Combination CTLA-4 Blockade and 4-1BB Activation Enhances Tumor Rejection by Increasing T-Cell Infiltration, Proliferation, and Cytokine Production

Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
PLoS ONE (Impact Factor: 3.23). 04/2011; 6(4):e19499. DOI: 10.1371/journal.pone.0019499
Source: PubMed


The co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) attenuates immune responses and prevent autoimmunity, however, tumors exploit this pathway to evade the host T-cell response. The T-cell co-stimulatory receptor 4-1BB is transiently upregulated on T-cells following activation and increases their proliferation and inflammatory cytokine production when engaged. Antibodies which block CTLA-4 or which activate 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma as single agents.

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Available from: Aymen Al-Shamkhani
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    • "Multiple models have shown the synergistic effect of such combination in promoting tumor regression and survival. Combination therapy can augment CD8 + effector T cell proliferation and possibly alter the proportion of T-bet high cells within the exhausted T cell population787980. Phase I-II clinical trials are ongoing, including some trials aimed at patients with advanced B cell NHL (NCT02253992). "
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    • "Adding anti–CTLA-4 further increased the potency of this approach, resulting in ~80% tumor rejection of established mammary 4 T1 tumors in mice [46]. Combining CTLA-4 blockade and 4-1BB co-stimulation with a granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting melanoma vaccine greatly improved tumor eradication and promoted survival compared with vaccine plus either agent [47]. Combination treatment increased proliferation and tumor infiltration by both CD4+ and CD8+ T cells, and intratumor inflammatory cytokine production. "
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    • "However, CD8+ T cells do not always traffic into tissues, which has been a special problem when CD8+ T cells are used for tumor immunotherapy [68]. While BAFF has not been studied in this context, it is interesting that 4-1BB stimulation has been shown to promote CD8+ T cell entry into the tumor microenvironment [69], [70]. While these studies used an agonistic anti-4-1BB antibody, the present report shows how a vaccine strategy using SP-D-4-1BBL can promote lymphocyte migration into diseased tissues. "
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