Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Novel immune engagers and cellular therapies for metastatic castration-resistant prostate cancer: do we take a BiTe or ride BiKEs, TriKEs, and CARs?

Prostate Cancer and Prostatic Diseases volume 24, pages 986–996 (2021)Cite this article

Subjects

Abstract

Background

Checkpoint inhibitors and currently approved cellular products for metastatic castration-resistant prostate cancer have not resulted in revolutionary changes in outcomes compared to other solid tumors. Much of this lack of progress is attributed to the unique tumor microenvironment of prostate cancer that is often immunologically cold and immunosuppressive. These unique conditions emphasize the need for novel therapeutic options. In this review, we will discuss progress made in design of T- and NK cell immune engagers in addition to chimeric antigen receptor products specifically designed for prostate cancer that are currently under investigation in clinical trials.

Methods

We searched peer-reviewed literature on the PubMed and the ClinicalTrials.gov databases for active clinical trials using the terms “bispecific T-cell engager,” “bispecific killer engager,” “trispecific killer engager,” “chimeric antigen receptor,” “metastatic castration-resistant prostate cancer,” and “neuroendocrine prostate cancer.”

Results

Ten bispecific T-cell engager studies and nine chimeric antigen receptor-based products were found. Published data were compiled and presented based on therapeutic class.

Conclusions

Multiple immune engagers and cell therapies are in the development pipeline and demonstrate promise to address barriers to better outcomes for metastatic castration-resistant prostate cancer patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structure of T- and NK cell immune engagers.
Fig. 2: Structure of chimeric antigen receptors.

Similar content being viewed by others

References

  1. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl J Med. 2010;363:411–22.

    Article  CAS  PubMed  Google Scholar 

  2. Madan RA, Antonarakis ES, Drake CG, Fong L, Yu EY, McNeel DG, et al. Putting the pieces together: completing the mechanism of action jigsaw for Sipuleucel-T. J Natl Cancer Inst. 2020;112:562–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. DiPaola RS, Plante M, Kaufman H, Petrylak DP, Israeli R, Lattime E, et al. A phase I trial of pox PSA vaccines (PROSTVAC-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM) in patients with prostate cancer. J Transl Med. 2006;4:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Simons JW, Carducci MA, Mikhak B, Lim M, Biedrzycki B, Borellini F, et al. Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naive prostate cancer. Clin Cancer Res. 2006;12:3394–401.

    Article  CAS  PubMed  Google Scholar 

  5. Goldman B, DeFrancesco L. The cancer vaccine roller coaster. Nat Biotechnol. 2009;27:129–39.

    Article  CAS  PubMed  Google Scholar 

  6. Khair DO, Bax HJ, Mele S, Crescioli S, Pellizzari G, Khiabany A, et al. Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front Immunol. 2019;10:453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ellis PM, Vella ET, Ung YC. Immune checkpoint inhibitors for patients with advanced non-small-cell lung cancer: a systematic review. Clin Lung Cancer. 2017;18:444–59 e1.

    Article  CAS  PubMed  Google Scholar 

  8. Ok CY, Young KH. Checkpoint inhibitors in hematological malignancies. J Hematol Oncol. 2017;10:103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020;11:3801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Antonarakis ES. A new molecular taxonomy to predict immune checkpoint inhibitor sensitivity in prostate cancer. Oncologist. 2019;24:430–2.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Duan Q, Zhang H, Zheng J, Zhang L. Turning cold into hot: firing up the tumor microenvironment. Trends Cancer. 2020;6:605–18.

    Article  CAS  PubMed  Google Scholar 

  12. Bonaventura P, Shekarian T, Alcazer V, Valladeau-Guilemond J, Valsesia-Wittmann S, Amigorena S, et al. Cold tumors: a therapeutic challenge for immunotherapy. Front Immunol. 2019;10:168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: facts and hopes. Clin Cancer Res. 2017;23:6764–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  15. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74.

    Article  CAS  PubMed  Google Scholar 

  16. Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, et al. The immune checkpoint regulator PD-L1 is highly expressed in aggressive primary prostate cancer. Clin Cancer Res. 2016;22:1969–77.

