90Y-labeled monoclonal antibodies for cancer therapy

Monoclonal antibody 17-1A, which has specificity for colorectal carcinoma, was labeled with ⁹⁰Y (10–20% radiolabeling yield). Tissue distribution studies in tumor-bearing nude mice were carried out. ⁹⁰Y-labeled 17-1A showed good uptake in the SW 948 colon carcinoma cell line. However, ⁹⁰Y-labeled A5C3, a monoclonal antihepatitis virus antibody studied as a control, showed similar uptake in this tumor. Neither antibody was taken up well by a WM-9 melanoma. It is believed that the loss of specificity observed is due to the low specific activity of the ⁹⁰Y-labeled monoclonal antibody preparations used. This hypothesis is supported by radioimmunoassay data.     

Comparison of five bifunctional chelate techniques for 90Y-labeled monoclonal antibody CO17-1 A

Monoclonal antibody CO17-1A was radiolabeled with ⁹⁰Y by five bifunctional chelate techniques. Radiation absorbed dose estimates for normal organs and tumor were calculated for each preparation based on timed tissue distribution studies in nude mice bearing SW 948 human colorectal carcinoma xenografts. The cyclic DTPA anhydride technique was inferior to the four other techniques studied. Data for SCN-Bz-DTPA and SCN-Bz-Mx-DTPA, which were conjugated to ϵ-lysyl amino groups, were similar to those for NH₂-Bz-DTPA and NH₂-Bz-Mx-DTPA, which were conjugated site specifically to oligo-saccharides.     

Autoradiolysis of iodinated monoclonal antibody preparations

We investigated the effects of ionizing radiation on the immunointegrity of antibody fragments (Fab) because large amounts of high specific activity ¹³¹I may damage the proteins. We found that 1000 Gy of external ¹³⁷Cs γ radiation was sufficient to destroy 80–90% of the immunointegrity of the initial preparation. This effect was also produced by internally added [¹³¹I]NaI in a quantity sufficient to provide the same radiation absorbed dose. Since radioiodinated monoclonal antibodies labeled to high specific activity are being evaluated for radioimmunotherapy, the above observation is significant since high levels of internal radiation occur with therapeutic doses of ¹³¹I-labeled antibody. Human serum albumin in low concentration (2%) added to the iodinated antibody solutions was successful in preventing loss of immunoreactivity and can be used to protect and stabilize therapeutic quantities of radiolabeled monoclonal antibody preparations.     

Clinical effects of monoclonal antibody 17-1A combined with granulocyte/macrophage-colony-stimulating factor and interleukin-2 for treatment of patients with advanced colorectal carcinoma

Granulocyte/macrophage-colony-stimulating factor (GM-CSF) has previously been indicated to enhance the therapeutic effect of the anti-colorectal carcinoma mAb17-1A as well as to augment in vivo immune effector functions. In vitro interleukin-2 (IL-2) augmented GM-CSF-induced antibody-dependent cellular cytotoxicity, a mechanism considered to be of significance for the therapeutic effect of mAb. A treatment regimen was elaborated that combined mAb17-1A (400 mg at day 3 of a 10-day treatment cycle) with the simultaneous administration of GM-CSF (250 μmg/m² once daily) and IL-2 (2.4 × 10⁶ U/m² twice daily) for 10 days. The treatment cycle was repeated once a month. Twenty patients with advanced colorectal carcinoma were included in the study. One patient obtained a partial remission and 2 patients stable disease for 7 and 4 months respectively. The median survival time from the start of mAb therapy was 8 months. Owing to allergic reactions, the planned mAb17-1A dose had to be reduced by repeated infusions. At the fourth treatment cycle only 25% received the planned mAb dose. In 3 patients the GM-CSF and IL-2 dose was reduced because of side-effects. The subjective tolerability of the treatment was considered good or acceptable in more than 80% of the patients. The increment in white blood cell subsets induced by the cytokines decreased by increasing number of courses. This particular regimen did not augment the therapeutic effect of mAb17-1A anticipated from in vitro data but rather hampered the clinical effect of the antibody. The reason for this is not clear but a possibility might be the induction of immune suppression in vivo resulting from an impaired human anti-(mouse Ab) and anti-idiotypic antibody response as well as antibody-dependent cellular cytotoxicity, on the basis of a comparison of mAb17-1A/GM-CSF/IL-2- and mAb17-1A/GM-CSF-treated patients. Received: 25 February 1999 / Accepted: 15 July 1999     

