Skip to main content
SpringerLink
Log in

Myxoma virus combined with rapamycin treatment enhances adoptive T cell therapy for murine melanoma brain tumors

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Adoptive transfer of tumor-specific T cells has shown some success for treating metastatic melanoma. We evaluated a novel strategy to improve adoptive therapy by administering both T cells and oncolytic myxoma virus to mice with syngeneic B16.SIY melanoma brain tumors. Adoptive transfer of activated CD8+ 2C T cells that recognize SIY peptide doubled survival time, but SIY-negative tumors recurred. Myxoma virus killed B16.SIY cells in vitro, and intratumoral injection of virus led to selective and transient infection of the tumor. Virus treatment recruited innate immune cells to the tumor and induced IFNβ production in the brain, resulting in limited oncolytic effects in vivo. To counter this, we evaluated the safety and efficacy of co-administering 2C T cells, myxoma virus, and either rapamycin or neutralizing antibodies against IFNβ. Mice that received either triple combination therapy survived significantly longer with no apparent side effects, but eventually relapsed. Importantly, rapamycin treatment did not impair T cell-mediated tumor destruction, supporting the feasibility of combining adoptive immunotherapy and rapamycin-enhanced virotherapy. Myxoma virus may be a useful vector for transient delivery of therapeutic genes to a tumor to enhance T cell responses.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sampson JH, Carter JH Jr, Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 88(1):11–20. doi:10.3171/jns.1998.88.1.0011

    Article  PubMed  CAS  Google Scholar 

  2. Rosenberg SA, Dudley ME (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21(2):233–240. doi:10.1016/j.coi.2009.03.002

    Article  PubMed  CAS  Google Scholar 

  3. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239. doi:10.1200/JCO.2008.16.5449

    Article  PubMed  CAS  Google Scholar 

  4. Hong JJ, Rosenberg SA, Dudley ME, Yang JC, White DE, Butman JA, Sherry RM (2010) Successful Treatment of Melanoma Brain Metastases With Adoptive Cell Therapy. Clin Cancer Res. doi:10.1158/1078-0432.CCR-10-1507

  5. Jager E, Ringhoffer M, Karbach J, Arand M, Oesch F, Knuth A (1996) Inverse relationship of melanocyte differentiation antigen expression in melanoma tissues and CD8 + cytotoxic-T-cell responses: evidence for immunoselection of antigen-loss variants in vivo. Int J Cancer 66(4):470–476. doi: 10.1002/(SICI)1097-0215(19960516)66:4<470:AID-IJC10>3.0.CO;2-C

    Article  PubMed  CAS  Google Scholar 

  6. Riker A, Cormier J, Panelli M, Kammula U, Wang E, Abati A, Fetsch P, Lee KH, Steinberg S, Rosenberg S, Marincola F (1999) Immune selection after antigen-specific immunotherapy of melanoma. Surgery 126(2):112–120. doi:S0039606099002044

    Article  PubMed  CAS  Google Scholar 

  7. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8 + T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99(25):16168–16173

    Article  PubMed  CAS  Google Scholar 

  8. Goldberger O, Volovitz I, Machlenkin A, Vadai E, Tzehoval E, Eisenbach L (2008) Exuberated numbers of tumor-specific T cells result in tumor escape. Cancer Res 68(9):3450–3457. doi:10.1158/0008-5472.CAN-07-5006

    Article  PubMed  CAS  Google Scholar 

  9. Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6(11):836–848. doi:10.1038/nri1961

    Article  PubMed  CAS  Google Scholar 

  10. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD (2008) Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 20(5):267–275

    Article  PubMed  CAS  Google Scholar 

  11. Thomas DL, Kim M, Bowerman NA, Narayanan S, Kranz DM, Schreiber H, Roy EJ (2009) Recurrence of intracranial tumors following adoptive T cell therapy can be prevented by direct and indirect killing aided by high levels of tumor antigen cross-presented on stromal cells. J Immunol 183(3):1828–1837. doi:10.4049/jimmunol.0802322

