Enhancement of Antitumor Immunity by CTLA-4 Blockade

Leach, Dana R.; Krummel, Matthew F.; Allison, James P.

doi:10.1126/science.271.5256.1734

Cited by 3,189 publications

(2,053 citation statements)

References 30 publications

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“…Anti-CD40 mAb increased OT-I cells to a similar level. In contrast, three other mAb, anti-CTLA-4, anti-CD25 and anti-OX40, which have all shown therapeutic activity in tumour settings [19][20][21], boosted OT-I cells only modestly (Table 1), with anti-CTLA-4 mAb being the most active with around 2% OT-I cells at the peak response. It is important to note that the anti-CD25 mAb (PC61) was shown to deplete CD25 1 cells when assessed with a second non-blocking anti-CD25 mAb.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2008

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“…6,7 However, tumor cells also harness immune checkpoints to evade the immune system, including the CD80 or CD86/ CTLA4 pathway and the programmed cell deathligand 1 or 2/programmed cell death-1 that suppresses antitumor immune responses. 6,8 Blockade of these immune checkpoints has been shown to enhance antitumor immune surveillance in vivo 9 that led to the development of therapeutic reagents targeting several immune checkpoints. Among them, antagonizing anti-CTLA4 monoclonal antibodies were developed and approved for the treatment of advanced malignant melanoma patients by the US Food and Drug Administration.…”

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confidence: 99%

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

et al. 2015

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Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1 + and CD8 + tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (Po 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (Po0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P = 0.054) and expression of EGFR and MET (Po 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (Po 0.001) and ERBB2 (P = 0.013). The numbers of CD8 + and programmed cell death-1 + lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (Po 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1 + /CD8 + lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

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“…"What we hope is that immunotherapy wi l l s ome day c ure A crucial breakthrough came in 1996, when James Allison, an immunologist at MD Anderson Cancer Center, and his colleagues showed that it was possible to amplify anti-cancer immunity by taking the brakes off a molecular checkpoint that would otherwise dampen the immune response 1 . The body relies on these checkpoints to regulate inflammation and limit the risk of autoimmune disease.…”

Section: By C H a R L E S S C H M I Dtmentioning

confidence: 99%

Immunology: Another shot at cancer

Schmidt¹

2015

Nature

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Enhancement of Antitumor Immunity by CTLA-4 Blockade

Cited by 3,189 publications

References 30 publications

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

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

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

Immunology: Another shot at cancer

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