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GM-CSF elicits antibodies to tumor-associated proteins when used as a prostate cancer vaccine adjuvant

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Abstract

Antibody responses to off-target cancer-associated proteins have been detected following immunotherapies for cancer, suggesting these may be the result of antigen spread. We have previously reported that serum antibodies to prostate cancer-associated proteins were detectable using a high-throughput peptide array. We hypothesized that the breadth of antibody responses elicited by a vaccine could serve as a measure of the magnitude of its induced antigen spread. Consequently, sera from patients with prostate cancer, treated prior to or after vaccination in one of four separate clinical trials, were evaluated for antibody responses to an array of 177,604 peptides derived from over 1600 prostate cancer-associated gene products. Antibody responses to the same group of 5680 peptides previously reported were identified following vaccinations in which patients were administered GM-CSF as an adjuvant, but not with vaccine in the absence of GM-CSF. Hence, antibody responses to off-target proteins following vaccination may not necessarily serve as evidence of antigen spread and must be interpreted with particular caution following vaccine strategies that use GM-CSF, as GM-CSF appears to have direct effects on the production of antibodies. The evaluation of T cell responses to non-target antigens is likely a preferred approach for detection of immune-mediated antigen spread.

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References

  1. Gulley JL, Madan RA, Pachynski R, Mulders P, Sheikh NA, Trager J, Drake CG (2017) Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djw261

    Article  PubMed  PubMed Central  Google Scholar 

  2. Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W (2000) Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 96:3102–3108

    Article  CAS  Google Scholar 

  3. Ribas A, Glaspy JA, Lee Y et al (2004) Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother 27:354–367. https://doi.org/10.1097/00002371-200409000-00004

    Article  CAS  PubMed  Google Scholar 

  4. Butterfield LH, Ribas A, Dissette VB et al (2003) Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin Cancer Res 9:998–1008

    CAS  PubMed  Google Scholar 

  5. Tuohy VK, Kinkel RP (2000) Epitope spreading: a mechanism for progression of autoimmune disease. Arch Immunol Ther Exp 48:347–351

    CAS  Google Scholar 

  6. Nesslinger NJ, Ng A, Tsang KY, Ferrara T, Schlom J, Gulley JL, Nelson BH (2010) A viral vaccine encoding prostate-specific antigen induces antigen spreading to a common set of self-proteins in prostate cancer patients. Clin Cancer Res 16:4046–4056

    Article  CAS  Google Scholar 

  7. Smith HA, Maricque BB, Eberhardt J, Petersen B, Gulley JL, Schlom J, McNeel DG (2011) IgG responses to tissue-associated antigens as biomarkers of immunological treatment efficacy. J Biomed Biotech 2011:454861

    Google Scholar 

  8. Nguyen MC, Tu GH, Koprivnikar KE, Gonzalez-Edick M, Jooss KU, Harding TC (2010) Antibody responses to galectin-8, TARP and TRAP1 in prostate cancer patients treated with a GM-CSF-secreting cellular immunotherapy. Cancer Immunol Immunother 59:1313–1323. https://doi.org/10.1007/s00262-010-0858-5

    Article  CAS  PubMed  Google Scholar 

  9. GuhaThakurta D, Sheikh NA, Fan LQ et al (2015) Humoral immune response against non-targeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-14-2334

    Article  PubMed  PubMed Central  Google Scholar 

  10. Potluri HK, Ng TL, Newton MA, Zhang J, Maher CA, Nelson PS, McNeel DG (2020) Antibody profiling of patients with prostate cancer reveals differences in antibody signatures among disease stages. J Immunother Cancer. https://doi.org/10.1136/jitc-2020-001510

    Article  PubMed  PubMed Central  Google Scholar 

  11. McNeel DG, Becker JT, Eickhoff JC et al (2014) Real-time immune monitoring to guide plasmid DNA vaccination schedule targeting prostatic acid phosphatase in patients with castration-resistant prostate cancer. Clin Cancer Res 20:3692–3704. https://doi.org/10.1158/1078-0432.ccr-14-0169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McNeel DG, Eickhoff JC, Johnson LE et al (2019) Phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP [MVI-816]) in patients with progressive, nonmetastatic castration-sensitive prostate cancer. J Clin Oncol 37:3507–3517. https://doi.org/10.1200/JCO.19.01701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kyriakopoulos CE, Eickhoff JC, Ferrari AC, Schweizer MT, Wargowski E, Olson BM, McNeel DG (2020) Multicenter phase I trial of a DNA vaccine encoding the androgen receptor ligand-binding domain (pTVG-AR, MVI-118) in patients with metastatic prostate cancer. Clin Cancer Res 26:5162–5171. https://doi.org/10.1158/1078-0432.CCR-20-0945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wargowski E, Johnson LE, Eickhoff JC, Delmastro L, Staab MJ, Liu G, McNeel DG (2018) Prime-boost vaccination targeting prostatic acid phosphatase (PAP) in patients with metastatic castration-resistant prostate cancer (mCRPC) using Sipuleucel-T and a DNA vaccine. J Immunother Cancer 6:21. https://doi.org/10.1186/s40425-018-0333-y

