Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients

Abstract

A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte-macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.

Figures

Figure 1

MDX-CTLA-4 stimulated melanocyte immune recognition. (A) Reticular erythematous rash. (B) Perivascular lymphocyte infiltrate extending into epidermis with interface dermatitis. (C) CD4+ T cells apposed to dying melanocytes. (D) CD8+ T cells apposed to dying melanocytes. (Magnification: ×125, B; ×250, C and D.)

Figure 2

MDX-CTLA-4 induced hemorrhagic tumor necrosis in vaccinated patient 1. (A) Inflamed s.c. nodule. (B) Necrotic brain metastasis. (C) Necrotic lung metastasis. (D and E) Hemorrhagic tumor necrosis. (F) Rim of viable tumor with granulocytes and lymphocytes. (Magnification: ×250, D–F.)

Figure 3

MDX-CTLA-4 induced extensive tumor necrosis in vaccinated patient 2. (A and B) Tumor necrosis with granulocytes and lymphocytes. (C) CD4+ T cells. (D) CD8+ T cells. (E) CD20+ B cells. (F) Vasculopathy with perivascular and intramural lymphoid infiltrates associated with luminal thrombosis. (Magnification: ×125, A; ×250, B–F.)

Figure 4

MDX-CTLA-4 induced CD8+ T cell infiltrates but no tumor necrosis in vaccinated patients 3 and 4. (A) Lymphocyte infiltrate without tumor destruction. (B) CD8+ T cells. (C) CD4+ T cells. (D) CD20+ B cells. (Magnification: ×250, A and B; ×500, C and D.)

Figure 5

MDX-CTLA-4 induced alterations in the circulating ovarian carcinoma tumor marker CA-125. (A) Patient 8. (B) Patient 9. Arrows indicate MDX-CTLA-4 infusions.