel treatment induce tumor regression in a prostate cancer xenograft model. Mol. Ther. Oncolytics 18, 226–235 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Abken, H. Costimulation engages the gear in driving CARs. Immunity 44, 214–216 (2016).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Foster, A. E. et al. 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  Article  Google Scholar 

  58. 58.

    Shaw, J. et al. Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors. J. Clin. Oncol. 38, 734 (2020).

    Article  Google Scholar 

  59. 59.

    Gargett, T. & Brown, M. P. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. 60.

    Chmielewski, M. & Abken, H. TRUCKs: the fourth generation of CARs. Expert. Opin. Biol. Ther. 15, 1145–1154 (2015).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Yu, S., Yi, M., Qin, S. & Wu, K. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol. Cancer 18, 125 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Maus, M. V. & June, C. H. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin. Cancer Res. 22, 1875–1884 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Xie, G. et al. CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine 59, 102975 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Bouchkouj, N. et al. FDA approval summary: axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma. Clin. Cancer Res. 25, 1702–1708 (2019).

    PubMed  Article  Google Scholar 

  65. 65.

    O’Leary, M. C. et al. FDA approval summary: tisagenlecleucel for treatment of patients with relapsed or refractory b-cell precursor acute lymphoblastic leukemia. Clin. Cancer Res. 25, 1142–1146 (2019).

    PubMed  Article  Google Scholar 

  66. 66.

    Jain, P. et al. Outcomes and management of patients with mantle cell lymphoma after progression on brexucabtagene autoleucel therapy. Br. J. Haematol. 192, e38–e42 (2020).

    PubMed  Google Scholar 

  67. 67.

    Hegde, M. et al. Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma. J. Clin. Oncol. 35, 10508 (2017).

    Article  Google Scholar 

  68. 68.

    Louis, C. U. et al. 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  Article  Google Scholar 

  69. 69.

    Hou, B., Tang, Y., Li, W., Zeng, Q. & Chang, D. Efficiency of CAR-T therapy for treatment of solid tumor in clinical trials: a meta-analysis. Dis. Markers 2019, 3425291 (2019).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Davis, M. I., Bennett, M. J., Thomas, L. M. & Bjorkman, P. J. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proc. Natl Acad. Sci. USA 102, 5981–5986 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Schmittgen, T. D., Teske, S., Vessella, R. L., True, L. D. & Zakrajsek, B. A. Expression of prostate specific membrane antigen and three alternatively spliced variants of PSMA in prostate cancer patients. Int. J. Cancer 107, 323–329 (2003).

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Wolf, P. et al. Three conformational antibodies specific for different PSMA epitopes are promising diagnostic and therapeutic tools for prostate cancer. Prostate 70, 562–569 (2010).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Carter, R. E., Feldman, A. R. & Coyle, J. T. Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase. Proc. Natl Acad. Sci. USA 93, 749–753 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Bostwick, D. G., Pacelli, A., Blute, M., Roche, P. & Murphy, G. P. Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer 82, 2256–2261 (1998).

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Paschalis, A. et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur. Urol. 76, 469–478 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Kawakami, M. & Nakayama, J. Enhanced expression of prostate-specific membrane antigen gene in prostate cancer as revealed by in situ hybridization. Cancer Res. 57, 2321–2324 (1997).

    CAS  PubMed  Google Scholar 

  77. 77.

    Kasperzyk, J. L. et al. Prostate-specific membrane antigen protein expression in tumor tissue and risk of lethal prostate cancer. Cancer Epidemiol. Biomarkers Prev. 22, 2354–2363 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Beckett, M. L., Cazares, L. H., Vlahou, A., Schellhammer, P. F. & Wright, G. L. Jr. Prostate-specific membrane antigen levels in sera from healthy men and patients with benign prostate hyperplasia or prostate cancer. Clin. Cancer Res. 5, 4034–4040 (1999).

    CAS  PubMed  Google Scholar 

  79. 79.

    Chang, S. S. et al. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res. 59, 3192–3198 (1999).

    CAS  PubMed  Google Scholar 

  80. 80.