Physiologically Based Pharmacokinetic Modeling Is Essential in 90Y-Labeled Anti-CD66 Radioimmunotherapy

IntroductionRadioimmunotherapy (RIT) with ⁹⁰Y-labeled anti-CD66 antibody is used to selectively irradiate the red marrow (RM) before blood stem cell transplantation of acute leukemia patients. To calculate the activity to administer, time-integrated activity coefficients are required. These are estimated prior to therapy using gamma camera and serum measurements after injection of ¹¹¹In labeled anti-CD66 antibody. Equal pre-therapeutic and therapeutic biodistributions are usually assumed to calculate the coefficients. However, additional measurements during therapy had shown that this assumption had to be abandoned. A physiologically based pharmacokinetic (PBPK) model was developed to allow the prediction of therapeutic time-integrated activity coefficients in eight patients.AimsThe aims of the study were to demonstrate using a larger patient group 1) the need to perform patient-specific dosimetry in ⁹⁰Y-labeled anti-CD66 RIT, 2) that pre-therapeutic and therapeutic biodistributions differ, and most importantly 3) that this difference in biodistributions can be accurately predicted using a refined model.ResultsVariability of the RM time-integrated activity coefficients ((37.3±7.5) h) indicates the need for patient-specific dosimetry. The relative differences between pre-therapeutic and therapeutic serum time-activity curves were (-25±16)%. The prediction accuracy of these differences using the refined PBPK models was (-3±20)%.ConclusionIndividual treatment is needed due to biological differences between patients in RIT with ⁹⁰Y-labeled anti-CD66 antibody. Differences in pre-therapeutic and therapeutic biokinetics are predominantly caused by different degrees of saturation due to different amounts of administered antibody. These differences could be predicted using the PBPK models.     

Improved radioimmunotherapy of colorectal cancer xenografts using antibody mixtures against carcinoembryonic antigen and colon-specific antigen-p

Summary Radioimmunotherapy of GW-39 human colonic tumor xenografts grown in the hamster cheek pouch with¹³¹I-labeled NP-4 anti-(carcinoembryonic antigen) (CEA) and¹³¹I-labeled Mu-9 anti-(color-specific antigen-p) (CSAp) murine monoclonal antibodies, administered in combination, was more effective than using either antibody alone for tumor masses less than 0.5 cm³ in size. The antibody mixture had no therapeutic advantage for larger tumors. Therapeutic efficacy was determined by measuring the change in tumor size over time, quantifying the absolute number of tumors responding to radioantibody therapy, and determining the percentage growth inhibition of each treatment at various times after radioantibody administration. Several mechanisms are discussed to explain the improved tumoricidal effect of the antibody mixture noted in this model system, such as (a) the possibility that an antibody mixture could target a greater number of tumor cells, (b) the potential for antibody mixtures to provide better tumor distribution and (c) the possibility that antibodies administered in combination can increase the magnitude of tumor uptake of individual radioantibodies, thereby resulting in a greater radiation dose delivered to the tumor.     

