Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma

Comı́n-Anduix, Begoña; Lee, Yohan; Jalil, Jason; Algazi, Alain P.; Rocha, Pilar de la; Camacho, L. H.; Bozón, Viviana; Bulanhagui, C. A.; Seja, Elizabeth; Villanueva, Arturo; Straatsma, Bradley R.; Gualberto, Antonio; Economou, James S.; Glaspy, John A.; Gómez-Navarro, Jesús; Ribas, Antoni

doi:10.1186/1479-5876-6-22

Cited by 73 publications

(81 citation statements)

References 50 publications

(75 reference statements)

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“…While prior and ongoing clinical trials have shown that anti-CTLA-4 antibody therapy can have potent anti-tumor effects in a subset of metastatic melanoma patients, there have been fewer studies of its functional impact on human antigenspecific immune responses (21,22). For example, there have only been anecdotal observations of induced immunity to NY-ESO-1 in patients with ovarian and prostate cancer treated with ipilimumab (12,23,24).…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

Yuan¹,

Gnjatic

Li³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

320

246

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Section: Discussionmentioning

confidence: 99%

CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

Yuan¹,

Gnjatic

Li³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

320

246

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“…Despite occasional cases of expansion of melanoma-specific T cells (14,15), the bulk of the data suggest that there is no detectable expansion of tumor antigen-specific lymphocytes, in particular when focusing on CD81 T-cell responses. The most consistent effects in peripheral blood cells after administering anti-CTLA4 antibodies have been limited to marginal increases in the surface expression of nonspecific activation markers predominantly on CD41 T lymphocytes (16)(17)(18). The picture is markedly different when analyzing changes inside tumors.…”

mentioning

confidence: 91%

Imaging of CTLA4 Blockade–Induced Cell Replication with ¹⁸F-FLT PET in Patients with Advanced Melanoma Treated with Tremelimumab

Ribas¹,

Benz²,

Allen-Auerbach³

et al. 2010

J Nucl Med

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Preclinical models predict that blockade of the coinhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA4) on lymphocytes results in the release of a cell cycle inhibitory checkpoint, allowing lymphocyte proliferation, tumor targeting, and regression. However, there is a paucity of data demonstrating that lymphocyte proliferation does occur in humans treated with CTLA4-blocking antibodies. Methods: We tested the role of whole-body molecular imaging in patients with advanced melanoma receiving the CTLA4-blocking antibody tremelimumab, allowing the analysis of changes in glucose metabolism using the PET probe 18 F-FDG and cell replication with the PET probe 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT). Results: PET/CT scans obtained at a median of 2 mo after initial dosing did not demonstrate significant changes in lesion size or 18 F-FDG or 18 F-FLT uptake when focusing on metastatic lesions. Similarly, there was no difference in 18 F-FDG uptake in the non-melanoma-involved spleen. However, there were significant increases in standardized uptake values for 18 F-FLT in the spleen using post-and pretremelimumab treatment scans. Conclusion: Molecular imaging with the PET probe 18 F-FLT allows mapping and noninvasive imaging of cell proliferation in secondary lymphoid organs after CTLA4 blockade in patients with metastatic melanoma. The cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a coinhibitory activation-induced surface receptor on T cells that functions as a major negative regulator of anti-self-immune responses. It provides a dominant negative signaling to T cells on binding to the costimulatory molecules CD80 (B7.1) and CD86 (B7.2) expressed on the surface of antigen-presenting cells (1). Most naïve T cells do not express surface CTLA4 because of its binding to AP50, a subunit of the clathrin adaptor AP-2 protein (2). Once a T cell is activated through its T-cell receptor, downstream T-cell receptor signaling through Src kinases results in tyrosine phosphorylation of CTLA4 and the uncoupling of CTLA4 from AP50, allowing its surface expression, which peaks at 48 h after activation. Cell surface CTLA4 has 100-1,000 times higher affinity for the costimulatory molecules expressed by antigen-presenting cells, thereby efficiently competing with the positive costimulatory receptor CD28 (1). The engagement of CTLA4 by costimulatory molecules results in decreased T-cell receptor signaling, interleukin 2 transcription (3), and cell cycle arrest at the G1 stage, with the final result of inducing T-cell anergy (4,5). A clear example of the critical role of CTLA4 on tolerance is the striking phenotype of CTLA4 knock-out mice, which develop rapid T-cell proliferation and autoimmune infiltration of multiple organs shortly after birth (6,7).Monoclonal antibodies blocking CTLA4 induce regression of immunogenic tumors in mice (8) and are being pursued as a treatment approach for patients with cancer. Two fully human antibodies with CTLA4-blocking activity-ipilimumab and tremelimumab-are in clinical develo...