    Backhaus, P. et al. Targeting PSMA by radioligands in non-prostate disease-current status and future perspectives. Eur. J. Nucl. Med. Mol. Imaging 45, 860–877 (2018).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Ristau, B. T., O’Keefe, D. S. & Bacich, D. J. The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of research. Urol. Oncol. 32, 272–279 (2014).

    PubMed  Article  Google Scholar 

  82. 82.

    Ma, Q. et al. Anti-prostate specific membrane antigen designer T cells for prostate cancer therapy. Prostate 61, 12–25 (2004).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Frigerio, B. et al. A single-chain fragment against prostate specific membrane antigen as a tool to build theranostic reagents for prostate cancer. Eur. J. Cancer 49, 2223–2232 (2013).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Zhong, X. S., Matsushita, M., Plotkin, J., Riviere, I. & Sadelain, M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol. Ther. 18, 413–420 (2010).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Ma, Q., Gomes, E. M., Lo, A. S. & Junghans, R. P. Advanced generation anti-prostate specific membrane antigen designer T cells for prostate cancer immunotherapy. Prostate 74, 286–296 (2014).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Stephan, M. T. et al. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat. Med. 13, 1440–1449 (2007).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Gade, T. P. et al. Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res. 65, 9080–9088 (2005).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Zuccolotto, G. et al. PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. PLoS ONE 9, e109427 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Serganova, I. et al. Enhancement of PSMA-directed CAR adoptive immunotherapy by PD-1/PD-L1 blockade. Mol. Ther. Oncolytics 4, 41–54 (2017).

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Kloss, C. C. et al. Dominant-negative TGF-beta receptor enhances PSMA-targeted Human CAR T cell proliferation and augments prostate cancer eradication. Mol. Ther. 26, 1855–1866 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Reiter, R. E. et al. Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc. Natl Acad. Sci. USA 95, 1735–1740 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Bahrenberg, G., Brauers, A., Joost, H. G. & Jakse, G. Reduced expression of PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors. Biochem. Biophys. Res. Commun. 275, 783–788 (2000).

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Gu, Z. et al. Prostate stem cell antigen (PSCA) expression increases with high Gleason score, advanced stage and bone metastasis in prostate cancer. Oncogene 19, 1288–1296 (2000).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Han, K. R. et al. Prostate stem cell antigen expression is associated with Gleason score, seminal vesicle invasion and capsular invasion in prostate cancer. J. Urol. 171, 1117–1121 (2004).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Lam, J. S. et al. Prostate stem cell antigen is overexpressed in prostate cancer metastases. Clin. Cancer Res. 11, 2591–2596 (2005).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Yang, X. et al. Prostate stem cell antigen and cancer risk, mechanisms and therapeutic implications. Expert. Rev. Anticancer Ther. 14, 31–37 (2014).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Saeki, N., Gu, J., Yoshida, T. & Wu, X. Prostate stem cell antigen: a Jekyll and Hyde molecule? Clin. Cancer Res. 16, 3533–3538 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Saffran, D. C. et al. Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts. Proc. Natl Acad. Sci. USA 98, 2658–2663 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Priceman, S. J. et al. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer. Oncoimmunology 7, e1380764 (2018).

    PubMed  Article  Google Scholar 

  100. 100.

    Abate-Daga, D. et al. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum. Gene Ther. 25, 1003–1012 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Wu, D. et al. PSCA is a target of chimeric antigen receptor T cells in gastric cancer. Biomarker Res. 8, 3 (2020).

    Article  Google Scholar 

  102. 102.

    Ni, J. et al. Role of the EpCAM (CD326) in prostate cancer metastasis and progression. Cancer Metastasis Rev. 31, 779–791 (2012).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Benko, G., Spajić, B., Krušlin, B. & Tomas, D. Impact of the EpCAM expression on biochemical recurrence-free survival in clinically localized prostate cancer. Urol. Oncol. 31, 468–474 (2013).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Poczatek, R. B. et al. Ep-Cam levels in prostatic adenocarcinoma and prostatic intraepithelial neoplasia. J. Urol. 162, 1462–1466 (1999).

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Went, P. T. et al. Frequent EpCam protein expression in human carcinomas. Hum. Pathol. 35, 122–128 (2004).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Zellweger, T. et al. Expression patterns of potential therapeutic targets in prostate cancer. Int. J. Cancer 113, 619–628 (2005).