    Article  CAS  PubMed  Google Scholar 

  17. Nappi L, Kesch C, Vahid S, Fazli L, Eigl BJ, Kollmannsberger CK, et al. Immunogenomic landscape of neuroendocrine small cell prostate cancer. J Clin Oncol. 2019;37:217.

    Article  Google Scholar 

  18. Miller AM, Lundberg K, Ozenci V, Banham AH, Hellstrom M, Egevad L, et al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol. 2006;177:7398–405.

    Article  CAS  PubMed  Google Scholar 

  19. Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res. 2007;13:6947–58.

    Article  CAS  PubMed  Google Scholar 

  20. Tien AH, Xu L, Helgason CD. Altered immunity accompanies disease progression in a mouse model of prostate dysplasia. Cancer Res. 2005;65:2947–55.

    Article  CAS  PubMed  Google Scholar 

  21. Zhao SG, Lehrer J, Chang SL, Das R, Erho N, Liu Y, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst. 2019;111:301–10.

    Article  PubMed  CAS  Google Scholar 

  22. Lundholm M, Hagglof C, Wikberg ML, Stattin P, Egevad L, Bergh A, et al. Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions. Sci Rep. 2015;5:15651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marshall CH, Antonarakis ES. Emerging treatments for metastatic castration-resistant prostate cancer: immunotherapy, PARP inhibitors, and PSMA-targeted approaches. Cancer Treat Res Commun. 2020;23:100164.

    Article  PubMed  Google Scholar 

  24. Nicholson LT, Fong L. Immune checkpoint inhibition in prostate cancer. Trends Cancer. 2020;6:174–7.

    Article  CAS  PubMed  Google Scholar 

  25. Cha HR, Lee JH, Ponnazhagan S. Revisiting immunotherapy: a focus on prostate cancer. Cancer Res. 2020;80:1615–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chang SS. Overview of prostate-specific membrane antigen. Rev Urol. 2004;6:S13–8.

    PubMed  PubMed Central  Google Scholar 

  27. Karan D. Prostate immunotherapy: should all guns be aimed at the prostate-specific antigen? Immunotherapy. 2013;5:907–10.

    Article  CAS  PubMed  Google Scholar 

  28. Ni J, Cozzi PJ, Duan W, Shigdar S, Graham PH, John KH, et al. Role of the EpCAM (CD326) in prostate cancer metastasis and progression. Cancer Metastasis Rev. 2012;31:779–91.

    Article  CAS  PubMed  Google Scholar 

  29. Barroca-Ferreira J, Pais JP, Santos MM, Goncalves AM, Gomes IM, Sousa I, et al. Targeting STEAP1 protein in human cancer: current trends and future challenges. Curr Cancer Drug Targets. 2018;18:222–30.

    Article  CAS  PubMed  Google Scholar 

  30. Khalili N, Keshavarz-Fathi M, Shahkarami S, Hirbod-Mobarakeh A, Rezaei N. Passive-specific immunotherapy with monoclonal antibodies for prostate cancer: a systematic review. J Oncol Pharm Pr. 2019;25:903–17.

    Article  Google Scholar 

  31. U.S. Food and Drug Administration. Drug Approval Package: Blincyto [Internet]. Silver Spring: U.S. Food and Drug Administration; 2017. [Updated 2017 June 20; cited 2020 Dec 28]. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125557Orig1s000TOC.cfm.

  32. Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: a review. Pharm Ther. 2018;185:122–34.

    Article  CAS  Google Scholar 

  33. Seimetz D, Lindhofer H, Bokemeyer C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 2010;36:458–67.

    Article  CAS  PubMed  Google Scholar 

  34. Larochelle M, Downing NS, Ross JS, David FS. Assessing the potential clinical impact of reciprocal drug approval legislation on access to novel therapeutics in the USA: a cohort study. BMJ Open. 2017;7:e014582.

    Article  PubMed  PubMed Central  Google Scholar 

  35. European Medicines Agency. Revomab: Withdrawal of the marketing authorization in the European Union [Internet]. London: European Medicines Agency; 2015. [Updated 2017 July 10; cited 2020 Dec 28]. https://www.ema.europa.eu/en/documents/public-statement/public-statementremovab-withdrawal-marketing-authorisation-european-union_en.pdf.

  36. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46:D1074–D82.