    Article  PubMed  CAS  Google Scholar 

  12. Diaz RM, Galivo F, Kottke T, Wongthida P, Qiao J, Thompson J, Valdes M, Barber G, Vile RG (2007) Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res 67(6):2840–2848. doi:10.1158/0008-5472.CAN-06-3974

    Article  PubMed  CAS  Google Scholar 

  13. Qiao J, Wang H, Kottke T, Diaz RM, Willmon C, Hudacek A, Thompson J, Parato K, Bell J, Naik J, Chester J, Selby P, Harrington K, Melcher A, Vile RG (2008) Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors. Gene Ther 15(8):604–616. doi:10.1038/sj.gt.3303098

    Article  PubMed  CAS  Google Scholar 

  14. Zhang YQ, Tsai YC, Monie A, Wu TC, Hung CF (2010) Enhancing the therapeutic effect against ovarian cancer through a combination of viral oncolysis and antigen-specific immunotherapy. Mol Ther 18(4):692–699. doi:10.1038/mt.2009.318

    Article  PubMed  CAS  Google Scholar 

  15. Sypula WFJ, Ma Y, Bell J, McFadden G (2004) Myxoma virus tropism in human tumor cells. Gene Ther Mol Biol 8:103–114

    Google Scholar 

  16. Lun X, Yang W, Alain T, Shi ZQ, Muzik H, Barrett JW, McFadden G, Bell J, Hamilton MG, Senger DL, Forsyth PA (2005) Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas. Cancer Res 65(21):9982–9990

    Article  PubMed  CAS  Google Scholar 

  17. Lun XQ, Zhou H, Alain T, Sun B, Wang L, Barrett JW, Stanford MM, McFadden G, Bell J, Senger DL, Forsyth PA (2007) Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res 67(18):8818–8827

    Article  PubMed  CAS  Google Scholar 

  18. Woo Y, Kelly KJ, Stanford MM, Galanis C, Chun YS, Fong Y, McFadden G (2008) Myxoma virus is oncolytic for human pancreatic adenocarcinoma cells. Ann Surg Oncol 15(8):2329–2335. doi:10.1245/s10434-008-9924-z

    Article  PubMed  Google Scholar 

  19. Wu Y, Lun X, Zhou H, Wang L, Sun B, Bell JC, Barrett JW, McFadden G, Biegel JA, Senger DL, Forsyth PA (2008) Oncolytic efficacy of recombinant vesicular stomatitis virus and myxoma virus in experimental models of rhabdoid tumors. Clin Cancer Res 14(4):1218–1227. doi:10.1158/1078-0432.CCR-07-1330

    Article  PubMed  CAS  Google Scholar 

  20. Kim M, Madlambayan GJ, Rahman MM, Smallwood SE, Meacham AM, Hosaka K, Scott EW, Cogle CR, McFadden G (2009) Myxoma virus targets primary human leukemic stem and progenitor cells while sparing normal hematopoietic stem and progenitor cells. Leukemia 23(12):2313–2317. doi:10.1038/leu.2009.219

    Article  PubMed  CAS  Google Scholar 

  21. Stanford MM, Shaban M, Barrett JW, Werden SJ, Gilbert PA, Bondy-Denomy J, Mackenzie L, Graham KC, Chambers AF, McFadden G (2008) Myxoma virus oncolysis of primary and metastatic B16F10 mouse tumors in vivo. Mol Ther 16(1):52–59

    Article  PubMed  CAS  Google Scholar 

  22. Lun X, Alain T, Zemp FJ, Zhou H, Rahman MM, Hamilton MG, McFadden G, Bell J, Senger DL, Forsyth PA (2010) Myxoma virus virotherapy for glioma in immunocompetent animal models: optimizing administration routes and synergy with rapamycin. Cancer Res 70(2):598–608. doi:10.1158/0008-5472.CAN-09-1510

    Article  PubMed  CAS  Google Scholar 

  23. McFadden G (2005) Poxvirus tropism. Nat Rev Microbiol 3(3):201–213. doi:10.1038/nrmicro1099

    Article  PubMed  CAS  Google Scholar 

  24. Jackson EW, Dorn CR, Saito JK, McKercher DG (1966) Absence of serological evidence of myxoma virus infection in humans exposed during an outbreak of myxomatosis. Nature 211(5046):313–314