Pilot study of the Urals population by tooth electron paramagnetic resonance dosimetry

During 1949–1956, about 76 × 10⁶ m³ of radioactive liquid waste containing a total activity of 10¹⁷ Bq was discharged into the Techa River by the first Russian industrial nuclear facility Mayak. As a consequence, the population living in the river valley received considerable internal and external radiation doses. The results of a first application of electron paramagnetic resonance (EPR) of tooth enamel for a retrospective individual dose evaluation of the residents of the Techa riverside are presented. Three main contributions to the dose absorbed in tooth enamel have been considered: external exposure mainly from the Techa River sediments, internal exposure mainly due to ⁹⁰Sr; and background radiation including all other sources of exposure except the Techa River. The teeth of 86 inhabitants of the town Kamensk-Uralskii were analysed to determine the age-dependent contribution of the background radiation to the enamel dose. For 22 residents of the middle and lower Techa riverside, measurements of the ⁹⁰Sr whole-body content and EPR measurements of the absorbed dose in enamel were used to establish a correlation between these two quantities. Finally, absorbed doses in the enamel of five residents of the upper Techa riverside were determined by the EPR method. Contributions of the background radiation and the internal ⁹⁰Sr contamination were subtracted to determine the external exposure of the residents.     

Correlation of beta-camera imaging and immunohistochemistry in radioimmunotherapy using90Y-labeled monoclonal antibodies in ovarian cancer animal models

Tumor stroma contains much fibrin and monoclonal antifibrin antibody targeting is possible in tumors. In this study, nude mouse human ovarian carcinoma xenograft specimens were investigated after treatment with⁹⁰Y-labeled monoclonal antifibrin antibody Fab fragment or with⁹⁰Y-labeled OC125-monoclonal antibody F(ab′)₂ fragments. The mice received the radioimmunotherapy activity either intratumorally, intraperitoneally, or intravenously. Beta-camera imaging (BCI) is a novel device for studying activity distribution in tissue specimens and, together with immunohistochemistry (IHC) with OC125, antifibrin, anticarcinoembryonic antigen, anti-cytokeratin, and anti-placental alkaline phosphatase antibodies, was used for correlation of activity distribution of tissue specimens. These results were in concordance: Antigen distribution measured with IHC and radioactivity distribution were similar with the same antibodies, antifibrin, and OC125: However, these antigens demonstrated rather different distribution. Tissue studies revealed that activity was concentrated also in the necrotic tumor tissue, indicating that cell death was also caused by radiation. Differences in the tumor cell morphology were observed using different routes of administration. With BCI, it is possible to quantitate activities in frozen sections (microdosimetry), and these results were in concordance with absolute activities as measured by tissue sampling and well-counting. Three-dimensional reconstruction of tissue slices combined with radioactivity distribution measured with BCI allows estimation of total absorbed radiation dose in tumor after an appropriate dose planning.     

3D image-based dosimetry for Yttrium-90 radioembolization of hepatocellular carcinoma: Impact of imaging method on absorbed dose estimates

BackgroundTo improve therapy outcome of Yttrium-90 selective internal radiation therapy (⁹⁰Y SIRT), patient-specific post-therapeutic dosimetry is required. For this purpose, various dosimetric approaches based on different available imaging data have been reported. The aim of this work was to compare post-therapeutic 3D absorbed dose images using Technetium-99m (^99mTc) MAA SPECT/CT, Yttrium-90 (⁹⁰Y) bremsstrahlung (BRS) SPECT/CT, and ⁹⁰Y PET/CT.MethodsTen SIRTs of nine patients with unresectable hepatocellular carcinoma (HCC) were investigated. The ^99mTc SPECT/CT data, obtained from ^99mTc-MAA-based treatment simulation prior to ⁹⁰Y SIRT, were scaled with the administered ⁹⁰Y therapy activity. 3D absorbed dose images were generated by dose kernel convolution with scaled ^99mTc/⁹⁰Y SPECT/CT, ⁹⁰Y BRS SPECT/CT, and ⁹⁰Y PET/CT data of each patient. Absorbed dose estimates in tumor and healthy liver tissue obtained using the two SPECT/CT methods were compared against ⁹⁰Y PET/CT.ResultsThe percentage deviation of tumor absorbed dose estimates from ⁹⁰Y PET/CT values was on average −2 ± 18% for scaled ^99mTc/⁹⁰Y SPECT/CT, whereas estimates from ⁹⁰Y BRS SPECT/CT differed on average by −50 ± 13%. For healthy liver absorbed dose estimates, all three imaging methods revealed comparable values.ConclusionThe quantification capabilities of the imaging data influence ⁹⁰Y SIRT tumor dosimetry, while healthy liver absorbed dose values were comparable for all investigated imaging data. When no ⁹⁰Y PET/CT image data are available, the proposed scaled ^99mTc/⁹⁰Y SPECT/CT dosimetry method was found to be more appropriate for HCC tumor dosimetry than ⁹⁰Y BRS SPECT/CT based dosimetry.     

