Characterization of CD4<sup>+</sup>CD25<sup>+</sup> Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma

Cesana, Giovanni; DeRaffele, Gail; Cohen, Seth A.; Moroziewicz, Dorota; Mitcham, Josephine; Stoutenburg, John; Cheung, Ken; Hesdorffer, Charles; Kim‐Schulze, Seunghee; Kaufman, Howard L.

doi:10.1200/jco.2005.03.6830

Cited by 326 publications

(209 citation statements)

References 39 publications

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“…In RCC and melanoma, a correlation between decreasing numbers of Tregs and response to IL-2 therapy was described previously. 37 In our trial, induction of antigen-specific IL-10 secretion in patients may not only be explained by a TH2-polarization of the immune response. Alternatively, IL-10 release could also be the consequence of immunosuppressive networks induced by the vaccine, in particular Tregs.…”

Section: Discussionmentioning

confidence: 58%

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

et al. 2010

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Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A*0201 + patients with histologicallyconfirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5-40Â10 6 interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A*0201 + tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/ CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-g secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.

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Section: Discussionmentioning

confidence: 58%

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

et al. 2010

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“…This observation suggests that a subset of tumor-infiltrating CD4 ϩ T cells may impede antitumor T and NK cell function (10). This inhibitory T cell subset may include CD4 ϩ CD25 ϩ Foxp3 ϩ T cells (referred to as regulatory T (Treg) 3 cells) capable of significantly inhibiting T cell immunity (11,12). In support of this scenario are studies reporting that in vivo depletion of CD4 ϩ T cells is moderately effective in raising immunity against established tumors.…”

Section: Targeting Molecular and Cellular Inhibitory Mechanisms For Imentioning

confidence: 51%

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

Webster¹,

Thompson²,

Harris

et al. 2007

The Journal of Immunology

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Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.

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“…We are uncertain why some but not all patient Vg9Vd2 T cells respond to in vitro culture but we speculate one reason of poor proliferation of Vg9Vd2 T cells is the effect of regulatory T cells (Treg). A previous study showed that the percentage of Treg was high in circulating blood of malignant melanoma patients 55 and suggested that Treg have a negative effect upon Vg9Vd2 T cell proliferation in vitro. 56 We are continuing to investigate this issue.…”

Section: Discussionmentioning

confidence: 99%

Vγ9Vδ2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs—Rituximab and trastuzumab

Tokuyama

Hagi

Mattarollo

et al. 2008

Intl Journal of Cancer

130

121

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Vc9Vd2 T cells exert potent cytotoxicity toward various tumor cells and adoptive transfer of Vc9Vd2 T cells is an attractive proposition for cell based immunotherapy. Vc9Vd2 T cells expanded in the presence of Zoledronate and IL-2 express CD16 (FccRIII), which raises the possibility that Vc9Vd2 T cells could be used in conjunction with tumor targeting monoclonal antibody drugs to increase antitumor cytotoxicity by antibody dependent cellular cytotoxicity (ADCC). Cytotoxic activity against CD20-positive B lineage lymphoma or chronic lymphocytic leukemia (CLL) and HER2-positive breast cancer cells was assessed in the presence of rituximab and trastuzumab, respectively. Cytotoxicity of Vc9Vd2 T cells against CD20-positive targets was higher when used in combination with rituximab. Similarly, Vc9Vd2 T cells used in combination with trastuzumab resulted in greater cytotoxicity against HER2-positive cells in comparison with either agent alone and this effect was restricted to the CD16 1 Vc9Vd2 T cell population. Our results show that CD16 1 Vc9Vd2 T cells recognize monoclonal antibody coated tumor cells via CD16 and exert ADCC similar to that observed with NK cells, even when target cells are relatively resistant to monoclonal antibodies or Vc9Vd2 T cells alone. Combination therapy involving ex vivo expanded CD16 1 Vc9Vd2 T cells and monoclonal antibodies may enhance the clinical outcomes for patients treated with monoclonal antibody therapy. '

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Characterization of CD4⁺CD25⁺ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma

Abstract: The number of Tregs, defined as CD4+CD25(hi) T cells is increased in patients with MM and RCC. High-dose IL-2 resulted in a significant decrease of Tregs in those patients achieving an objective clinical response to IL-2 therapy.

Cited by 326 publications

References 39 publications

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

Vγ9Vδ2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs—Rituximab and trastuzumab

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Characterization of CD4+CD25+ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma

Abstract: The number of Tregs, defined as CD4+CD25(hi) T cells is increased in patients with MM and RCC. High-dose IL-2 resulted in a significant decrease of Tregs in those patients achieving an objective clinical response to IL-2 therapy.

Cited by 326 publications

References 39 publications

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

Vγ9Vδ2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs—Rituximab and trastuzumab

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Characterization of CD4⁺CD25⁺ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma