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Experimental Photoimmunotherapy of Ovarian Cancer


Photoimmunotherapy (PIT) involves the administration of a photosensitizer (PS) conjugated to antibodies (Mab), followed by light activation of the photoimmunoconjugate (PIC). The systemic toxicity associated with radio- and chemo-immunoconjugates may thus be significantly reduced in PIT due to the dual selectivity provided by the tumor localizing ability of the Mab and the spatial control of illumination. An area of cancer therapy that has seen vigorous activity in recent years is the approach of cancer cell growth control via the interruption of growth factor mediated molecular pathways; in this regard studies directed toward the inactivation of the Epidermal Growth Factor Receptor (EGFR) signaling are possibly the most developed but remain inadequate for Long-term control or cures. The goal of this research is to develop (PIT) targeted to the EGFR for the destruction of minimal residual ovarian cancer (OVCa). Rationale: (I) EGFR is overexpressed in many cancers including OVCa (ii) its overexpression is associated with the aggressive and invasive phenotype and chemoresistant cells, hallmarks of recurrent disease and (iii) cancer cell proliferation is more dependent on signaling via this molecular pathway than normal cells. A conjugation strategy has been developed which produces purified PICs that retain both their EGFR-blocking capability and photochemical activity. The proposed Mab is C225 and the PSs are Benzoporphyrin derivative monoacid (BPD) and Chlorin e6 (Ce6). C225 is a chimeric IgG Mab in Phase I1-111trials. These PICs will be characterized in vitro as to their substitution ratios, size, and interactions with both target and non-target cells in vitro. Sub-cellular localization and intracellular processing will be investigated. The PICs will be compared to non-specific rabbit IgG PICs, Mab PICs targeted to different receptors and to PSs alone. In vivo PIT will be investigated in an orthotopic murine model of human ovarian cancer. The strategy will be to (i) establish the optimal conditions for PIC administration. (ii) Determine the toxicology of PIC/PIT and treat the mice at the maximum tolerated doses of both PS and light. Short-term (3 days) reduction in tumor burden and long-term survival will be determined. (iii) Finally, a combination of immunotherapy with C225 for short-term response and survival will be investigated. It is expected that these studies will provide a measure of the efficacy of Lp. PIT in comparison with standard PDT and C225 immunotherapy and form the basis of clinical protocols in the future.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.