Biological characterization of a chimeric mouse-human IgM antibody directed against the 17-1A antigen

Summary The pharmacokinetics of ¹¹¹In-labeled 260F9, a murine monoclonal antibody directed against a breast-cancer-associated antigen, was determined in seven patients with advanced breast cancer. Six patients were administered 1 mg antibody containing 1 mCi ¹¹¹In. The seventh patient was administered 20 mg unlabeled antibody followed by 1 mg ¹¹¹In-labeled antibody all via a peripheral vein. Immunoprecipitation, HPLC and SDS-PAGE gels demonstrated the stability of radiolabel on the antibody. The serum clearance of the radiolabel closely fits (r ²>0.95) a two-compartment model for the first six patients. The apparent volume of distribution of the radiolabel approximated to the plasma volume (3 1) and its mean residence time was 23.7 h. The radiolabel had an average t _1/2 of 22.9±12.21 h at the 1-mg dose. At the 20-mg dose one-compartment elimination kinetics were observed with the radiolabel and antibody showing similar mean residence times (36–41 h) and a t _1/2 of 26–28 h. Whole-body imaging showed that the blood-pool:liver ratio of radioactivity increased fourfold (at 48 h postinfusion) at the higher dose and the percentage of the injected dose of radioactivity in the liver decreased from 25% to 8% (24 h postinfusion).In one patient 7–14 times more radioactivity was localized in a breast tumor than in fat (normal breast). Over the first 25 h an average (cumulative) 7.5% of the total dose was excreted in urine. A study of 260F9 in CDF-1 mice demonstrated that the radiolabel remained associated with the antibody in serum. The antibody, however, cleared 60-fold slower in mice than in patients and showed an increased mean residence time of 191 h. The disparity in the pharmacokinetics of the antibody seen in the mouse and in the clinic, points to the different behavior shown by murine monoclonal antibodies in humans. This points to the need for preliminary studies of antibodies in patients for preclinical evaluations of their effectiveness as drug-targeting agents.     

Influence of human biokinetics of strontium on internal ingestion dose of <Superscript>90</Superscript>Sr and absorbed dose of <Superscript>89</Superscript>Sr to organs and metastases