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Deng, Z., Wu, Y., Ma, W., Zhang, S. & Zhang, Y. Q. Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM. BMC Immunol. 16, 1 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    He, C. et al. Co-Expression of IL-7 improves NKG2D-based CAR T cell therapy on prostate cancer by enhancing the expansion and inhibiting the apoptosis and exhaustion. Cancers 12, 1969 (2020).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  109. 109.

    Santoro, S. P. et al. T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression. Cancer Immunol. Res. 3, 68–84 (2015).

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Liu, G., Rui, W., Zhao, X. & Lin, X. Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment. Cell Mol. Immunol. 18, 1085–1095 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Gorchakov, A. A., Kulemzin, S. V., Kochneva, G. V. & Taranin, A. V. Challenges and prospects of chimeric antigen receptor T-cell therapy for metastatic prostate cancer. Eur. Urol. 77, 299–308 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Slovin, S. F. et al. Chimeric antigen receptor (CAR+) modified T cells targeting prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC). J. Immunother. Cancer 31, 72 (2013).

    Google Scholar 

  113. 113.

    Junghans, R. P. et al. 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  Article  PubMed Central  Google Scholar 

  114. 114.

    Narayan, V. et al. A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 37, TPS347 (2019).

    Article  Google Scholar 

  115. 115.

    Becerra, C. R. et al. Ligand-inducible, prostate stem cell antigen (PSCA)-directed GoCAR-T cells in advanced solid tumors: preliminary results from a dose escalation. J. Clin. Oncol. 37, 283 (2019).

    Article  Google Scholar 

  116. 116.

    Gust, J., Ponce, R., Liles, W. C., Garden, G. A. & Turtle, C. J. Cytokines in CAR T cell-associated neurotoxicity. Front. Immunol. 11, 577027 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Subklewe, M., von Bergwelt-Baildon, M. & Humpe, A. Chimeric antigen receptor T cells: a race to revolutionize cancer therapy. Transfus. Med. Hemother 46, 15–24 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Hay, K. A. et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood 130, 2295–2306 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Shimabukuro-Vornhagen, A. et al. Cytokine release syndrome. J. Immunother. Cancer 6, 56 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Cobb, D. A. & Lee, D. W. Cytokine release syndrome biology and management. Cancer J. 27, 119–125 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Sterner, R. M. et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 133, 697–709 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Wang, Z. & Han, W. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. Biomark Res. 6, 4 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Sun, S., Hao, H., Yang, G., Zhang, Y. & Fu, Y. Immunotherapy with CAR-Modified T cells: toxicities and overcoming strategies. J. Immunol. Res. 2018, 2386187 (2018).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transpl. 25, 625–638 (2019).

    CAS  Article  Google Scholar 

  127. 127.

    Hunter, B. D. & Jacobson, C. A. CAR T-cell associated neurotoxicity: Mechanisms, clinicopathologic correlates, and future directions. J. Natl Cancer Inst. 111, 646–654 (2019).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  128. 128.

    Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Silver, D. A., Pellicer, I., Fair, W. R., Heston, W. D. & Cordon-Cardo, C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin. Cancer Res. 3, 81–85 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Langbein, T., Chaussé, G. & Baum, R. P. Salivary gland toxicity of PSMA radioligand therapy: relevance and preventive strategies. J. Nucl. Med. 59, 1172–1173 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Maleki Vareki, S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J. Immunother. Cancer 6, 157 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Muthuswamy, R., Corman, J. M., Dahl, K., Chatta, G. S. & Kalinski, P. Functional reprogramming of human prostate cancer to promote local attraction of effector CD8+ T cells. Prostate 76, 1095–1105 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Di Stasi, A. et al. 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  Article  CAS  Google Scholar 

  134. 134.

    Qian, D. Z. et al. CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity. Prostate 70, 433–442 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Hernandez, R. et al. Low-dose TRT reshapes the microenvironment of prostate tumors to potentiate response to immunotherapy. J. Nucl. Med. 61, 36 (2020).

    Article  CAS  Google Scholar 

  136. 136.

