2011
DOI: 10.1007/s00262-011-1120-5
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Intratumoral interleukin-2/agonist CD40 antibody drives CD4+-independent resolution of treated-tumors and CD4+-dependent systemic and memory responses

Abstract: Targeting interleukin-2 (IL-2) and/or agonist anti-CD40 antibody (Ab) into tumors represents an effective vaccination strategy that avoids systemic toxicity and resolves treated-site tumors. Here, we examined IL-2 and/or anti-CD40 Ab-driven local versus systemic T cell function and the installation of T cell memory. Single tumor studies showed that IL-2 induced a potent CD4+ and CD8+ T cell response that was limited to the draining lymph node and treated-site tumor, and lymph node tumor-specific CD8+ T cells d… Show more

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Cited by 29 publications
(28 citation statements)
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References 43 publications
(70 reference statements)
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“…This was indeed the case for the IL-2 monotherapy which induced a potent CD4 + and CD8 + T cell response that was limited to the dLN and treated-site tumor 8 . In contrast, anti-CD40 Ab treatment played an important role in expanding the systemic T cell response to non-dLNs, and distal untreated tumors which then regressed.…”
mentioning
confidence: 79%
“…This was indeed the case for the IL-2 monotherapy which induced a potent CD4 + and CD8 + T cell response that was limited to the dLN and treated-site tumor 8 . In contrast, anti-CD40 Ab treatment played an important role in expanding the systemic T cell response to non-dLNs, and distal untreated tumors which then regressed.…”
mentioning
confidence: 79%
“…Our previous studies showed that targeting large mesothelioma and lung carcinoma tumors with IL-2/ anti-CD40 Ab-based immunotherapy induces a permanent cure (Jackaman et al 2012a;Jackaman et al 2008;Jackaman and Nelson 2012) mediated by T cells, neutrophils (Jackaman et al 2008;Jackaman and Nelson 2012), NK cells (Jackaman et al 2012a), and macrophages (manuscript submitted). However, those proof-of-principle studies were conducted in young adult mice, and both cancers generally emerge in elderly populations when T cell immunity is declining (Haynes and Maue 2009).…”
Section: Discussionmentioning
confidence: 99%
“…Immunotherapy has shown promise in both cancers particularly mesothelioma (Bundell et al 2006;Jackaman et al 2003;Jackaman et al 2009;Jackaman et al 2012b;Jackaman et al 2008;Nelson 2010, Jackaman andNelson 2012;van Bruggen et al 2005); however, most preclinical analysis are performed in young adult mice and not representative of human cancers, such as mesothelioma, that usually occur in aging populations (Bianchi and Bianchi 2007). Furthermore, most immunotherapeutic strategies focus on T cell activation, yet T cell number and function decline with age meaning that other cells may have to be targeted (Haynes and Maue 2009).…”
Section: Introductionmentioning
confidence: 99%
“…Combining anti-CD40 mAb with IL-2 promoted and maintained a long-term protective memory [31]. Whilst the primary response was attributed to infiltrating tumor-antigen specific CD8 + T cells and PMNs [29], we found that NKs cells played a key role in the generation and maintenance of memory T cell responses [32].…”
Section: The Important Role Of Agonist Anti-cd40 In Modifying Thementioning
confidence: 99%
“…Local anti-CD40 Ab administration has been shown to eradicate treated-site tumors and induce a systemic CTL response that eradicates distal tumors [27, 30]. We have shown that generating local inflammation via IL2/anti-CD40 Ab therapy [29] results in collaborating CD4 + and CD8 + T cells that patrol the body to eradicate distal untreated tumors (Figure 2) and protect from rechallenge [31]. Interestingly, we found that different effector mechanisms can operate to eradicate treated site versus untreated distal tumors; that is, when agonist anti-CD40 Ab is combined with IL-2, the local effector response bypasses CD4 + help; however, collaborating CD4 + and CD8 + T cells were critically required for eradicating untreated distal tumors and for long-term protection [31].…”
Section: Using the Tumor Site As Its Own Source Of Antigen Stimulamentioning
confidence: 99%