The objective of the present work is to apply the plasma clearance parameters to strontium, previously determined in our laboratory, to improve the biokinetic and dosimetric models of strontium-90 (⁹⁰Sr) used in radiological protection; and also to apply this data for the estimation of the radiation doses from strontium-89 (⁸⁹Sr) after administration to patients for the treatment of the painful bone metastases. Plasma clearance and urinary excretion of stable strontium tracers of strontium-84 (⁸⁴Sr) and strontium-86 (⁸⁶Sr) were measured in GSF-National Research Center for Environment and Health (GSF) in 13 healthy German adult subjects after intravenous injection and oral administration. The biological half-life of strontium in plasma was evaluated from 49 plasma concentration data sets following intravenous injections. This value was used to determine the transfer rates from plasma to other organs and tissues. At the same time, the long-term retention of strontium in soft tissue and whole body was constrained to be consistent with measured values available. A physiological urinary path was integrated into the biokinetic model of strontium. Parameters were estimated using our own measured urinary excretion values. Retention and excretion of strontium were modeled using compartmental transfer rates published by the International Commission on Radiological Protection (ICRP), the SENES Oak Ridge Inc. (SENES), and the Urals Research Center for Radiation Medicine (TBM). The results were compared with values calculated by applying our GSF parameters (GSF). For the dose estimation of ⁸⁹Sr, a bone metastases model (GSF-M) was developed by adding a compartment, representing the metastases, into the strontium biokinetic model. The related parameters were evaluated based on measured data available in the literature. A set of biokinetic parameters was optimized to represent not only the early plasma kinetics of strontium but also the long-term retention measured in soft tissue and whole body. The ingestion dose coefficients of ⁹⁰Sr were computed and compared with different biokinetic model parameters. The ingestion dose coefficients were calculated as 2.8 × 10⁻⁸, 2.1 × 10⁻⁸, 2.5 × 10⁻⁸ and 3.8 × 10⁻⁸ Sv Bq⁻¹ for ICRP, SENES, TBM and GSF model parameters, respectively. Moreover, organ absorbed dose for the radiopharmaceutical of ⁸⁹Sr in bone metastases therapy was estimated based on the GSF and ICRP biokinetic model parameters. The effective doses were 3.3, 1.8 and 1.2 mSv MBq⁻¹ by GSF, GSF-M, and ICRP Publication 67 model parameters, respectively, compared to the value of 3.1 mSv MBq⁻¹ reported by ICRP Publication 80. The absorbed doses of red bone marrow and bone surface, 17 and 21 mGy MBq⁻¹ calculated by GSF parameters, and 7.1 and 8.8 mGy MBq⁻¹ by GSF-M parameters, are comparable to the clinical results of 3–19 mGy MBq⁻¹ for bone marrow and 16 mGy MBq⁻¹ for bone surface. Based on the GSF-M model, the absorbed dose of ⁸⁹Sr to metastases was estimated to be 434 mGy MBq⁻¹. The strontium clearance half-life of 0.25 h from the plasma obtained in the present study is obviously faster than the value of 1.1 h recommended by ICRP. There are no significant changes for ingestion dose coefficients of ⁹⁰Sr using different model parameters. A model including the metastases was particularly developed for dose estimation of ⁸⁹Sr treatment for the pain of bone metastases.     

Effect of image registration on 3D absorbed dose calculations in 177Lu-DOTATOC peptide receptor radionuclide therapy

Peptide receptor radionuclide therapy (PRRT) is an effective MRT (molecular radiotherapy) treatment, which consists of multiple administrations of a radiopharmaceutical labelled with ¹⁷⁷Lu or ⁹⁰Y. Through sequential functional imaging a patient specific 3D dosimetry can be derived. Multiple scans should be previously co-registered to allow accurate absorbed dose calculations. The purpose of this study is to evaluate the impact of image registration algorithms on 3D absorbed dose calculation.A cohort of patients was extracted from the database of a clinical trial in PRRT. They were administered with a single administration of ¹⁷⁷Lu-DOTATOC. All patients underwent 5 SPECT/CT sequential scans at 1 h, 4 h, 24 h, 40 h, 70 h post-injection that were subsequently registered using rigid and deformable algorithms. A similarity index was calculated to compare rigid and deformable registration algorithms. 3D absorbed dose calculation was carried out with the Raydose Monte Carlo code.The similarity analysis demonstrated the superiority of the deformable registrations (p < .001).Average absorbed dose to the kidneys calculated using rigid image registration was consistently lower than the average absorbed dose calculated using the deformable algorithm (90% of cases), with percentage differences in the range [−19; +4]%. Absorbed dose to lesions were also consistently lower (90% of cases) when calculated with rigid image registration with absorbed dose differences in the range [−67.2; 100.7]%. Deformable image registration had a significant role in calculating 3D absorbed dose to organs or lesions with volumes smaller than 100 mL.Image based 3D dosimetry for ¹⁷⁷Lu-DOTATOC PRRT is significantly affected by the type of algorithm used to register sequential SPECT/CT scans.     

