Autoimmunity Correlates With Tumor Regression in Patients With Metastatic Melanoma Treated With Anti–Cytotoxic T-Lymphocyte Antigen-4

Attia, Peter; Phan, Giao Q.; Maker, Ajay V.; Robinson, Michael R.; Quezado, Martha; Yang, James Chih‐Hsin; Sherry, Richard M.; Topalian, Suzanne L.; Kammula, Udai S.; Royal, Richard E.; Restifo, Nicholas P.; Haworth, Leah; Lévy, Catherine; Mavroukakis, Sharon; Nichol, G.; Yellin, Michael; Rosenberg, Steven A.

doi:10.1200/jco.2005.06.205

Cited by 957 publications

(736 citation statements)

References 43 publications

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“…40 Similarly, antibodies against T regs have been used in the management of malignant melanomas with promising results. 41 In conclusion, our study supports other reports that T regs are associated with more aggressive breast cancer phenotypes. The association of high numbers of T regs with more aggressive cancers, in conjunction with early immunotherapeutic data, suggests that T regs may represent an important potential therapeutic target in the treatment of aggressive breast carcinomas.…”

Section: Discussionsupporting

confidence: 91%

Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target

2008

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FoxP3 is a marker for immunosuppressive CD25 þ CD4 þ regulatory T cells. These regulatory T cells are thought to play a role in inducing immune tolerance to antigens and may be selectively recruited by carcinomas. We investigated whether breast carcinomas had significant numbers of FoxP3-positive regulatory T cells by immunohistochemistry, and if their presence was associated with other prognostic factors, such as Nottingham grade, hormone receptor immunohistochemical profile, tumor size, or lymph node metastases. Ninety-seven needle core or excisional breast biopsies with invasive breast carcinoma diagnosed at the University of Washington were stained with antibodies to FoxP3, estrogen receptor, and Her2/neu. The numbers of FoxP3-positive cells present within the neoplastic epithelium, and immediately adjacent stroma were counted manually in three high-powered fields (HPFs; Â 400) by two independent pathologists. The average scores were then correlated with the parameters of interest. A threshold of Z15 FoxP3-positive cells/HPF was used to define a FoxP3-positive case in some analyses. Higher average numbers of FoxP3-positive cells present significantly correlated with higher Nottingham grade status (P ¼ 0.000229). In addition, the presence of significant numbers (Z15/HPF) of FoxP3-positive cells in breast carcinoma was positively associated with higher Nottingham grade (P ¼ 0.00002585). Higher average numbers of FoxP3-positive cells were also significantly associated with larger tumor size (42.0 cm; P ¼ 0.012824) and trended toward an association with estrogen receptor negativity. Interestingly, 'triple-negative' (estrogen and progesterone receptor negative and Her2/neu negative) Nottingham grade III cases were also significantly associated with high numbers of FoxP3 cells. These results argue that regulatory T cells may play a role in inducing immune tolerance to higher grade, more aggressive breast carcinomas, and are a potential therapeutic target for these cancers.

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Section: Discussionsupporting

confidence: 91%

Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target

2008

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“…In general, the effectiveness of anti-tumor responses tends to correlate with the development of autoimmune diseases [82,83], especially when a systemic Treg cell depletion approach is adopted. There are, however, several ways to evoke effective tumor immunity without causing serious autoimmune reaction by targeting specific populations of Treg cells.…”

Section: Autoimmunity and Treg-targeting Cancer Immunotherapymentioning

confidence: 99%

Regulatory T cells in cancer immunotherapy

Nishikawa

Sakaguchi

2014

Current Opinion in Immunology

606

563

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“…In the case of CTLA-4, two blocking mAb are in phase I-III trials, following encouraging early testing in melanoma and ovarian carcinoma [8]. They are also being used in combination with tumour vaccines (peptides) [9,10] or various forms of chemotherapy (http://clinicaltrials.gov/). Importantly, tumour responses often develop over an extended period of weeks or months and tend to correlate with autoimmune manifestations and systemic inflammation, seen in at least a third of patients [11,12].…”

Section: Introductionmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

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Autoimmunity Correlates With Tumor Regression in Patients With Metastatic Melanoma Treated With Anti–Cytotoxic T-Lymphocyte Antigen-4

Abstract: Administration of anti-CTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses, which correlate with the induction of autoimmunity, in patients with metastatic melanoma.

Cited by 957 publications

References 43 publications

Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target

Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target

Regulatory T cells in cancer immunotherapy

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

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