    Article  CAS  PubMed  Google Scholar 

  37. Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121:5154–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stein AS, Schiller G, Benjamin R, Jia C, Zhang A, Zhu M, et al. Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. Ann Hematol. 2019;98:159–67.

    Article  CAS  PubMed  Google Scholar 

  39. Portell CA, Wenzell CM, Advani AS. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharm. 2013;5:5–11.

    CAS  Google Scholar 

  40. Bailis J, Deegen P, Thomas O, Bogner P, Wahl J, Liao M, et al. Preclinical evaluation of AMG 160, a next-generation bispecific T cell engager (BiTE) targeting the prostate-specific membrane antigen PSMA for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37:301.

    Article  Google Scholar 

  41. Tran B, Horvath L, Dorff TB, Greil R, Machiels J-PH, Roncolato F, 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. 2020;38:TPS261–TPS.

    Article  Google Scholar 

  42. Deegen P, Thomas O, Nolan-Stevaux O, Li S, Wahl J, Bogner P, et al. The PSMA targeting half-life extended BiTE((R)) therapy AMG 160 has potent antitumor activity in preclinical models of metastatic castration-resistant prostate cancer. Clin Cancer Res. 2021;27:2928–37.

  43. Paweletz KL, Li S, Bailis JM, Juan G. Combination of AMG 160, a PSMA x CD3 half-life extended bispecific T-cell engager (HLE BiTE) immune therapy, with an anti-PD-1 antibody in prostate cancer (PCa). J Clin Oncol. 2020;38:155.

    Article  Google Scholar 

  44. Tran B, Horvath L, Dorff T, Retting T, Lolkema MP, Machiels J, et al. 6090-Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2020;31:S507–S49.

    Article  Google Scholar 

  45. Cioffi M, Dorado J, Baeuerle PA, Heeschen C. EpCAM/CD3-bispecific T-cell engaging antibody MT110 eliminates primary human pancreatic cancer stem cells. Clin Cancer Res. 2012;18:465–74.

    Article  CAS  PubMed  Google Scholar 

  46. Kebenko M, Goebeler ME, Wolf M, Hasenburg A, Seggewiss-Bernhardt R, Ritter B, et al. A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE(R)) antibody construct, in patients with refractory solid tumors. Oncoimmunology. 2018;7:e1450710.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Giffin MJ, Cooke K, Lobenhofer EK, Estrada J, Zhan J, Deegen P, et al. AMG 757, a half-life extended, DLL3-targeted bispecific T-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021;27:1526–37.

    Article  CAS  PubMed  Google Scholar 

  48. Friedrich M, Raum T, Lutterbuese R, Voelkel M, Deegen P, Rau D, et al. Regression of human prostate cancer xenografts in mice by AMG 212/BAY2010112, a novel PSMA/CD3-Bispecific BiTE antibody cross-reactive with non-human primate antigens. Mol Cancer Ther. 2012;11:2664–73.

    Article  CAS  PubMed  Google Scholar 

  49. Hummel H-D, Kufer P, Grüllich C, Deschler-Baier B, Chatterjee M, Goebeler M-E, et al. Phase 1 study of pasotuxizumab (BAY 2010112), a PSMA-targeting Bispecific T cell Engager (BiTE) immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37:5034.

    Article  Google Scholar 

  50. Hummel H-D, Kufer P, Grüllich C, Deschler-Baier B, Chatterjee M, Goebeler M-E, et al. Phase I study of pasotuxizumab (AMG 212/BAY 2010112), a PSMA-targeting BiTE (Bispecific T-cell Engager) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38:124.

    Article  Google Scholar 

  51. Nolan-Stevaux O. Abstract DDT02-03: AMG 509: a novel, humanized, half-Life extended, bispecific STEAP1 × CD3 T cell recruiting XmAb® 2+1 antibody. Cancer Res. 2020;80:DDT02-3-DDT-3.

    Google Scholar 

  52. Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11:eaav0891.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Tsai HK, Lehrer J, Alshalalfa M, Erho N, Davicioni E, Lotan TL. Gene expression signatures of neuroendocrine prostate cancer and primary small cell prostatic carcinoma. BMC Cancer. 2017;17:759.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Hipp S, Voynov V, Drobits-Handl B, Giragossian C, Trapani F, Nixon AE, et al. A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res. 2020;26:5258–68.

