a-Fetoprotein (AFP) is a self protein expressed by fetal liver at high levels, but is transcriptionally repressed at birth. AFP is up-regulated in hepatocellular carcinomas, and patients with active disease could have plasma levels as high as1mg/mL.We previously identified four immunodominant HLA-A*0201-restricted peptides [hAFP [137][138][139][140][141][142][143][144][145] (PLFQVPEPV), hAFP [158][159][160][161][162][163][164][165][166] (FMNKFIYEI), hAFP [325][326][327][328][329][330][331][332][333][334] (GLSPNLNRFL), and hAFP 542-550 (GVALQTMKQ)] derived from human AFP that could stimulate specific T cell responses in healthy donor peripheral blood lymphocytes in vitro. We conducted a phase I/II clinical trial in which HLA-A*0201patients with AFP-positive hepatocellular carcinoma were immunized with three biweekly intradermal vaccinations of the four AFP peptides pulsed onto autologous dendritic cells (DC). DCs were prepared from adherent peripheral blood mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 7 days. Sixteen subjects were enrolled and 10 were treated. Peripheral blood lymphocytes were isolated from these patients before, during, and afterAFP peptide/DC immunization and were tested ex vivo with MHC tetramer and IFNg ELISPOTanalysis. Six of 10 subjects expanded statistically significant levels of AFP-specificTcells postvaccine to at least one peptide by MHC tetramer. Also, 6 of10 subjects increased IFNg producing AFP-specificTcell responses to at least one of the peptides postvaccination, by ELISPOT. We conclude that the humanTcell repertoire is capable of responding to the AFP self antigen after the administration of AFP peptidepulsed DC even in an environment of high circulating levels of this oncofetal antigen.We originally reported that the self antigen a-fetoprotein (AFP) could be recognized by both murine and human T cells and serve as a tumor rejection antigen in a murine tumor model (1, 2). AFP is produced by 50% to 80% of hepatocellular carcinomas (HCC), and its measurement in serum has played an important role in diagnosis and monitoring responses to treatment for the last several decades (3). AFP is expressed by the fetal liver with serum levels of 1 mg/mL, but is transcriptionally repressed shortly after birth (4 -6). Our ability to generate potent AFP-specific T cell immunity to murine AFP in mice and to human AFP in in vitro human T cell cultures clearly indicates that, despite being exposed to high plasma levels of this protein during embryonic development, some AFP-specific T cells are not deleted during ontogeny.Using a combination of strategies (HLA-A*0201/K b transgenic mice, human T cell cultures, and mass spectrometric analysis), we identified four immunodominant AFP-derived peptides that are naturally processed and presented in the context of HLA-A*0201 (1, 7 -9). At least three of these peptides could be isolated from the surface of an HLA-A*0201/AFP-positive human HCC cell line, HepG2. These peptides can stimulate T ...
