Skip to main content

Advertisement

SpringerLink
Log in

Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity

  • Short Communication
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Promising anti-tumor responses have been observed in the clinic using monoclonal antibodies (mAbs) that block immune checkpoints. One concern with these therapeutic agents remains the potential induction of immune breakthrough events (IBEs) resulting from the disruption of T cell homeostasis or the breaking of tolerance to self antigens. As an approach to maintaining anti-tumor responses but decreasing the likelihood of these events, the local expression of a mAb in combination with a GM-CSF-secreting cancer immunotherapy was evaluated. Using anti-cytotoxic T lymphocyte antigen (CTLA)-4 as a model antibody to test this hypothesis, tumor cell lines were generated that expressed the full-length mAb in addition to GM-CSF. Evaluation of these cell lines in two therapeutic tumor models revealed that local, cell-mediated delivery of anti-CTLA-4 from a GM-CSF-secreting tumor cell immunotherapy activated potent anti-tumor responses and prolonged overall survival at significantly lower serum mAb levels in the host. Furthermore, lowering the systemic exposure of the host to the immune modulatory mAb correlated with reduced evidence of systemic autoimmunity. This approach has broad utility for the delivery of mAbs or proteins locally from cellular immunotherapies to minimize IBEs while retaining the potent therapeutic effects of such combination treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Carter PJ (2006) Potent antibody therapeutics by design. Nat Rev Immunol 6:343–357

    Article  PubMed  CAS  Google Scholar 

  2. Peggs KS, Quezada SA, Korman AJ, Allison JP (2006) Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 18:206–213

    Article  PubMed  CAS  Google Scholar 

  3. Dranoff G (2003) GM-CSF-secreting melanoma vaccines. Oncogene 22:3188–3192

    Article  PubMed  CAS  Google Scholar 

  4. Nemunaitis J (2005) Vaccines in cancer: GVAX, a GM-CSF gene vaccine. Expert Rev Vaccines 4:259–274

    Article  PubMed  CAS  Google Scholar 

  5. Simmons AD, Li B, Gonzalez-Edick M, Lin C, Moskalenko M, Du T, Creson J, Vanroey MJ, Jooss K (2007) GM-CSF-secreting cancer immunotherapies: preclinical analysis of the mechanism of action. Cancer Immunol Immunother 56:1653–1665

    Article  PubMed  CAS  Google Scholar 

  6. Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297–339

    Article  PubMed  CAS  Google Scholar 

  7. Sanderson K, Scotland R, Lee P, Liu D, Groshen S, Snively J, Sian S, Nichol G, Davis T, Keler T, Yellin M, Weber J (2005) Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23:741–750

    Article  PubMed  CAS  Google Scholar 

  8. Finer MH, Dull TJ, Qin L, Farson D, Roberts MR (1994) Kat: a high-efficiency retroviral transduction system for primary human T lymphocytes. Blood 83:43–50

    PubMed  CAS  Google Scholar 

  9. Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D, Naldini L (1998) A third-generation lentivirus vector with a conditional packaging system. J Virol 72:8463–8471

    PubMed  CAS  Google Scholar 

  10. Li B, Lalani AS, Harding TC, Luan B, Koprivnikar K, Huan Tu G, Prell R, VanRoey MJ, Simmons AD, Jooss K (2006) Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res 12:6808–6816

    Article  PubMed  CAS  Google Scholar 

  11. Donnelly ML, Luke G, Mehrotra A, Li X, Hughes LE, Gani D, Ryan MD (2001) Analysis of the aphthovirus 2A/2B polyprotein “cleavage” mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal “skip”. J Gen Virol 82:1013–1025

    PubMed  CAS  Google Scholar 

  12. Donnelly ML, Hughes LE, Luke G, Mendoza H, ten Dam E, Gani D, Ryan MD (2001) The “cleavage” activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring “2A-like” sequences. J Gen Virol 82:1027–1041

    PubMed  CAS  Google Scholar 

  13. Ryan MD, King AM, Thomas GP (1991) Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. J Gen Virol 72(Pt 11):2727–2732

    Article  PubMed  CAS  Google Scholar 

  14. Fang J, Qian JJ, Yi S, Harding TC, Tu GH, VanRoey M, Jooss K (2005) Stable antibody expression at therapeutic levels using the 2A peptide. Nat Biotechnol 23:584–590

    Article  PubMed  CAS  Google Scholar 

  15. van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190:355–366

    Article  PubMed  Google Scholar 

  16. Tuve S, Chen BM, Liu Y, Cheng TL, Toure P, Sow PS, Feng Q, Kiviat N, Strauss R, Ni S, Li ZY, Roffler SR, Lieber A (2007) Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses. Cancer Res 67:5929–5939

    Article  PubMed  CAS  Google Scholar 

  17. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Restifo NP, Haworth LR, Levy C, Mavroukakis SA, Nichol G, Yellin MJ, Rosenberg SA (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043–6053

    Article  PubMed  CAS  Google Scholar 

  18. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377

    Article  PubMed  CAS  Google Scholar 

  19. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100:4712–4717

    Article  PubMed  CAS  Google Scholar 

  20. van Wijk F, Hoeks S, Nierkens S, Koppelman SJ, van Kooten P, Boon L, Knippels LM, Pieters R (2005) CTLA-4 signaling regulates the intensity of hypersensitivity responses to food antigens, but is not decisive in the induction of sensitization. J Immunol 174:174–179

    PubMed  Google Scholar 

  21. Kocak E, Lute K, Chang X, May KF Jr, Exten KR, Zhang H, Abdessalam SF, Lehman AM, Jarjoura D, Zheng P, Liu Y (2006) Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res 66:7276–7284

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank P. Working for critical reading of the manuscript, and R. Prell for helpful discussions. B. Batiste, J. Ho, T. Langer and S. Tanciongo are gratefully acknowledged for their technical assistance.

Author information

Authors and Affiliations

  1. Cell Genesys, Inc., 500 Forbes Blvd, South San Francisco, CA, 94080, USA

    Andrew D. Simmons, Marina Moskalenko, Jennifer Creson, Jianmin Fang, Saili Yi, Melinda J. VanRoey & Karin Jooss

  2. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    James P. Allison

Authors
  1. Andrew D. Simmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marina Moskalenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer Creson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianmin Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Saili Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Melinda J. VanRoey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James P. Allison
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Karin Jooss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew D. Simmons.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simmons, A.D., Moskalenko, M., Creson, J. et al. Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity. Cancer Immunol Immunother 57, 1263–1270 (2008). https://doi.org/10.1007/s00262-008-0451-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0451-3

Keywords

Search

Navigation