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“…The whole construct was then inserted into a self-inactivating third generation lentiviral vector (21) or a retroviral vector derived from a murine stem cell virus (pMSCV) backbone (22) containing a 5′ long terminal repeat-driven truncated version of the sr39tk (15) fused with enhanced green fluorescent protein (eGFP), or a firefly luciferase gene (14). (R&D Systems) and ELISPOT assays as described (26). For the multiplex cytokine-release assay, supernatants were obtained at 24, 48, and 72 h of coincubation and analyzed following the manufacturer's instructions using a Bio-Plex Mouse Cytokine Panel (Bio-Rad Laboratories).…”

Section: Methodsmentioning

confidence: 99%

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses

Koya

Mok²,

Comı́n-Anduix

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A key issue in advancing the use of adoptive cell transfer (ACT) of T cell receptor (TCR) engineered lymphocytes for cancer therapy is demonstrating how TCR transgenic cells repopulate lymphopenic hosts and target tumors in an antigen-specific fashion. ACT of splenocytes from fully immunocompetent HLA-A2.1/K b mice transduced with a chimeric murine/human TCR specific for tyrosinase, together with lymphodepletion conditioning, dendritic cell (DC)-based vaccination, and highdose interleukin-2 (IL-2), had profound antitumor activity against large established MHC-and antigen-matched tumors. Genetic labeling with bioluminescence imaging (BLI) and positron emitting tomography (PET) reporter genes allowed visualization of the distribution and antigen-specific tumor homing of TCR transgenic T cells, with trafficking correlated with antitumor efficacy. After an initial brief stage of systemic distribution, TCR-redirected and genetically labeled T cells demonstrated an early pattern of specific distribution to antigenmatched tumors and locoregional lymph nodes, followed by a more promiscuous distribution 1 wk later with additional accumulation in antigen-mismatched tumors. This approach of TCR engineering and molecular imaging reporter gene labeling is directly translatable to humans and provides useful information on how to clinically develop this mode of therapy.adoptive cell transfer therapy | molecular imaging | tumor immunotherapy A doptive cell transfer (ACT) of antigen-specific T cells involves the administration of large pools of autologous antigen-specific T cells generated by ex vivo expansion of cytotoxic T lymphocytes (CTLs) from peripheral blood mononuclear cells (PBMC) (1) or by expanding tumor antigen-reactive tumor-infiltrating lymphocytes (TIL) (2). These approaches have resulted in significant antitumor activity in patients with metastatic melanoma, but they are primarily limited by the need for lengthy ex vivo cell expansion time (several weeks) followed by the selection of antigen-specific cells for ACT. T cell receptor (TCR) engineering represents an alternative approach that attempts to shorten this process because the transfer of the alpha and beta TCR genes is necessary and sufficient to endow recipient T cells with the specificity of donor T cells (3, 4). The pioneering work by investigators at the Surgery Branch, National Cancer Institute, provided proof of principle that the ACT of TCR-engineered lymphocytes in humans is feasible and leads to objective tumor responses in patients with metastatic melanoma (5, 6).However, early clinical studies with ACT of TCR-engineered cells suggest that their antitumor activity lags behind the response rates achieved with ACT of TILs (2). Using two different TCRs, the response rate of ACT of TCR transgenic cells to patients with metastatic melanoma was in the range of 25%, whereas the same full ACT protocol but using TILs generated response rates in the 50-70% range in patients with metastatic melanoma (6, 7). There are several possible explanations for this di...

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Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma

Abstract: Background: CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.

Cited by 73 publications

References 50 publications

CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

Imaging of CTLA4 Blockade–Induced Cell Replication with ¹⁸F-FLT PET in Patients with Advanced Melanoma Treated with Tremelimumab

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses

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Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma

Abstract: Background: CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.

Cited by 73 publications

References 50 publications

CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

Imaging of CTLA4 Blockade–Induced Cell Replication with 18F-FLT PET in Patients with Advanced Melanoma Treated with Tremelimumab

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses

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Imaging of CTLA4 Blockade–Induced Cell Replication with ¹⁸F-FLT PET in Patients with Advanced Melanoma Treated with Tremelimumab