nach oben

Erschienen in:

01.08.2011 | Focussed Research Review

CTLA-4 blockade increases antigen-specific CD8⁺ T cells in prevaccinated patients with melanoma: three cases

verfasst von: Jianda Yuan, Brian Ginsberg, David Page, Yanyun Li, Teresa Rasalan, Humilidad F. Gallardo, Yinyan Xu, Sylvia Adams, Nina Bhardwaj, Klaus Busam, Lloyd J. Old, James P. Allison, Achim Jungbluth, Jedd D. Wolchok

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 8/2011

Einloggen, um Zugang zu erhalten

Abstract

Background

Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential for immunogenicity and may produce an effector-memory T-cell response.

Methods

To determine the effect of CTLA-4 blockade on antigen-specific responses following vaccination, in-depth immune monitoring was performed on three ipilimumab-treated patients prevaccinated with gp100 DNA (IMF-24), gp100^209–217 and tyrosinase peptides plus GM-CSF DNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11); peripheral blood mononuclear cells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culture with HLA-A*0201-restricted gp100^209–217 (ITDQVPFSV), tyrosinase^369–377 (YMDGTMSQV), or 20-mer NY-ESO-1 overlapping peptides, respectively. Tumors from IMF-32 were analyzed by immunohistochemistry to help elucidate mechanism(s) underlying tumor escape.

Results

Following vaccination, patients generated weak to no CD4⁺ or CD8⁺ T-cell response specific to the vaccine antigen but demonstrated increases in effector-memory (CCR7^loCD45RA^lo) tetramer⁺CD8⁺ T cells. After ipilimumab induction, patients experienced a robust, although sometimes transient, antigen-specific response for gp100 (IMF-32 and IMF-24) or NY-ESO-1 (IMF-11) and produced polyfunctional intracellular cytokines. Primary and metastatic tumors expressed tyrosinase but not gp100 or class I/II MHC molecules.

Conclusion

Vaccination induced a measurable antigen-specific T-cell response that increased following CTLA-4 blockade, potentially “boosting” the vaccine-primed response. Tumor escape may be related to antigen loss or lack of MHC expression necessary for immune activity. These results in a limited number of patients support the need for further research into combining vaccination with ipilimumab and provide insight into mechanisms underlying tumor escape.

Nur mit Berechtigung zugänglich

Jemal A, Siegel R, Ward E et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96PubMedCrossRef

Atkins MB, Lotze MT, Dutcher JP et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116PubMed

Eigentler TK, Caroli UM, Radny P, Garbe C (2003) Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol 4:748–759PubMedCrossRef

Chapman PB, Einhorn LH, Meyers ML et al (1999) Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745–2751PubMed

Petrella T, Quirt I, Verma S et al (2007) Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review. Cancer Treat Rev 33:484–496PubMedCrossRef

Karbach J, Gnjatic S, Bender A et al (2010) Tumor-reactive CD8⁺ T-cell responses after vaccination with NY-ESO-1 peptide, CpG 7909 and Montanide ISA-51: association with survival. Int J Cancer 126:909–918PubMed

Wolchok JD, Yuan J, Houghton AN et al (2007) Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma. Mol Ther 15:2044–2050PubMedCrossRef

Perales MA, Yuan J, Powel S et al (2008) Phase I/II study of GM-CSF DNA as an adjuvant for a multipeptide cancer vaccine in patients with advanced melanoma. Mol Ther 16:2022–2029PubMedCrossRef

Spaner DE, Astsaturov I, Vogel T et al (2006) Enhanced viral and tumor immunity with intranodal injection of canary pox viruses expressing the melanoma antigen, gp100. Cancer 106:890–899PubMedCrossRef

10.

Smith CL, Dunbar PR, Mirza F et al (2005) Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence. Int J Cancer 113:259–266PubMedCrossRef

11.

Lacelle MG, Jensen SM, Fox BA (2009) Partial CD4 depletion reduces regulatory T-cells induced by multiple vaccinations and restores therapeutic efficacy. Clin Cancer Res 15:6881–6890PubMedCrossRef

12.

Nicholaou T, Ebert LM, Davis ID et al (2009) Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma. Clin Cancer Res 15:2166–2173PubMedCrossRef

13.

Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T-cells to stimulation. J Exp Med 182:459–465PubMedCrossRef

14.

Salomon B, Lenschow DJ, Rhee L et al (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4⁺CD25⁺ immunoregulatory T-cells that control autoimmune diabetes. Immunity 12:431–440PubMedCrossRef

15.

Karandikar NJ, Vanderlugt CL, Walunas TL et al (1996) CTLA-4: a negative regulator of autoimmune disease. J Exp Med 184:783–788PubMedCrossRef

16.

Brunner MC, Chambers CA, Chan FK et al (1999) CTLA-4-mediated inhibition of early events of T-cell proliferation. J Immunol 162:5813–5820PubMed

17.

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 190:355–366PubMedCrossRef

18.

Maker AV, Attia P, Rosenberg SA (2005) Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 175:7746–7754PubMed

19.

Quezada SA, Peggs KS, Curran MA, Allison JP (2006) CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T-cells. J Clin Invest 116:1935–1945PubMedCrossRef

20.

Quezada SA, Peggs KS, Simpson TR et al (2008) Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T-cell depletion against established melanoma. J Exp Med 205:2125–2138PubMedCrossRef

21.

Hodi FS, Mihm MC, Soiffer RJ et al (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 100:4712–4717PubMedCrossRef

22.

