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

TLDR

Cancer cells evade immune attack due to weak immunogenicity and CTLA‑4–mediated T‑cell inhibition, limiting the effectiveness of therapeutic vaccines that rely on dendritic‑cell presentation of tumor antigens. The study aimed to preliminarily evaluate the biological activity of CTLA‑4 blockade in humans by administering MDX‑CTLA4 to nine previously vaccinated advanced‑cancer patients. MDX‑CTLA4, a CTLA‑4 blocking antibody, was infused into these patients to assess its impact on tumor immunity. MDX‑CTLA4 induced extensive tumor necrosis with immune infiltrates in all three metastatic melanoma patients and reduced or stabilized CA‑125 in both ovarian carcinoma patients, while failing to elicit necrosis in four melanoma patients and causing no serious toxicities but mild melanocyte reactivity in five of seven patients, indicating that CTLA‑4 blockade can enhance tumor immunity in some vaccinated 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.