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kumar A, Coleman I, Morrissey C et al (2016) Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med 22:369–378. https://doi.org/10.1038/nm.4053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Robinson D, Van Allen EM, Wu YM et al (2015) Integrative clinical genomics of advanced prostate cancer. Cell 162:454. https://doi.org/10.1016/j.cell.2015.06.053

    Article  CAS  PubMed  Google Scholar 

  17. Mishra N, Caciula A, Price A et al. (2018) Diagnosis of Zika virus infection by peptide array and enzyme-linked immunosorbent assay. mBio. 9. doi: https://doi.org/10.1128/mBio.00095-18

  18. Lo KC, Sullivan E, Bannen RM et al (2020) Comprehensive profiling of the rheumatoid arthritis antibody repertoire. Arthritis Rheumatol 72:242–250. https://doi.org/10.1002/art.41089

    Article  CAS  PubMed  Google Scholar 

  19. Team RC (2019) R: a language and environment for statistical computing. R Foundation for Statistical Computing. https://www.R-project.org/.

  20. Team R (2019) RStudio: integrated development environment for R. RStudio, Inc. https://www.rstudio.com.

  21. Bates D, Machler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models using lme4. J Stat Soft 67:1–48

    Article  Google Scholar 

  22. Luke SG (2017) Evaluating significance in linear mixed-effects models in R. Behav Res Methods 49:1494–1502. https://doi.org/10.3758/s13428-016-0809-y

    Article  PubMed  Google Scholar 

  23. Kuznetsova A, Brockhoff PB, Christensen RHB (2017) ImerTest package: tests in linear mixed effects models. J Stat Soft 82:1–26

    Article  Google Scholar 

  24. Dranoff G, Jaffee E, Lazenby A et al (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A 90:3539–3543

    Article  CAS  Google Scholar 

  25. Le DT, Picozzi VJ, Ko AH et al (2019) Results from a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). Clin Cancer Res 25:5493–5502. https://doi.org/10.1158/1078-0432.CCR-18-2992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nemunaitis J, Jahan T, Ross H et al (2006) Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther 13:555–562. https://doi.org/10.1038/sj.cgt.7700922

    Article  CAS  PubMed  Google Scholar 

  27. Bendandi M, Gocke CD, Kobrin CB et al (1999) Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med 5:1171–1177

    Article  CAS  Google Scholar 

  28. Jager E, Ringhoffer M, Dienes HP et al (1996) Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. Int J Cancer 67:54–62

    Article  CAS  Google Scholar 

  29. Kusakabe K, Xin KQ, Katoh H et al (2000) The timing of GM-CSF expression plasmid administration influences the Th1/Th2 response induced by an HIV-1-specific DNA vaccine. J Immunol 164:3102–3111. https://doi.org/10.4049/jimmunol.164.6.3102

    Article  CAS  PubMed  Google Scholar 

  30. Choi KJ, Kim JH, Lee YS et al (2006) Concurrent delivery of GM-CSF and B7–1 using an oncolytic adenovirus elicits potent antitumor effect. Gene Ther 13:1010–1020. https://doi.org/10.1038/sj.gt.3302759

    Article  CAS  PubMed  Google Scholar 

  31. Slingluff CL Jr, Petroni GR, Olson WC et al (2009) Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial. Clin Cancer Res 15:7036–7044

    Article  CAS  Google Scholar 

  32. Burgess AW, Camakaris J, Metcalf D (1977) Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. J Biol Chem 252:1998–2003

    Article  CAS  Google Scholar 

  33. Sheng JR, Li L, Ganesh BB, Vasu C, Prabhakar BS, Meriggioli MN (2006) Suppression of experimental autoimmune myasthenia gravis by granulocyte-macrophage colony-stimulating factor is associated with an expansion of FoxP3+ regulatory T cells. J Immunol 177:5296–5306. https://doi.org/10.4049/jimmunol.177.8.5296

    Article  CAS  PubMed  Google Scholar 

  34. Gaudreau S, Guindi C, Menard M, Besin G, Dupuis G, Amrani A (2007) Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells. J Immunol 179:3638–3647. https://doi.org/10.4049/jimmunol.179.6.3638