Phan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377PubMedCrossRef

23.

Lynch T, Neal J, Bondarenko I et al (2010) Phase 2 trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIb/IV non-small cell lung cancer (NSCLC). Presented at the 2010 European Society for Clinical Oncology (ESMO) Annual Meeting; October 8–12, 2010, Milan, Italy. Abstract 375PD

24.

Slovin SF, Beer TM, Higano CS et al (2009) Initial phase II experience of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration resistant prostate cancer (mCRPC). Presented at the 2009 American Society for Clinical Oncology (ASCO) Meeting; May 29–June 2, 2009, Orlando, FL. Abstract 5138

25.

Yuan J, Gnjatic S, Li H et al (2008) CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T-cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci USA 105:20410–20415PubMedCrossRef

26.

Klein O, Ebert LM, Nicholaou T et al (2009) Melan-A-specific cytotoxic T-cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4. Clin Cancer Res 15:2507–2513PubMedCrossRef

27.

Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCrossRef

28.

Fong L, Kwek SS, O’Brien S et al (2009) Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 69:609–615PubMedCrossRef

29.

Ribas A, Comin-Anduix B, Chmielowski B et al (2009) Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clin Cancer Res 15:6267–6276PubMedCrossRef

30.

Ku GY, Yuan J, Page DB et al (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116:1767–1775PubMedCrossRef

31.

Wolchok JD, Hoos A, O’Day S et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420PubMedCrossRef

32.

Yuan J, Ku GY, Gallardo HF et al (2009) Safety and immunogenicity of a human and mouse gp100 DNA vaccine in a phase I trial of patients with melanoma. Cancer Immun 9:5PubMed

33.

Barrow C, Browning J, MacGregor D et al (2006) Tumor antigen expression in melanoma varies according to antigen and stage. Clin Cancer Res 12:764–771PubMedCrossRef

34.

Carthon BC, Wolchok JD, Yuan J et al (2010) Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 16:2861–2871PubMedCrossRef

35.

Romero P, Zippelius A, Kurth I et al (2007) Four functionally distinct populations of human effector-memory CD8⁺ T lymphocytes. J Immunol 178:4112–4119PubMed

36.

Casazza JP, Betts MR, Price DA et al (2006) Acquisition of direct antiviral effector functions by CMV-specific CD4⁺ T lymphocytes with cellular maturation. J Exp Med 203:2865–2877PubMedCrossRef

37.

Genescà M, Rourke T, Li J et al (2007) Live attenuated lentivirus infection elicits polyfunctional simian immunodeficiency virus Gag-specific CD8⁺ T-cells with reduced apoptotic susceptibility in rhesus macaques that control virus replication after challenge with pathogenic SIVmac239. J Immunol 179:4732–4740PubMed

38.

Duvall MG, Precopio ML, Ambrozak DA et al (2008) Polyfunctional T-cell responses are a hallmark of HIV-2 infection. Eur J Immunol 38:350–363PubMedCrossRef

39.

Precopio ML, Betts MR, Parrino J et al (2007) Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8⁺ T-cell responses. J Exp Med 204:1405–1416PubMedCrossRef

40.

Adams S, O’Neill DW, Nonaka D et al (2008) Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J Immunol 181:776–784PubMed

41.

Lin Y, Gallardo HF, Ku GY et al (2009) Optimization and validation of a robust human T-cell culture method for monitoring phenotypic and polyfunctional antigen-specific CD4 and CD8 T-cell responses. Cytotherapy 11:1–11CrossRef

42.

Vence L, Palucka AK, Fay JW et al (2007) Circulating tumor antigen-specific regulatory T-cells in patients with metastatic melanoma. Proc Natl Acad Sci USA 104:20884–20889PubMedCrossRef

43.

Thomson TM, Real FX, Murakami S et al (1988) Differentiation antigens of melanocytes and melanoma: analysis of melanosome and cell surface markers of human pigmented cells with monoclonal antibodies. J Invest Dermatol 90:459–466PubMedCrossRef

44.

US National Institutes of Health. www.ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT00836407?term=ipilimumab&rank=6; http://www.clinicaltrials.gov/ct2/show/NCT00357461?term=ipilimumab&rank=26; http://www.clinicaltrials.gov/ct2/show/NCT00124670?term=ipilimumab&rank=42

Titel: CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: three cases
verfasst von: Jianda Yuan
Brian Ginsberg
David Page
Yanyun Li
Teresa Rasalan
Humilidad F. Gallardo
Yinyan Xu
Sylvia Adams
Nina Bhardwaj
Klaus Busam
Lloyd J. Old
James P. Allison
Achim Jungbluth
Jedd D. Wolchok
Publikationsdatum: 01.08.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 8/2011
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1011-9

Neu im Fachgebiet Onkologie

25.04.2024 | Nierenkarzinom | Nachrichten

Springer Medizin

CTLA-4 blockade increases antigen-specific CD8⁺ T cells in prevaccinated patients with melanoma: three cases

Abstract

Background

Methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie

Springer Medizin

Abstract

Background

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 8/2011

Phase I/II study of adoptive transfer of γδ T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma

Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands

Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study

Polyfunctionality of a DKK1 self-antigen-specific CD8+ T lymphocyte clone in lung cancer

Ten years of progress in vaccination against cancer: the need to counteract cancer evasion by dual targeting in future therapies

Intraperitoneal administration of poly(I:C) with polyethylenimine leads to significant antitumor immunity against murine ovarian tumors

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie