In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5615-5615
Abstract:
Blockade of CTLA-4 activates/augments CD4+ and CD8+ tumor-specific T cell responses and results in tumor rejection. However, concomitant immune related adverse events (irAEs) in some anti-CTLA-4 mAb treated patients, such as skin rash and gastrointestinal inflammation, suggest that the breaking of tolerance to some normal self-antigens may accompany anti-tumor responses. As a consequence, patients are treated with immunosuppressive drugs, such as corticosteroids. Surprisingly, corticosteroids have not been reported to affect the anti-tumor responses induced by anti-CTLA-4 mAb; indeed, complete and enduring tumor regression has been seen in patients treated for irAEs with various immunosuppressive medications. In this study, we investigated the impact of corticosteroids on anti-tumor immune responses elicited by anti-CTLA-4 mAb in BALB/c mice bearing CMS5a-NY-ESO-1, a transplantable fibrosarcoma expressing NY-ESO-1 (an extensively studied human cancer/testis antigen). After CMS5a-NY-ESO-1 tumor inoculation, graded doses of methylprednisolone injection were initiated. Low doses of corticosteroids, similar to those used to treat patients with irAEs, did not suppress anti-tumor effects of anti-CTLA-4 mAb. However, high doses of corticosteroids, exceeding those used to treat patients with irAEs, impaired tumor growth inhibition by anti-CTLA-4 mAb. Furthermore, when high doses of corticosteroids were injected after the complete regression of tumors, approximately 30% of mice exhibited recurrence of CMS5a-NY-ESO-1 tumors at the initial tumor inoculation sites. This was associated with suppression of CD4+ and CD8+ T cell responses, indicating that anti-CTLA-4 mAb treatment induced an equilibrium-state of anti-tumor immunity, but not tumor eradication in these mice. Analyses of NY-ESO-1-specific CD4+ and CD8+ T cell responses in these mice showed that corticosteroids decreased the number of NY-ESO-1 specific T cells. We propose that dose and timing are important considerations for use of immunosuppression to treat irAEs of CTLA-4 blockade. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5615.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-5615
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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