    Jachetti, E. et al. Cross-talk between myeloid-derived suppressor cells and mast cells mediates tumor-specific immunosuppression in prostate cancer. Cancer Immunol. Res. 6, 552–565 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Yuri, P. et al. Increased tumor-associated macrophages in the prostate cancer microenvironment predicted patients’ survival and responses to androgen deprivation therapies in Indonesian patients cohort. Prostate Int. 8, 62–69 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Watanabe, M. et al. Increased infiltration of CCR4-positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis. Prostate 79, 1658–1665 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Wieser, R., Attisano, L., Wrana, J. L. & Massague, J. Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region. Mol. Cell Biol. 13, 7239–7247 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Mohammed, S. et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol. Ther. 25, 249–258 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Mussolino, C., Alzubi, J., Pennucci, V., Turchiano, G. & Cathomen, T. Genome and epigenome editing to treat disorders of the hematopoietic system. Hum. Gene Ther. 28, 1105–1115 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, eaba7365 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 144.

    Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl Med. 9, eaaj2013 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  145. 145.

    Turchiano, G. et al. Quantitative evaluation of chromosomal rearrangements in gene-edited human stem cells by CAST-Seq. Cell Stem Cell 28, 1136–1147 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. 146.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Sachdeva, M. et al. Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality. Nat. Commun. 10, 5100 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Simon, S. & Labarriere, N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 7, e1364828 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Kloss, C. C., Condomines, M., Cartellieri, M., Bachmann, M. & Sadelain, M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71–75 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Kailayangiri, S., Altvater, B., Wiebel, M., Jamitzky, S. & Rossig, C. Overcoming heterogeneity of antigen expression for effective CAR T cell targeting of cancers. Cancers 12, 1075 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  151. 151.

    Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219–1226 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. 152.

    Schneider, D. et al. Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci. Transl Med. 13, eabc6401 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. 153.

    Klesmith, J. R. et al. Retargeting CD19 chimeric antigen receptor T cells via engineered CD19-fusion proteins. Mol. Pharm. 16, 3544–3558 (2019).

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Sachdeva, M., Duchateau, P., Depil, S., Poirot, L. & Valton, J. 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  Article  Google Scholar 

  155. 155.

    Baeuerle, P. A. et al. Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nat. Commun. 10, 2087 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. 156.

    Xu, Y. et al. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discov. 4, 62 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. 157.

    Kohl, U., Arsenieva, S., Holzinger, A. & Abken, H. CAR T Cells in trials: recent achievements and challenges that remain in the production of modified T cells for clinical applications. Hum. Gene Ther. 29, 559–568 (2018).

    PubMed  Article  CAS  Google Scholar 

  158. 158.

    Mock, U. et al. Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy. Cytotherapy 18, 1002–1011 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 159.

    Alzubi, J. et al. Automated generation of gene-edited CAR T cells at clinical scale. Mol. Ther. Methods Clin. Dev. 20, 379–388 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160.

    Bailey, S. R. & Maus, M. V. Gene editing for immune cell therapies. Nat. Biotechnol. 37, 1425–1434 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  161. 161.

    Liu, E. et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 382, 545–553 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Kissick, H. T. et al. Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation. Proc. Natl Acad. Sci. USA 111, 9887–9892 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Mercader, M. et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc. Natl Acad. Sci. USA 98, 14565–14570 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Isaacs, J. T., Furuya, Y. & Berges, R. The role of androgen in the regulation of programmed cell death/apoptosis in normal and malignant prostatic tissue. Semin. Cancer Biol. 5, 391–400 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Ardiani, A., Gameiro, S. R., Kwilas, A. R., Donahue, R. N. & Hodge, J. W. Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway. Oncotarget 5, 9335–9348 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Krajewska, M. et al. Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin. Cancer Res. 9, 4914–4925 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Tandon, M., Vemula, S. V. & Mittal, S. K. Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin. Ther. Targets 15, 31–51 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Petty, A. et al. A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. PLoS ONE 7, e42120 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Salem, A. F. et al. Prostate cancer metastases are strongly inhibited by agonistic Epha2 ligands in an orthotopic mouse model. Cancers (Basel) 12, 2854 (2020).

    CAS  Article  Google Scholar 

  170. 170.

    Sanchez, C. et al. Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer. Prostate Cancer Prostatic Dis. 16, S121 (2013).

