EXPERIMENTAL PHOTOIMMUNOTHERAPY OF OVARIAN CANCER
Principal Investigator: Tayyaba Hasan
Abstract: 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.
Funding Period: 1992-05-01 - 2009-06-30
more information: NIH RePORT
- Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugatesBryan Q Spring
Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
Proc Natl Acad Sci U S A 111:E933-42. 2014..By introducing targeted activation to enhance tumor selectively in complex anatomical sites, this study offers prospects for catching early recurrent micrometastases and for treating occult disease. ..
- Epidermal growth factor receptor-targeted photosensitizer selectively inhibits EGFR signaling and induces targeted phototoxicity in ovarian cancer cellsAdnan O Abu-Yousif
Wellman Center for Photomedicine, Department of Dermatology, Bartlett Hall 314, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA 02114, USA
Cancer Lett 321:120-7. 2012..Our results suggest that photoimmunotargeting is a useful dual strategy for the selective destruction of cancer cells and also exerts the receptor-blocking biological function of the antibody...
- Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancerImran Rizvi
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Cancer Res 70:9319-28. 2010..This approach combining biological modeling with high-content imaging provides a platform to rapidly screen therapeutic strategies for a broad array of metastatic tumors...
- Quantitative imaging reveals heterogeneous growth dynamics and treatment-dependent residual tumor distributions in a three-dimensional ovarian cancer modelJonathan P Celli
Harvard Medical School, Massachusetts General Hospital, Wellman Center for Photomedicine, Boston, Massachusetts 02114, USA
J Biomed Opt 15:051603. 2010..In contrast, PDT treatment disrupts micronodular structure, causing punctate regions of toxicity, shifting the distribution toward smaller sizes, and potentially increasing vulnerability to subsequent chemotherapeutic treatment...
- In vitro ovarian tumor growth and treatment response dynamics visualized with time-lapse OCT imagingConor L Evans
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom St, Boston, MA 02114, USA
Opt Express 17:8892-906. 2009..The development of a time-lapse OCT system, capable of automated, multidimensional acquisition, further provided insights into the growth and chemotherapeutic response of ovarian cancer...
- Decreased metastatic phenotype in cells resistant to aminolevulinic acid-photodynamic therapyAdriana Casas
Centro de Investigaciones sobre Porfirinas y Porfirias, CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, 1056 Ciudad de Buenos Aires, Córdoba 2351 1er subsuelo, CP 1120AAF, Buenos Aires, Argentina
Cancer Lett 271:342-51. 2008..These findings may be crucial for the outcome of ALA-PDT of metastatic tumours, although further studies are needed to extrapolate the results to the clinic employing another photosensitisers and cell types...
- Strategies for enhanced photodynamic therapy effectsSarika Verma
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Photochem Photobiol 83:996-1005. 2007....
- Tumor cell lines resistant to ALA-mediated photodynamic therapy and possible tools to target surviving cellsAdriana Casas
Centro de Investigaciones sobre Porfirinas y Porfirias CIPYP, 1056 Ciudad de Buenos Aires, Argentina
Int J Oncol 29:397-405. 2006..Those hypoxic cells can be also a preferential target of bioreductive drugs and hypoxia-directed gene therapy, and would be sensitive to treatment with other photosensitizers...
- Targeted photodynamic therapyNicolas Solban
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Lasers Surg Med 38:522-31. 2006..Photodynamic therapy (PDT) is an emerging modality for the treatment of various neoplastic and non-neoplastic pathologies...
- Liposomal delivery of photosensitising agentsBin Chen
Dartmouth Medical School Department of Surgery, Lebanon, NH 03756, USA
Expert Opin Drug Deliv 2:477-87. 2005..This review will cover progress in the use of liposomal photosensitisers, summarise current liposomal formulations, and project future directions for the liposomal delivery of photosensitising agents...
- Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivoMarcela G del Carmen
Wellman Center for Photomedicine, Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
J Natl Cancer Inst 97:1516-24. 2005....
- Photochemical targeting of epidermal growth factor receptor: a mechanistic studyMark D Savellano
Department of Surgery, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
Clin Cancer Res 11:1658-68. 2005..In this investigation, we suggest a strategy to overcome these limitations and present the successful targeting of epidermal growth factor receptor (EGFR) using a well-characterized PIC...