Analysis of circulating regulatory T cells in patients with metastatic prostate cancer pre- versus post-vaccination

Vergati, Matteo; Cereda, Vittore; Madan, Ravi A.; Gulley, James L.; Huen, Ngar Yee; Rogers, Connie J.; Hance, Kenneth W.; Arlen, Philip M.; Schlom, Jeffrey; Tsang, Kwong Y.

doi:10.1007/s00262-010-0927-9

Cited by 50 publications

(46 citation statements)

References 57 publications

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“…Tregs are crucial in maintaining peripheral tolerance to self antigens, and hence dampen effector T cell responses against many tumor antigens (31) . These suppressive cell types pose an obstacle to effective anti-tumor immunity, with both Tregs (32) and MDSC (33) being shown to affect vaccine induced immune responses. Hence, we thought it valuable to assess the frequency of these suppressive cells in the participants both pre- and post-vaccine.…”

Section: Discussionmentioning

confidence: 99%

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

Hardwick

Carroll

Kaltcheva

et al. 2014

Clinical Cancer Research

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PURPOSE: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in patients with refractory gastrointestinal cancers. EXPERIMENTAL DESIGN: Three patients were vaccinated with 1.0 × 108 pfu p53MVA followed by nine patients at 5.6 × 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA induced immune response and examination of PD-1 checkpoint inhibition in vitro. RESULTS: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T cell compartment (p=0.03). However in most patients this did not expand further with the second and third immunization. The frequency of PD-1+ T cells detectable in patients PBMC was significantly higher than in healthy controls. Furthermore, the frequency of PD-1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (p=0.02) and antibody blockade of PD-1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T cell and antibody responses to the MVA backbone were also apparent. CONCLUSION: p53MVA was well tolerated and induced robust CD8+ T cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit.

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Section: Discussionmentioning

confidence: 99%

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

Hardwick

Carroll

Kaltcheva

et al. 2014

Clinical Cancer Research

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“…Regulatory T-cell activity was successfully blocked in mice with the monoclonal anti-CD-25 antibody daclizumab [4]. In phase II studies concerning the immunosuppressive effect of regulatory T lymphocytes, a survival advantage was registered in castration-resistant prostate cancer [14,15]. Only sipuleucel-T (ProvengeÔ) is approved for the treatment of castrationresistant prostate cancer.…”

Section: Discussionmentioning

confidence: 98%

“…These initiate the production of interleukin, interferon and tumour necrosis factor-, and stimulate the proliferation of cytotoxic cells and lymphokine-activated killer cells, as well as the cytotoxicity of macrophages. IL-2 is referred to as a T-cell growth factor [12][13][14][15]. The regulatory T lymphocytes CD8 + and CD25 + , activated by IL-2, are found in prostate cancer tissue.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical expression of interleukin-2 receptor and interleukin-6 in patients with prostate cancer and benign prostatic hyperplasia: Association with asymptomatic inflammatory prostatitis NIH category IV

Engelhardt¹,

Seklehner²,

Brustmann³

et al. 2014

Scandinavian Journal of Urology

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“…We have previously demonstrated that FOXP3 + T-regs appear to relatively decrease postbooster in normal responders, which was shown upon hepatitis A vaccination in healthy donors and in breast cancer patients receiving a Her-2/neu vaccine (34). Also, the application of a prostate cancer vaccine resulted in lower T-reg numbers postvaccination in investigated patients; additionally reduced T-reg activity postbooster correlated positively with the overall survival of these patients (35). The decrease of T-regs as percentage of CD4 T cells postbooster is most likely not in absolute numbers, but rather a result of Ag-specific T-effector cell expansion postbooster.…”

Section: Discussionmentioning

confidence: 99%

Tick-Borne Encephalitis (TBE) and Hepatitis B Nonresponders Feature Different Immunologic Mechanisms in Response to TBE and Influenza Vaccination with Involvement of Regulatory T and B Cells and IL-10

Garner-Spitzer

Wagner

Paulke‐Korinek

et al. 2013

The Journal of Immunology

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Low responsiveness/nonresponsiveness is characterized by an insufficient immune response upon primary and/or booster vaccination and affects 1–10% of vaccinees. In the current study, we aimed to investigate whether nonresponsiveness is an Ag/vaccine-specific phenomenon and to clarify underlying immunological mechanisms. Nonresponders to tick-borne encephalitis (TBE) or hepatitis B Ag with a history of previous TBE vaccinations were booster vaccinated with TBE and influenza vaccine and compared with TBE high responders in terms of humoral and cellular immune response. Postboosters in TBE high responder existing TBE titers increased, and solid humoral responses to influenza vaccine were induced. In TBE nonresponders, low to undetectable prevaccination TBE titers remained low, whereas sufficient influenza Abs were induced. In both TBE groups, a positive correlation of humoral and cellular immune response was seen as high/low TBE titers were associated with sufficient/lack of Ag-specific T cell proliferation. Furthermore, responses to influenza were robust in terms of Abs and cytokine production. In contrast, in hepatitis B nonresponders, sufficient humoral responses to TBE and influenza Ags were induced despite lacking specific IL-2 and IFN-γ production. Importantly, these patients showed high IL-10 baseline levels in vitro. HLA-DR subtypes associated with hepatitis B nonresponsiveness were overrepresented in this group, and high IL-10 levels were linked to these subtypes. Whereas TBE and hepatitis B nonresponders had increased IL-10–producing FOXP3+ T regulatory cells upon vaccination, only in hepatitis B nonresponders, showing elevated prevaccination IL-10 levels, a prominent population of B regulatory cells was detected. We conclude that immunological pathways of nonresponsiveness follow different patterns depending both on vaccine Ag and genetic predisposition of the vaccinee.

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Analysis of circulating regulatory T cells in patients with metastatic prostate cancer pre- versus post-vaccination

Cited by 50 publications

References 57 publications

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

Immunohistochemical expression of interleukin-2 receptor and interleukin-6 in patients with prostate cancer and benign prostatic hyperplasia: Association with asymptomatic inflammatory prostatitis NIH category IV

Tick-Borne Encephalitis (TBE) and Hepatitis B Nonresponders Feature Different Immunologic Mechanisms in Response to TBE and Influenza Vaccination with Involvement of Regulatory T and B Cells and IL-10

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