    Article  PubMed  CAS  Google Scholar 

  25. Homicsko K, Lukashev A, Iggo RD (2005) RAD001 (everolimus) improves the efficacy of replicating adenoviruses that target colon cancer. Cancer Res 65(15):6882–6890. doi:10.1158/0008-5472.CAN-05-0309

    Article  PubMed  CAS  Google Scholar 

  26. Alonso MM, Gomez-Manzano C, Jiang H, Bekele NB, Piao Y, Yung WK, Alemany R, Fueyo J (2007) Combination of the oncolytic adenovirus ICOVIR-5 with chemotherapy provides enhanced anti-glioma effect in vivo. Cancer Gene Ther 14(8):756–761. doi:10.1038/sj.cgt.7701067

    Article  PubMed  CAS  Google Scholar 

  27. Alonso MM, Jiang H, Yokoyama T, Xu J, Bekele NB, Lang FF, Kondo S, Gomez-Manzano C, Fueyo J (2008) Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. Mol Ther 16(3):487–493. doi:10.1038/sj.mt.6300400

    Article  PubMed  CAS  Google Scholar 

  28. Lun XQ, Jang JH, Tang N, Deng H, Head R, Bell JC, Stojdl DF, Nutt CL, Senger DL, Forsyth PA, McCart JA (2009) Efficacy of systemically administered oncolytic vaccinia virotherapy for malignant gliomas is enhanced by combination therapy with rapamycin or cyclophosphamide. Clin Cancer Res 15(8):2777–2788. doi:10.1158/1078-0432.CCR-08-2342

    Article  PubMed  CAS  Google Scholar 

  29. Alain T, Lun X, Martineau Y, Sean P, Pulendran B, Petroulakis E, Zemp FJ, Lemay CG, Roy D, Bell JC, Thomas G, Kozma SC, Forsyth PA, Costa-Mattioli M, Sonenberg N (2010) Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production. Proc Natl Acad Sci USA 107(4):1576–1581. doi:10.1073/pnas.0912344107

    Article  PubMed  CAS  Google Scholar 

  30. Lun X, Chan J, Zhou H, Sun B, Kelly JJ, Stechishin OO, Bell JC, Parato K, Hu K, Vaillant D, Wang J, Liu TC, Breitbach C, Kirn D, Senger DL, Forsyth PA (2010) Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma. Mol Ther 18(11):1927–1936. doi:10.1038/mt.2010.183

    Article  PubMed  CAS  Google Scholar 

  31. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF (2004) PD-L1/B7H–1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8 + T cells. Cancer Res 64(3):1140–1145

    Article  PubMed  CAS  Google Scholar 

  32. Liu J, Wennier S, Reinhard M, Roy E, MacNeill A, McFadden G (2009) Myxoma virus expressing interleukin-15 fails to cause lethal myxomatosis in European rabbits. J Virol 83(11):5933–5938. doi:10.1128/JVI.00204-09

    Article  PubMed  CAS  Google Scholar 

  33. Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A, Yu P, Fu YX, Weichselbaum RR, Rowley DA, Kranz DM, Schreiber H (2007) Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 204(1):49–55

    Article  PubMed  CAS  Google Scholar 

  34. Calzascia T, Di Berardino-Besson W, Wilmotte R, Masson F, de Tribolet N, Dietrich PY, Walker PR (2003) Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain. J Immunol 171(5):2187–2191

    PubMed  CAS  Google Scholar 

  35. Kline J, Brown IE, Zha YY, Blank C, Strickler J, Wouters H, Zhang L, Gajewski TF (2008) Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. Clin Cancer Res 14(10):3156–3167. doi:10.1158/1078-0432.CCR-07-4696

    Article  PubMed  CAS  Google Scholar 

  36. Surh CD, Sprent J (2008) Homeostasis of naive and memory T cells. Immunity 29(6):848–862. doi:10.1016/j.immuni.2008.11.002

    Article  PubMed  CAS  Google Scholar 

  37. Ge Q, Hu H, Eisen HN, Chen J (2002) Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments. Proc Natl Acad Sci USA 99(5):2989–2994. doi:10.1073/pnas.05271409999/5/2989

    Article  PubMed  CAS  Google Scholar 

  38. Wang F, Ma Y, Barrett JW, Gao X, Loh J, Barton E, Virgin HW, McFadden G (2004) Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. Nat Immunol 5(12):1266–1274

    Article  PubMed  CAS  Google Scholar 

  39. Bartee E, Mohamed MR, Lopez MC, Baker HV, McFadden G (2009) The addition of tumor necrosis factor plus beta interferon induces a novel synergistic antiviral state against poxviruses in primary human fibroblasts. J Virol 83(2):498–511. doi:10.1128/JVI.01376-08

    Article  PubMed  CAS  Google Scholar 

  40. Fujita M, Scheurer ME, Decker SA, McDonald HA, Kohanbash G, Kastenhuber ER, Kato H, Bondy ML, Ohlfest JR, Okada H (2010) Role of type 1 IFNs in antiglioma immunosurveillance–using mouse studies to guide examination of novel prognostic markers in humans. Clin Cancer Res 16(13):3409–3419. doi:10.1158/1078-0432.CCR-10-0644

    Article  PubMed  CAS  Google Scholar 

  41. Willmon CL, Saloura V, Fridlender ZG, Wongthida P, Diaz RM, Thompson J, Kottke T, Federspiel M, Barber G, Albelda SM, Vile RG (2009) Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. Cancer Res 69(19):7713–7720. doi:10.1158/0008-5472.CAN-09-1013

    Article  PubMed  CAS  Google Scholar 

  42. Xu B, Grander D, Sangfelt O, Einhorn S (1994) Primary leukemia cells resistant to alpha-interferon in vitro are defective in the activation of the DNA-binding factor interferon-stimulated gene factor 3. Blood 84(6):1942–1949

    PubMed  CAS  Google Scholar 

  43. Wong LH, Krauer KG, Hatzinisiriou I, Estcourt MJ, Hersey P, Tam ND, Edmondson S, Devenish RJ, Ralph SJ (1997) Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma. J Biol Chem 272(45):28779–28785

    Article  PubMed  CAS  Google Scholar 

  44. Dunn GP, Sheehan KC, Old LJ, Schreiber RD (2005) IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Res 65(8):3447–3453. doi:10.1158/0008-5472.CAN-04-4316

    PubMed  CAS  Google Scholar 

  45. Stanford MM, Barrett JW, Nazarian SH, Werden S, McFadden G (2007) Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells. J Virol 81(3):1251–1260

    Article  PubMed  CAS  Google Scholar 

  46. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460(7251):108–112. doi:10.1038/nature08155

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the anonymous donor that funded this research, Thomas Gajewski and Maciej Lesniak for the B16.SIY cells, and the Flow Cytometry Facility at University of Illinois at Urbana–Champaign.

Author information

Authors and Affiliations

  1. Neuroscience Program, University of Illinois at Urbana–Champaign, Urbana, IL, USA

    Diana L. Thomas & Edward J. Roy

  2. Department of Pathobiology, University of Illinois at Urbana–Champaign, Urbana, IL, USA

    Rosalinda Doty & Amy L. MacNeill

  3. Department of Molecular and Integrative Physiology, University of Illinois at Urbana–Champaign, Urbana, IL, USA

    Vesna Tosic & Edward J. Roy

  4. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA

    Jia Liu & Grant McFadden

  5. Department of Biochemistry, University of Illinois at Urbana–Champaign, Urbana, IL, USA

    David M. Kranz

  6. Department of Pathology, University of Illinois at Urbana–Champaign, Urbana, IL, USA

    Edward J. Roy

Authors
  1. Diana L. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosalinda Doty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vesna Tosic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David M. Kranz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Grant McFadden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Amy L. MacNeill
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Edward J. Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward J. Roy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thomas, D.L., Doty, R., Tosic, V. et al. Myxoma virus combined with rapamycin treatment enhances adoptive T cell therapy for murine melanoma brain tumors. Cancer Immunol Immunother 60, 1461–1472 (2011). https://doi.org/10.1007/s00262-011-1045-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-011-1045-z

Keywords

Search

Navigation