Blockade of CTLA-4 with MDX-010 in humans can induce both autoimmunity and cancer regression
Year: 2003 Printable Version
Abstract No: 3424
Author(s): G. Q. Phan, L. R. Haworth, P. H. Duray, T. A. Davis, S. A. Rosenberg; NIH/NCI/Surgery Branch, Bethesda, MD; NIH/NCI/Laboratory of Pathology, Bethesda, MD; Medarex Inc., Bloomsbury, NJ
Abstract: Background: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; CD152) is an immunosuppressive molecule expressed on activated T cells and a subset of CD4+CD25+ T cells. Blockade of CTLA-4 has been shown in murine models to enhance tumor rejection.
Method: Fourteen patients with metastatic melanoma received intravenous administration of a fully human anti-CTLA-4 antibody (MDX-010) at 3 mg/kg every 3 weeks as tolerated in conjunction with subcutaneous vaccination with two modified HLA-A*0201-restricted gp100 peptides, gp100:209-217(210M) and gp100:280-288(288V) in Montanide ISA 51.
Results: Three patients had objective cancer regression, including one with a complete response with resolution of two subcutaneous masses, 31 lung nodules and one brain metastasis. Six patients (43%) developed seven Grade III/IV autoimmune events including three patients with dermatitis, two with colitis/enterocolitis and one with hepatitis that were self-limited or responsive to systemic steroids. One additional patient developed hypophysitis that responded to replacement hormones. All patients returned to baseline function. Biopsies of the colon, skin or liver of the affected patients showed marked infiltration of lymphocytes, monocytes and eosinophils; immunohistochemistry revealed a predominance of CD3+ cells within the infiltrate. Evaluation of peripheral blood lymphocytes pre- and post-therapy revealed significantly increased expression of surface activation markers (HLA-DR, CD45RO) and successful immunization of all patients against gp100:209-217(210M).
Conclusions: CTLA-4 is a critical component of the immune system responsible for peripheral tolerance to "self" tissue and tumor antigens in humans. Blockade of CTLA-4 with MDX-010 can alter self-tolerance as well as mediate cancer regression. Further characterization of the clinical potential for this antibody is ongoing.
[As per the cc yesterday the autoimmune responses are very good signs that the drug is doing what it is supposed to do]. |