    Article  CAS  PubMed  Google Scholar 

  55. Bryceson YT, March ME, Ljunggren HG, Long EO. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood. 2006;107:159–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vallera DA, Zhang B, Gleason MK, Oh S, Weiner LM, Kaufman DS, et al. Heterodimeric bispecific single-chain variable-fragment antibodies against EpCAM and CD16 induce effective antibody-dependent cellular cytotoxicity against human carcinoma cells. Cancer Biother Radiopharm. 2013;28:274–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schmohl JU, Gleason MK, Dougherty PR, Miller JS, Vallera DA. Heterodimeric bispecific single chain variable fragments (scFv) killer engagers (BiKEs) enhance NK-cell activity against CD133+ colorectal cancer cells. Target Oncol. 2016;11:353–61.

    Article  CAS  PubMed  Google Scholar 

  58. Schmohl JU, Felices M, Taras E, Miller JS, Vallera DA. Enhanced ADCC and NK cell activation of an anticarcinoma bispecific antibody by genetic insertion of a modified IL-15 cross-linker. Mol Ther. 2016;24:1312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dragonfly. Our Platform: TriNKET [Internet]. Waltham: Dragonfly; 2018. [cited 28 Dec 2020]. https://www.dragonflytx.com/copy-of-about-us-1.

  60. Cheng Y, Zheng X, Wang X, Chen Y, Wei H, Sun R, et al. Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers. Cancer Biol Med. 2020;17:1026–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rezvani AR, Maloney DG. Rituximab resistance. Best Pr Res Clin Haematol. 2011;24:203–16.

    Article  CAS  Google Scholar 

  62. Schmohl JU, Felices M, Todhunter D, Taras E, Miller JS, Vallera DA. Tetraspecific scFv construct provides NK cell mediated ADCC and self-sustaining stimuli via insertion of IL-15 as a cross-linker. Oncotarget. 2016;7:73830–44.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA. 1989;86:10024–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xie YJ, Dougan M, Jailkhani N, Ingram J, Fang T, Kummer L, et al. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci USA. 2019;116:7624–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Knochelmann HM, Smith AS, Dwyer CJ, Wyatt MM, Mehrotra S, Paulos CM. CAR T cells in solid tumors: blueprints for building effective therapies. Front Immunol. 2018;9:1740.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Wang X, Riviere I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics. 2016;3:16015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tyagarajan S, Spencer T, Smith J. Optimizing CAR-T cell manufacturing processes during pivotal clinical trials. Mol Ther Methods Clin Dev. 2020;16:136–44.

    Article  CAS  PubMed  Google Scholar 

  68. First-Ever CAR T-cell Therapy Approved in U.S. Cancer Discovery. 2017;7:OF1. https://doi.org/10.1158/2159-8290.CD-NB2017-126.

  69. Roberts ZJ, Better M, Bot A, Roberts MR, Ribas A. Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL. Leuk Lymphoma. 2018;59:1785–96.

    Article  CAS  PubMed  Google Scholar 

  70. Eshhar Z, Waks T, Gross G, Schindler DG. 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. Proc Natl Acad Sci USA. 1993;90:720–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Slovin SF, Wang X, Hullings M, Arauz G, Bartido S, Lewis JS, 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 Clin Oncol. 2013;31:72.

    Article  Google Scholar 

  73. Slovin SF. Chimeric antigen receptor T-cell therapy in prostate cancer: reality or folly? Eur Urol. 2020;77:309–10.

    Article  CAS  PubMed  Google Scholar 

  74. Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, et al. Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther. 2018;26:1855–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science. 2015;350:aab4077.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Becerra CR, Hoof P, Paulson AS, Manji GA, Gardner O, Malankar A, 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. 2019;37:283.

    Article  Google Scholar 

  77. Shimabukuro-Vornhagen A, Godel P, Subklewe M, Stemmler HJ, Schlosser HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6:56.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N. Engl J Med. 2017;377:2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013;21:904–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. van den Berg JH, Gomez-Eerland R, van de Wiel B, Hulshoff L, van den Broek D, Bins A, et al. Case report of a fatal serious adverse event upon administration of T cells transduced with a MART-1-specific T-cell receptor. Mol Ther. 2015;23:1541–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Disco. 2015;5:1282–95.