Antibody-PET imaging might be of value for the selection of radioimmunotherapy (RIT) candidates to confirm tumor targeting and to estimate radiation doses to tumor and normal tissues. One of the requirements to be set for such a scouting procedure is that the biodistributions of the diagnostic and therapeutic radioimmunoconjugates should be similar. In the present study we evaluated the potential of the positron emitters zirconium-89 ((89)Zr) and iodine-124 ((124)I) for this approach, as these radionuclides have a relatively long half-life that matches with the kinetics of MAbs in vivo (t(1/2) 3.27 and 4.18 days, respectively). After radiolabeling of the head and neck squamous cell carcinoma (HNSCC)-selective chimeric antibody (cMAb) U36, the biodistribution of two diagnostic (cMAb U36-N-sucDf-(89)Zr and cMAb U36-(124)I) and three therapeutic radioimmunoconjugates (cMAb U36-p-SCN-Bz-DOTA-(88)Y-with (88)Y being substitute for (90)Y, cMAb U36-(131)I, and cMAb U36-MAG3-(186)Re) was assessed in mice with HNSCC-xenografts, at 24, 48, and 72 hours after injection. Two patterns of biodistribution were observed, one pattern matching for (89)Zr- and (88)Y-labeled cMAb U36 and one pattern matching for (124)I-, (131)I-, and (186)Re-cMAb U36. The most remarkable differences between both patterns were observed for uptake in tumor and liver. Tumor uptake levels were 23.2 +/- 0.5 and 24.1 +/- 0.7%ID/g for the (89)Zr- and (88)Y-cMAb U36 and 16.0 +/- 0.8, 15.7 +/- 0.79 and 17.1 +/- 1.6%ID/g for (124)I-, (131)I-, and (186)Re-cMAb U36-conjugates, respectively, at 72 hours after injection. For liver these values were 6.9 +/- 0.8 ((89)Zr), 6.2 +/- 0.8 ((88)Y), 1.7 +/- 0.1 ((124)I), 1.6 +/- 0.1 ((131)I), and 2.3 +/- 0.1 ((186)Re), respectively. These preliminary data justify the further development of antibody-PET with (89)Zr-labeled MAbs for scouting of therapeutic doses of (90)Y-labeled MAbs. In such approach (124)I-labeled MAbs are most suitable for scouting of (131)I- and (186)Re-labeled MAbs.
Low-energy emission radioimmunotherapy with doses of up to 350 mCi/m2 of 125I-mAb A33 did not cause bowel or bone marrow toxicity. The modest antitumor activity in these heavily pretreated patients is encouraging because of lack of toxicity at the doses studied. The long radioactivity retention in tumors suggests that isotopes with a long half-life may have a therapeutic advantage, based on calculated dose delivery to tumor versus normal tissue. Due to the low bone marrow dose, further 125I trials with humanized mAb A33 are warranted, and controlled studies must be conducted to evaluate the combination of radioimmunotherapy and chemotherapy.
The aim of this study was to develop a clinically applicable noninvasive method to quantify changes in androgen receptor (AR) levels based on 18 F-16b-fluoro-5a-dihydrotestosterone ( 18 F-FDHT) PET in prostate cancer patients undergoing therapy. Methods: Thirteen patients underwent dynamic 18 F-FDHT PET over a selected tumor. Concurrent venous blood samples were acquired for blood metabolite analysis. A second cohort of 25 patients injected with 18 F-FDHT underwent dynamic PET of the heart. These data were used to generate a population-based input function, essential for pharmacokinetic modeling. Linear compartmental pharmacokinetic models of increasing complexity were tested on the tumor tissue data. Four suitable models were applied and compared using the Bayesian information criterion (BIC). Model 1 consisted of an instantaneously equilibrating space, followed by a unidirectional trap. Models 2a and 2b contained a reversible space between the instantaneously equilibrating space and the trap, into which metabolites were excluded (2a) or allowed (2b). Model 3 built on model 2b with the addition of a second reversible space preceding the unidirectional trap and from which metabolites were excluded. Results: The half-life of the 18 F-FDHT in blood was between 6 and 7 min. As a consequence, the uptake of 18 F-FDHT in prostate cancer lesions reached a plateau within 20 min as the blood-borne activity was consumed. Radiolabeled metabolites were shown not to bind to ARs in in vitro studies with CWR22 cells. Model 1 produced reasonable and robust fits for all datasets and was judged best by the BIC for 16 of 26 tumor scans. Models 2a, 2b, and 3 were judged best in 7, 2, and 1 cases, respectively. Conclusion: Our study explores the clinical potential of using 18 F-FDHT PET to estimate free AR concentration. This process involved the estimation of a net uptake parameter such as the k trap of model 1 that could serve as a surrogate measure of AR expression in metastatic prostate cancer. Our initial studies suggest that a simple body mass-normalized standardized uptake value correlates reasonably well to model-based k trap estimates, which we surmise may be proportional to AR expression. Validation studies to test this hypothesis are underway.
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