    Article  CAS  PubMed  Google Scholar 

  35. Willart MA, Deswarte K, Pouliot P, Braun H, Beyaert R, Lambrecht BN, Hammad H (2012) Interleukin-1alpha controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33. J Exp Med 209:1505–1517. https://doi.org/10.1084/jem.20112691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mausberg AK, Jander S, Reichmann G (2009) Intracerebral granulocyte-macrophage colony-stimulating factor induces functionally competent dendritic cells in the mouse brain. Glia 57:1341–1350. https://doi.org/10.1002/glia.20853

    Article  PubMed  Google Scholar 

  37. Sorgi CA, Rose S, Court N et al (2012) GM-CSF priming drives bone marrow-derived macrophages to a pro-inflammatory pattern and downmodulates PGE2 in response to TLR2 ligands. PLoS ONE 7:e40523. https://doi.org/10.1371/journal.pone.0040523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y, Noda M, Takeuchi H, Mizuno T, Suzumura A (2012) GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. J Neuroinflammation 9:268. https://doi.org/10.1186/1742-2094-9-268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shibata Y, Berclaz PY, Chroneos ZC, Yoshida M, Whitsett JA, Trapnell BC (2001) GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 15:557–567. https://doi.org/10.1016/s1074-7613(01)00218-7

    Article  CAS  PubMed  Google Scholar 

  40. Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, Kopf M (2008) GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J Exp Med 205:2281–2294. https://doi.org/10.1084/jem.20071119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Harris RJ, Pettitt AR, Schmutz C, Sherrington PD, Zuzel M, Cawley JC, Griffiths SD (2000) Granulocyte-macrophage colony-stimulating factor as an autocrine survival factor for mature normal and malignant B lymphocytes. J Immunol 164:3887–3893. https://doi.org/10.4049/jimmunol.164.7.3887

    Article  CAS  PubMed  Google Scholar 

  42. Ni K, O’Neill HC (1992) Proliferation of the BCL1 B cell lymphoma induced by IL-4 and IL-5 is dependent on IL-6 and GM-CSF. Immunol Cell Biol 70(Pt 5):315–322. https://doi.org/10.1038/icb.1992.40

    Article  CAS  PubMed  Google Scholar 

  43. Snapper CM, Moorman MA, Rosas FR, Kehry MR, Maliszewski CR, Mond JJ (1995) IL-3 and granulocyte-macrophage colony-stimulating factor strongly induce Ig secretion by sort-purified murine B cell activated through the membrane Ig, but not the CD40, signaling pathway. J Immunol 154:5842–5850

    CAS  PubMed  Google Scholar 

  44. McNeel DG, Dunphy EJ, Davies JG et al (2009) Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer. J Clin Oncol 27:4047–4054

    Article  CAS  Google Scholar 

  45. Johnson LE, Frye TP, Arnot AR, Marquette C, Couture LA, Gendron-Fitzpatrick A, McNeel DG (2006) Safety and immunological efficacy of a prostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP). Vaccine 24:293–303

    Article  CAS  Google Scholar 

  46. McNeel DG, Eickhoff JC, Wargowski E, Zahm C, Staab MJ, Straus J, Liu G (2018) Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer. Oncotarget P9:25586–25596. https://doi.org/10.18632/oncotarget.25387

    Article  Google Scholar 

  47. Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ken Lo for array construction and analysis.

Funding

This work was supported by the National Institutes of Health (R01 CA219154, TL1 TR002375, T32 GM140935, and P30 CA014520). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Wisconsin Institutes for Medical Research, University of Wisconsin Carbone Cancer Center, 1111 Highland Avenue, Madison, WI, 53705, USA

    Hemanth K. Potluri & Douglas G. McNeel

  2. Department of Biostatistics and Medical Informatics, University of Wisconsin, 1111 Highland Avenue, Madison, WI, 53705, USA

    Tun L. Ng & Michael A. Newton

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  1. Hemanth K. Potluri
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  2. Tun L. Ng
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  4. Douglas G. McNeel
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Correspondence to Douglas G. McNeel.

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Douglas G. McNeel has ownership interest, has received research support, and serves as consultant to Madison Vaccines, Inc. which has licensed intellectual property related to this content. None of the other authors have relevant potential conflicts of interest.

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Précis: Sera from patients treated with vaccination in four separate clinical trials were evaluated for antibody responses to off-target proteins as a measure of antigen spread. Antibodies were only detected in patients administered GM-CSF as an adjuvant.

Hemanth K. Potluri and Tun Lee Ng are co first authors.

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Potluri, H.K., Ng, T.L., Newton, M.A. et al. GM-CSF elicits antibodies to tumor-associated proteins when used as a prostate cancer vaccine adjuvant. Cancer Immunol Immunother 71, 2267–2275 (2022). https://doi.org/10.1007/s00262-022-03150-3

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  • DOI: https://doi.org/10.1007/s00262-022-03150-3

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