    Article  CAS  Google Scholar 

  83. de Larrea CF, Staehr M, Lopez AV, Ng KY, Chen Y, Godfrey WD, et al. Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape-driven relapse in multiple myeloma. Blood Cancer Disco. 2020;1:146–54.

    Article  Google Scholar 

  84. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–100.

    Article  CAS  PubMed  Google Scholar 

  85. Oei VYS, Siernicka M, Graczyk-Jarzynka A, Hoel HJ, Yang W, Palacios D, et al. Intrinsic functional potential of NK-cell subsets constrains retargeting driven by chimeric antigen receptors. Cancer Immunol Res. 2018;6:467–80.

    Article  CAS  PubMed  Google Scholar 

  86. Oberschmidt O, Kloess S, Koehl U. Redirected primary human chimeric antigen receptor natural killer cells as an “off-the-shelf immunotherapy” for improvement in cancer treatment. Front Immunol. 2017;8:654.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Mehta RS, Rezvani K. Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Front Immunol. 2018;9:283.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T, et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol. 2017;8:533.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Pfefferle A, Huntington ND. You have got a fast CAR: chimeric antigen receptor NK cells in cancer therapy. Cancers. 2020;12:706.

    Article  CAS  PubMed Central  Google Scholar 

  90. Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J. CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine. 2020;59:102975.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Hernandez-Hoyos G, Sewell T, Bader R, Bannink J, Chenault RA, Daugherty M, et al. MOR209/ES414, a novel bispecific antibody targeting PSMA for the treatment of metastatic castration-resistant prostate cancer. Mol Cancer Therap. 2016;15:2155–65.

    Article  CAS  Google Scholar 

  92. Kelly WK, Danila DC, Edenfield WJ, Aggarwal RR, Petrylak DP, Sartor AO, et al. Phase I study of AMG 509, a STEAP1 x CD3 T cell-recruiting XmAb 2+1 immune therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38:TPS5589–TPS.

    Article  Google Scholar 

  93. Drake CG, Zhang J, Stein MN, Xu Y, Seebach FA, Lowy I, et al. A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2020;38:TPS5592–TPS.

    Article  Google Scholar 

  94. Dorff TB, Blanchard S, Carruth P, Wagner J, Kuhn P, Chaudhry A, et al. A phase I study to evaluate PSCA-targeting chimeric antigen receptor (CAR)-T cells for patients with PSCA+ metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38:TPS250–TPS.

    Article  Google Scholar 

  95. Tao K, He M, Tao F, Xu G, Ye M, Zheng Y, et al. Development of NKG2D-based chimeric antigen receptor-T cells for gastric cancer treatment. Cancer Chemother Pharmacol. 2018;82:815–27.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

NAZ is supported by 2T32HL007062 Hematology Research Training Program T32, University of Minnesota (PI: Dr Gregory Vercellotti) and an Academic Investment Education Program grant from the University of Minnesota Medical School. CJR is the BJ Kennedy Chair of Clinical Medical Oncology at the University of Minnesota Medical School.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA

    Nicholas A. Zorko & Charles J. Ryan

Authors
  1. Nicholas A. Zorko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles J. Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles J. Ryan.

Ethics declarations

Conflict of interest

NAZ does not have any competing financial interests to declare. CJR receives the following support: Receipt of grants/research supports Clovis Oncology- Research Grant, Sanofi-Genzyme- Research Grant, Bayer - Research Grant and Consultation. Receipt of honoraria or consultation fees Advisory Boards: Advanced Accelerator Applications – Consultation, Roivant – Consultation, Pfizer – Consultation, Dendreon – Consultation, Myovant (Payment to U of M), Clovis (Payment to U of M), Bayer (Payment to U of M).

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zorko, N.A., Ryan, C.J. Novel immune engagers and cellular therapies for metastatic castration-resistant prostate cancer: do we take a BiTe or ride BiKEs, TriKEs, and CARs?. Prostate Cancer Prostatic Dis 24, 986–996 (2021). https://doi.org/10.1038/s41391-021-00381-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-021-00381-w

This article is cited by

Search

Advanced search

Quick links