    Article  CAS  Google Scholar 

  171. 171.

    DeSelm, C. et al. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol. Ther. 26, 2542–2552 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Weiss, T., Weller, M., Guckenberger, M., Sentman, C. L. & Roth, P. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. Cancer Res. 78, 1031–1043 (2018).

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Phillips, R. et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 6, 650–659 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    Owens, K. & Bozic, I. Modeling CAR T-cell therapy with patient preconditioning. Bull. Math. Biol. 83, 42 (2021).

    PubMed  Article  Google Scholar 

  175. 175.

    Gattinoni, L. et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202, 907–912 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Neelapu, S. S. CAR-T efficacy: is conditioning the key? Blood 133, 1799–1800 (2019).

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Xu, J. et al. Combination therapy: a feasibility strategy for CAR-T cell therapy in the treatment of solid tumors. Oncol. Lett. 16, 2063–2070 (2018).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Ramakrishnan, R. et al. Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy. Cancer Res. 72, 5483–5493 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Motyka, B. et al. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 103, 491–500 (2000).

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Trapani, J. A. et al. A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. J. Cell Biol. 160, 223–233 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    CAS  PubMed  Article  Google Scholar 

  182. 182.

    Martins, I. et al. Chemotherapy induces ATP release from tumor cells. Cell Cycle 8, 3723–3728 (2009).

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Michaud, M. et al. An autophagy-dependent anticancer immune response determines the efficacy of melanoma chemotherapy. Oncoimmunology 3, e944047 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Garg, A. D. et al. Molecular and translational classifications of DAMPs in immunogenic cell death. Front. Immunol. 6, 588 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Proietti, E. et al. Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice. J. Clin. Invest. 101, 429–441 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. 187.

    Traverso, I. et al. Cyclophosphamide inhibits the generation and function of CD8+ regulatory T cells. Hum. Immunol. 73, 207–213 (2012).

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Ghiringhelli, F. et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur. J. Immunol. 34, 336–344 (2004).

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Jayram, G. & Eggener, S. E. Patient selection for focal therapy of localized prostate cancer. Curr. Opin. Urol. 19, 268–273 (2009).

    PubMed  Article  Google Scholar 

  190. 190.

    Nassiri, N. et al. Focal therapy eligibility determined by magnetic resonance imaging/ultrasound fusion biopsy. J. Urol. 199, 453–458 (2018).

    PubMed  Article  Google Scholar 

  191. 191.

    Ahdoot, M., Lebastchi, A. H., Turkbey, B., Wood, B. & Pinto, P. A. Contemporary treatments in prostate cancer focal therapy. Curr. Opin. Oncol. 31, 200–206 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    van der Poel, H. G. et al. Focal therapy in primary localised prostate cancer: the european association of urology position in 2018. Eur. Urol. 74, 84–91 (2018).

    PubMed  Article  Google Scholar 

  193. 193.

    Lovf, M. et al. Multifocal primary prostate cancer exhibits high degree of genomic heterogeneity. Eur. Urol. 75, 498–505 (2019).

    PubMed  Article  CAS  Google Scholar 

  194. 194.

    Priceman, S. J. et al. 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  Article  Google Scholar 

  195. 195.

    Brown, C. E. et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin. Cancer Res. 21, 4062–4072 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. 196.

    Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

This work was supported by grants of the Federal Ministry of Education and Research (BMBF-01EO0813 to T.C.), the Horizon 2020 Programme of the European Commission (CARAT-667980 to T.C.), the Federal Ministry of Economic Affairs and Energy (BMWi-03THW15H04 to C.G. and T.C.), and the Research Commission of the Faculty of Medicine of the Albert-Ludwigs-University of Freiburg (no. WOL1111/16 to P.W. and T.C.).

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Correspondence to Philipp Wolf or Toni Cathomen.

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T.C. has sponsored research collaborations with Cellectis and serves on the scientific advisory board of Excision BioTherapeutics. The other authors declare no competing interests.

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Wolf, P., Alzubi, J., Gratzke, C. et al. The potential of CAR T cell therapy for prostate cancer. Nat Rev Urol 18, 556–571 (2021). https://doi.org/10.1038/s41585-021-00488-8

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