Three Antigenic Regions in p17 of Human Immunodeficiency Virus Type 1 (HIV-1) Revealed by Mouse Monoclonal Antibodies and Human Antibodies in HIV-1 Carrier Sera

We investigated the murine antibody response to recombinant p17 (rp17) of human immunodeficiency virus type 1 (HIV-1) and the human antibody response directed to p17 in HIV-1 infection. Three large peptides covering residues 12-29, 53-87 and 87-115 of p17 were synthesized. The cysteine residues 57 and 87 of peptide 53-87 were reoxidized to form a disulfide bridge. Eighteen out of 19 murine monoclonal anti-rp17 antibodies had relatively high affinities (K_A = 1.9 × 10⁵?1.4 × 10⁸ M^?1) with one of the 3 p17 peptides in the liquid phase. Each monoclonal antibody reacted only with one particular peptide and had no reactivity with the other 2 p17 peptides. All the monoclonal antibodies reacted with rp17 in the liquid phase with a reasonable degree of affinity (K_A = 2.0 × 10⁵?1.8 × 10⁷ M^?1). Four HIV-1 carrier sera, which were positive in ELISA using rp17 as the antigen, reacted positively in an ELISA using 3 p17 peptides which were used to titrate murine monoclonal antibodies. Murine monoclonal antibodies having specificity for the 3 p17 peptides stained live HIV-1-infected cells by means of indirect membrane immunofluorescence, irrespective of their specificity. This suggests that the various portions of p17 (at least 3 regions of p17) were exposed on the surface of live infected cells, probably as short polypeptide chains.     

Separation and concentration of Δ-6-keto-PGF1α using monoclonal antibody to ω3-olefin structure of trienoic prostanoids

A monoclonal antibody against cis-3-hexen-1-ol was prepared and used to separate and/or concentrate Δ¹⁷-6-keto-prostaglandin F_1α (PGF_1α) in the human sera. cis-3-Hexen-1-ol was conjugated with the human serum albumin (HSA) according to the N-succinimidylester method and hyperimmunized to BALB/c mouse. The monoclonal afntibodies were obtained from hybridoma clones established by a fusion between SP2/0-Ag14-k13 mouse myeloma cells and splenocytes of a mouse. A monoclonal antibody, named 4G9-12B, recognized the epitope characteristic for ω3-olefin structure. The 4G9-12B antibody became more specific for Δ¹⁷-6-keto-PGF_1α than 6-keto-PGF_1α by applying inhibition ELISA using amino-residue coating plates. Using the prepared immunoaffinity columns of this antibody, Δ¹⁷-6-keto-PGF_1α was clearly detected in 6 pg/ml of the human blood sera by GC/MS analysis. These results suggest that the monoclonal antibody to the partial structure of trienoic prostanoid, ω3-olefin unit, and that its immunoaffinity columns are useful in separating and concentrating Δ¹⁷-6-keto-PGF_1α in the human blood or urine.     

Quantitative autoradiographic evaluation of the influence of protein dose on monoclonal antibody distribution in human ovarian adenocarcinoma xenografts

Summary We studied the effect of monoclonal antibody protein dose on the uniformity of radioiodinated antibody distribution within tumor masses using quantitative autoradiography. Groups (n = 11–13/group) of athymic nude mice with subcutaneous HTB77 human ovarian carcinoma xenografts were injected intraperitoneally with an¹²⁵I-labeled anticarcinoma-associated antigen murine monoclonal antibody, 5G6.4, using a high or a low protein dose (500 µg or 5 µg). At 6 days post-injection the macroscopic and microscopic intratumoral biodistribution of radiolabeled antibody was determined. The degree of heterogeneity of the labeled antibody distribution within each tumor was quantified and expressed as thecoefficient of variation (CV) of the activity levels in serial histological sections. Tumors from mice given the 500-µg protein doses had substantially lower CV values, 0.327±0.027, than did tumors from animals given 5-µg protein doses, 0.458±0.041, (P = 0.0078), indicating that the higher protein dose resulted in more homogeneous distribution of radioactivity in tumors than did the lower dose. While the percentage of the injected dose reaching the tumor was comparable between groups, injecting the higher dose of protein resulted in significantly lower tumor to non-tumor uptake ratios than those obtained for the lower protein dose. These data indicate, in this system, that to achieve more uniform intratumoral antibody (and radiation for radioimmunotherapy) delivery, a relatively high protein dose must be administered. However, to obtain this increased uniformity, a substantial drop in tumor/background uptake ratios was seen. Quantitative autoradiographic evaluation of human tumor xenografts is a useful method to assess the intratumoral distribution of antibodies.     

