Folate receptor targeted immunotherapy of cancer: Mechanism of action and augmentation of therapeutic efficacy

Emanuela I Sega, Purdue University

Abstract

Human cancers frequently over-express a high affinity cell surface receptor for the vitamin folic acid (KD=10-9M). This same receptor has also been shown to bind folate-hapten conjugates with 10 -9M affinity, permitting the decoration of cancer cell surfaces with highly immunogenic molecules. Using syngeneic tumors in immunocompetent mice, we have shown that targeting of folate-linked haptens to tumors in anti-hapten-immunized hosts can lead to rapid accumulation of autologous anti-hapten antibodies on the tumor cell surfaces and subsequent tumor elimination via antibody dependent cellular cytotoxicity (ADCC). This strategy yields 100 % cures of established tumors in murine cancer models if the immune system is boosted with low doses of immunostimulatory cytokines (IL-2, IFN-α). To investigate the immunological mechanisms underlying these antitumor responses, we evaluated, in vitro, the participation of both humoral and cellular effector mechanisms, including complement fixation (i.e. CDC), antibody-dependent cellular cytotoxicity (ADCC), and phagocytosis, in the tumor destruction process. In addition, in vivo depletion of T-cell subsets, NK (asialo-GM1+) cells, or macrophages demonstrated that CD4+ T cells, CD8+ T cells, NK cells, and macrophages are essential components of the tumor regression process. In an effort to enhance the efficacy of the folate-targeted immunotherapy against large tumors, other therapies that could conceivably synergize with the hapten-targeted immunotherapy were explored. We demonstrate here that strong synergy is observed between tumor irradiation and immunotherapy. Furthermore, the combination of immunotherapy plus radiotherapy yields an improved response from even those tumors on the same animal that were not irradiated, suggesting that the combined therapies generate a systemic and synergistic antitumor response that can suppress tumor growth of even nonirradiated tumor masses. Additionally, we show that co-administration of the folate-hapten immunotherapy with a folate-targeted toll-like receptor ligand (CpG, the TLR 9 ligand known to have immunostimulatory activity) was also found to substantially increase mouse survival under conditions where neither therapy alone had a strong effect. These data suggest that the combination of immunotherapy with a few selected other therapies may be beneficial in the treatment of large metastatic folate receptor positive tumors.

Degree

Ph.D.

Advisors

Low, Purdue University.

Subject Area

Biochemistry

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