Immunophotodiagnosis of colon carcinomas in patients injected with fluoresceinated chimeric antibodies against carcinoembryonic antigen.

Abstract

Based on previous experiments in nude mice, showing that fluoresceinated monoclonal antibodies against carinoembryonic antigen localized specifically in human carcinoma xenografts and could be detected by laser-induced fluorescence, we performed a feaibilit study to determine whether this immunopho method could be applied in the clinic. Six patients, with known primary colorectal carcinoma, received an i.v. injection of 4.5 or 9 mg of mousehuman chimeric anti-carcinoembryonic antigen monoclonal antibody coupled with 0.10-0.28 mg offluorescein (molar ratio 1/10 to 1/14). The monoclonal antibody was also labeled with 0.2-0.4 mCi of 12-I (1 Ci = 37 GBq). Photodetection of the tumor was done ex vivo on surgically resected tissues for the six patients and in vivo by fluorescence rectosigmoidoscopy for the sixth patient. Upon laser irradiation, ciearly detectable heterogeneous green fluorescence from the dye-antibody conjugate was visually observed on all six tumors; almost no such fluorescence was detectable on normal mucosa. The yellowish tissue autofluorescence, which was emitted from both tumor and normal mucosa, could be subtracted by real-time image processing. Radioactivity measurements confirmed the specificity of tumor localization by the conjugate; tissue concentrations of up to 0.059% Injected dose per g of tumor and 10 times les (0.006%) per g of normal mucosa were found. The overall results demonstrate the feasibility of tumor immunophotodiagnosis at the clinical level.chlorins, have been coupled to monoclonal antibodies (mAbs), but these conjugates were studied primarily in vitro (6)(7)(8), and the few experimental immunophototherapy studies did not yield highly significant results (9). The obvious advantage of using mAbs as vectors for tumor localization of dyes is the ability of a mAb to bind specifically to an antigen that is more abundant in tumor than in normal tissue. Furthermore, this technique allows selection of the dye on the basis of its photophysical and spectral properties, independently of its weak tumor-localizing properties.We chose human-mouse chimeric mAb directed against carcinoembryonic antigen (CEA) (10) because anti-CEA antibodies have given the best experimental and clinical results for colorectal carcinoma localization (11, 12) and chimeric mAbs were less immunogenic in patients than their murine counterpart (13). We selected fluorescein as the dye, primarily for its favorable photophysical properties, as shown in the innumerable in vitro applications of mAb-fluorescein conjugates and secondly because it can be injected in large doses into patients without side effects (14).We have previously shown that anti-CEA mAb-fluorescein conjugates injected i.v. in nude mice bearing human colon carcinoma xenografts allow clear immunophotodetection of these tumors (15). The purpose of the present pilot clinical trial was to determine whether such type of tumor immunophotodiagnosis is feasible in patients.Despite major progress in understanding the process of malignant transformation ...

Tumor-Specific Uptake of Fluorescent Bevacizumab–IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study

“…Several approaches have been used showcasing the potential of fluorescence imaging in humans, varying from single-dose to dose-escalation designs differing from our microdosing approach. In particular, the ex vivo validation steps for visualization of tumor microdistribution of the NIR fluorescent tracer and its relationship to histologic immunohistochemical parameters provides a framework that was not reported earlier in previous clinical studies in, for example, fluorescein-conjugated CEA-targeted imaging in colorectal cancer (25), folate receptor-a imaging in ovarian cancer (26), the study of Rosenthal and colleagues using cetuximab-IRDye800CW in head and neck cancer (29), and a protease-activatable probe in soft tissue sarcoma and breast cancer (30). Therefore, the impact of our study is that it provides the necessary framework of evaluation and reporting of future clinical studies of fluorescence image-guided surgery.…”

“…This precludes its use for tumor-specific targeting by NIRF imaging, as in this study. At this point, two clinical landmark studies have been published on the use of fluorescent targeted antibodies: one study targeting CEA in colorectal cancer (25), and more recently EGFR in head and neck cancer (29). Several approaches have been used showcasing the potential of fluorescence imaging in humans, varying from single-dose to dose-escalation designs differing from our microdosing approach.…”

“…Two phase I feasibility studies in, respectively, patients with colorectal cancer imaged with a chimeric fluorescein-conjugated carcinoembryonic antigen (CEA)-targeted antibody (25) and patients with ovarian cancer using folate-fluorescein isothiocyanate (FITC, light emission at 400-650 nm) targeting the folate receptor-a demonstrated the great potential of optical imaging during surgery using a clinical prototype camera (26). However, clinical implementation studies have been obstructed by characteristics such as the limited penetration depth of fluorescent dyes such as fluorescein with emission in the visible light spectrum, the negative effects of optical properties, such as absorption, scattering, and the autofluorescence of tissue in the visible spectrum.…”

Serum albumin as a vehicle for zinc phthalocyanine: photodynamic activities in solid tumour models

“…Although the BSA vehicle allowed the biodistribution of the dye throughout the whole animal, increased tumour selectivity would obviously be desirable. Covalent coupling of other dyes (fluorescein, indocyanin) to a monoclonal antibody directed against tumour cells in nude mice bearing colon or squamous cell carcinomas has been demonstrated (Folli et al, 1992(Folli et al, , 1994Pelegrin et al, 1991), and a similar approach for ZnPc targeting may further enhance tumour specificity.…”

Selectivity of the photosensitiser Tookad® for photodynamic therapy evaluated in the Syrian golden hamster cheek pouch tumour model

“…In order to lower the threshold of response, an improved targeting of tumour tissue is desirable.. This may be achieved by coupling Tookad s to molecules, which may achieve better selectivity in neoplasic tissue (Folli et al, 1992).…”