Fish otoliths as biological dosimeter: internal dose calculation

Otoliths are organs used by fish for hearing and keeping balance. They consist of biogenic crystals of hydroxyapatite and do not contain any living cells. Upon exposure to ionizing radiation, otolith hydroxyapatite accumulates radiation-induced stable CO₂^? radicals whose amount is proportional to absorbed dose. In electron paramagnetic resonance (EPR) dosimetry, carbonate ions are registered and, hence, the total accumulated dose in the fish otolith can be quantified. Therefore, otoliths can be used as individual fish dosimeters to support radiobiological and radioecological studies. An important aspect of otolith-based EPR dosimetry on fish from contaminated water bodies is the potential presence of bone-seeking ⁹⁰Sr. Consequently, cumulative absorbed doses measured with EPR in otoliths may reflect the superposition of internal exposure to ⁹⁰Sr/⁹⁰Y and external exposure due to radionuclides circulating in soft tissue of the fish as well as due to environmental contamination. The objective of the present study was to develop a method that allows for an assessment of the contribution of ⁹⁰Sr to the total dose in otolith. The method has been tested using otoliths from seven fish taken from reservoirs located in the Southern Urals contaminated with radionuclides including ⁹⁰Sr. It has been shown that dose to otoliths is largely determined by ⁹⁰Sr in the hydroxyapatite. The internal dose component can be calculated using activity concentration-to-dose conversion factors, which vary slightly in the range of 2.0–2.8?×?10^–3 Gy year^?1 per Bq g^?1 depending on fish species and age. Internal doses to fish from water bodies with different levels of ⁹⁰Sr contamination were calculated in the range from 2 mGy to?~?200 Gy. External dose contribution was derived for two fish only to be about 100 and 40 Gy. It is concluded that EPR dosimetry on fish otoliths is a promising tool when external exposure prevails or is comparable to internal exposure due to ⁹⁰Sr.

     

Adoptive immunotherapy with peripheral blood lymphocytes cocultured in vitro with autologous tumor cells and interleukin-2

A clinical trial of adoptive immunotherapy was carried out with peripheral blood lymphocytes (PBL), cocultured in vitro with autologous tumor cells and interieukin-2 (IL-2), in 14 patients with advanced melanoma. PBL from these patients were cocultured with irradiated autologous tumor cells for 7 days, which was followed by expansion in IL-2-containing medium. These lymphocytes were returned to the patient along with intravenous IL-2 at doses up to 2×10⁶ IU m^–2 day^–1. A dose of 300 mg/m² cyclophosphamide was administered to each patient intravenously 4 days prior to each treatment. Following coculture, the lymphocytes were primarily CD3⁺ T cells and they expressed varied degrees of cytotoxicity against autologous melanoma cells. In 9 patients the activated cells were al least 80% CD4⁺ and in 2 cases they were mostly CD8+. Some of the activated cells exhibited suppressor or helper activity in a functional regulatory coculture assay. No major therapeutic response was observed in this study. Minor responses were observed in 2 patients. Toxicities were those expected from the IL-2 dose administered.This work has been supported by an American Cancer Society Institutional Research Grant (ACS-IRG 91-230), by the University of Connecticut Clinical Research Center (grant 0021), and by the Hartford Hospital Research Fund (grant 1017-20-018). Dr. Sporn is a recipient of American Cancer Society Clinical Oncology Career Development Award 90-230     

A phase II trial of murine monoclonal antibody 17-1A and interferon-γ: Clinical and immunological data

