Transient T cell depletion causes regression of melanoma metastases

Rasku, Mary Ann; Clem, Amy; Telang, Sucheta; Taft, B.; Gettings, Kelly F.; Gragg, Hana; Cramer, Daniel E.; Lear, Sheron C.; McMasters, Kelly M.; Miller, Donald M.; Chesney, Jason

doi:10.1186/1479-5876-6-12

Cited by 135 publications

(94 citation statements)

References 22 publications

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“…We and others saw impressive augmentation of T-cell-based immunotherapies despite incomplete Treg depletion, 46 and recent clinical trials have documented similar changes in Treg populations after CD25-based targeting using CD25-directed immunotoxins LMB-2 47 or RFT5-SMPT-dgA. 48,49 We posit that neither complete nor prolonged Treg depletion is necessary to improve the efficacy of adoptive immunotherapy and that Treg depletion mirroring the degree we show here to improve outcomes in the context of adoptive immunotherapy is readily translatable to the clinic. RhIL-7 therapy, administered without Treg depletion, enhanced both the number and function of adoptively transferred T cells and significantly enhanced outcomes in both Rag1 Ϫ/Ϫ and Thy-B recipients.…”

Section: Discussionmentioning

confidence: 99%

Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts

Cui

Zhang

Meadors

et al. 2009

Blood

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Lymphopenia enhances the effectiveness of adoptive immunotherapy by facilitating expansion of transferred T cells but also limits the T-cell repertoire available to mediate immune responses and, in humans, is associated with chronic immune dysfunction. Previous studies concluded that lymphopenia augments adoptive immunotherapy by diminishing Tregs and increasing homeostatic cytokines. We sought to determine whether targeted therapies that replicate the physiology of lymphopenia in lymphoreplete hosts could provide a similarly supportive milieu. Pmel-1 T cells were transferred to B16-bearing lymphopenic versus lymphoreplete mice receiving ␣CD25 and/or recombinant human interleukin-7. Although CD25-based Treg depletion was inefficient because of peripheral expansion of CD4 ؉ CD25 ؊ FOXP3 ؉ cells, outcomes were better in ␣CD25-treated lymphoreplete hosts than in lymphopenic hosts, and adoptive immunotherapy was most effective in lymphoreplete hosts receiving ␣CD25 plus recombinant human interleukin-7. Lymphopenic hosts supported increased proliferation of adoptively transferred antigen-specific T cells, but cells transferred to lymphoreplete recipients receiving targeted therapies showed superior function. Further, determinant spreading was substantial in lymphoreplete hosts but absent in lymphopenic hosts. These results demonstrate that targeted therapies delivered to mimic the "physiology of lymphopenia" enhance the efficacy of adoptive immunotherapy in lymphoreplete hosts and provide a potentially superior alternative to the induction of lymphopenia. (Blood. 2009;114:3831-3840)

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Section: Discussionmentioning

confidence: 99%

Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts

Cui

Zhang

Meadors

et al. 2009

Blood

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“…In several clinical trials, denileukin diftitox was administered in patients with metastatic carcinoma or melanoma (Dannull et al, 2005;Zou, 2006;Mahnke et al, 2007;Morse et al, 2008;Rasku et al, 2008). A reduction of circulating FOXP3 þ Treg was generally obtained, but very few clinical responses were observed.…”

Section: Foxp3 þ Treg and Cancer Treatmentmentioning

confidence: 99%

Human FOXP3 and cancer

et al. 2010

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FOXP3 is a transcription factor necessary and sufficient for induction of the immunosuppressive functions in regulatory T lymphocytes. Its expression was first considered as specific of this cell type, but FOXP3 can also be transiently expressed in T-cell antigen receptoractivated human nonregulatory T cells. Recent data indicate that FOXP3 is also expressed by some nonlymphoid cells, in which it can repress various oncogenes that are restored following FOXP3 deletion or mutation. This review summarizes major advances in (1) the understanding of Foxp3 functions in human regulatory T cells, (2) the prognostic significance of Foxp3-expressing T cells in human malignancies and (3) the significance of Foxp3 expression in human tumor cells.

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“…Thus far, clinical studies in which Ontak was administered to melanoma patients showed that it may reduce the number of circulating Tregs and cause regression of melanoma metastases (27)(28)(29).…”

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confidence: 99%

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

Jacobs

Punt

Lesterhuis

et al. 2010

Clinical Cancer Research

213

175

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Purpose: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody-mediated depletion of CD25 high regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines.Experimental Design: Thirty HLA-A2.1 + metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined.Results: Daclizumab efficiently depleted all CD25 high immune cells, including CD4 + FoxP3 + CD25 high cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25 + cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25 + T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group.Conclusions: Although daclizumab depleted the CD4 + FoxP3 + CD25 high Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25 + effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important. Clin Cancer Res; 16(20); 5067-78. ©2010 AACR.Melanoma is considered one of the most immunogenic types of cancers. This is based on the following arguments: (a) several melanoma-specific antigens have been identified (1, 2); (b) functional lymphocytes specific for melanoma antigens are increased in melanoma patients (3); (c) immune-stimulating agents can have a positive effect on disease outcome (4, 5); and (d) spontaneous melanoma regressions with simultaneous onset of vitiligo have been reported (6).Immunotherapeutic clinical trials have succeeded in expanding melanoma-specific effector T cells in vivo, but favorable outcomes are still limited because tumor-induced mechanisms of immune evasion may render the host tolerant for melanoma antigens (7,8). Immunosuppression at the tumor microenvironment mediated by regulatory T cells (Treg) is one of the most critical mechanisms of tumor-immune escape and a major hurdle for successful immunotherapy (9-11).In melanoma patients, selective...

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Transient T cell depletion causes regression of melanoma metastases

Cited by 135 publications

References 22 publications

Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts

Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts

Human FOXP3 and cancer

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

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