Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

Abstract

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.

Figures

Fig. 1.

Computed axial tomography scans illustrating pretherapy disease status (Left) and complete responses (Right) for patient 13 (A and B) and patient 11 (C–F). Arrows show sites of metastases.

Fig. 2.

Histopathologic analyses of selected patients experiencing autoimmune events. (A) Skin biopsy (patient 2) showing severe dermatitis with epidermal spongiosis, papillary dermal edema, and a prominent inflammatory infiltrate in both the superficial and deep dermis. (B) Colon biopsy (patient 9) illustrating severe colitis with infiltration of the lamina propria with neutrophils, lymphocytes, monocytes, plasmacytes, and eosinophils suggestive of autoimmune reactions. Neutrophils and lymphocytes also infiltrate the crypts; numerous mitotic figures are seen in the epithelial cells lining the crypts. (C) Immunohistochemistry of the colon biopsy (patient 9) reveals that the majority of cells are CD3+. (D) Liver biopsy (patient 12) showing areas of necrosis and lobular inflammation with (mainly) lymphocytic infiltration into the portal triad. (Magnifications: A, ×10; B–D, ×20.)