Summary A group of 15 patients with metastatic colorectal adenocarcinoma received a combination of interferon (0.1 mg/m², days 1–15) and the murine monoclonal antibody 17-1A (400 mg, days 5, 7, 9 and 12). The treatment was tolerated with minimal toxicity. Of the 14 evaluable patients, 13 developed human antibody to murine 17-1A, with 11 patients demonstrating antibody to the variable region of 17-1A (anti-idiotype). Antibody to the variable region was inhibited by 17-1A but not by mouse immunoglobulin. Sera from patients with substantial anti-idiotype reactivity were capable of inhibiting the binding of murine 17-1A to antigen expressing LS174-T cells thus indicating the presence of antibody directed against the 17-1A combining site (mirror-image anti-idiotype). The median survival of the whole group was 56 weeks and there was no correlation between clinical response/survival and the development of anti-idiotype antibody.Supported by the Veterans Administration Medical Center and by Public Health Services grant CA 45 232 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services     

Dose Escalation of Lobaplatin Concurrent with IMRT for the Treatment of Stage III-IVb NPC: A Phase I Clinical Trial

The maximum tolerated dose (MTD) of lobaplatin as a single agent chemotherapy concurrent with intensity-modulated radiotherapy (IMRT) in Asian population with nasopharyngeal carcinoma (NPC) remains unclear. From June 2016 to December 2017, 17 patients diagnosed with stage III-IVb NPC from an Asian population were prospectively enrolled. Patients were administered lobaplatin with 25-50?mg/m² escalation of dosage on day 1. Every 21?days (days 1, 22, and 43) during radiotherapy, cycles were repeated. We administered radiotherapy as 2.12-2.27 Gy per fraction with five daily fractions each week for 6 to 7 weeks. The evaluation of lobaplatin-related toxic effects was based on the Common Terminology Criteria for Adverse Events version 4.0. During the weekly treatment period, complete blood counts and biochemistry were performed. Dose-limiting toxicities (DLTs) were determined by the following events during any cycle in which lobaplatin was administered. Each dose group consisted of at least three cases. We proceeded to the subsequent dose group in the absence of DLT with a dose increment of 5 mg/m² until DLT occurred. Periods from 1 week prior to the chemotherapy initiation to 3 weeks after the last chemotherapy were defined as DLT observation periods. MTD was determined by the dose that was immediately below the dose that produced DLT. After analysis, DLT occurred in three patients, including a group with two of three patients in 45 mg/m² lobaplatin and another group with one of five patients in 40 mg/m² lobaplatin. No grade 3-4 toxicity was observed in patients treated with lobaplatin <40 mg/m². The tumor response rate at 12?weeks after treatment was 100%. In summary, lobaplatin concurrent with IMRT was active in stage III-IVb NPC, and the MTD for the lobaplatin as single-agent chemotherapy was 40 mg/m² when combined with IMRT in an Asian population. This trial is registered with ClinicalTrials.gov, number NCT03188497.     

Radioimmunotherapy of small-cell lung cancer xenografts using131I-labelled anti-NCAM monoclonal antibody 123C3

We have studied the therapeutic efficacy of¹³¹I-labelled monoclonal antibody 123C3 in human small-cell lung carcinoma xenografts established from the NCI-H69 cell line in nude mice. Several radiation does were administered intraperitoneally and different treatment schedules were tested. The maximal tolerated dose, 2×500 Ci, resulted in complete remission of tumours smaller than 200 mm³ and long-lasting remission (more than 135 days) of the larger tumours. In control experiments, treatment with unlabelled monoclonal antibody 123C3 did not affect the tumour growth rate, while the effect of radiolabelled non-relevant, isotype-matched, monoclonal antibody M6/1 was minor and transient. Regrowth of the tumours occurred in all cases and could not be attributed to loss of neural cell adhesion molecule (NCAM) expression. Tumour recurrence is probably caused by insufficient radiation dosage. Radiation-induced toxicity was monitored by assessment of weight and bone marrow examination. Weight loss was observed in all treatment groups, but the mice regained their initial weight within 14 days, except for the group receiving the highest radiation dose (3×600 Ci). In this group all mice died as a result of radiotoxicity. Of the mice injected with 600 Ci radiolabelled control antibody, 50% died within 2 weeks after administration. Apparently the higher uptake of the radiolabelled monoclonal antibody in the tumour reduced systemic radiation toxicity.