Efficacy of HER2-Targeted Intraperitoneal225Ac α-Pretargeted Radioimmunotherapy for Small-Volume Ovarian Peritoneal Carcinomatosis
Sebastian ChungDaniela Burnes VargasChristopher S. ChandlerSumudu KatugampolaDarren R. VeachMichael R. McDevittShin SeoBrett A. VaughnSara S. RinneBlesida PunzalanMitesh PatelHong XuHong-Fen GuoPat ZanzonicoSébastien MonetteGuangbin YangOuathek OuerfelliGarrett M. NashAndrea CercekEdward K. FungRoger W. HowellSteven M. LarsonSarah M. ChealNai‐Kong V. Cheung
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Abstract:
Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle–emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor–bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel–Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness–weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor–bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.s: Fifth Conference on Radioimmunodetection and Radioimmunotherapy of Cancer: Session VI: Experimental Radioimmunotherapy: PDF Only
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O'Hara, J. A., Blumenthal, R. D., Grinberg, O. Y., Demidenko, E., Grinberg, S., Wilmot, C. M., Taylor, A. M., Goldenberg, D. M. and Swartz, H. M. Response to Radioimmunotherapy Correlates with Tumor pO2 Measured by EPR Oximetry in Human Tumor Xenografts.The efficacy of radiation treatment depends upon local oxygen concentration. We postulated that the variability in responsiveness of tumor xenografts to a fixed dose of radioimmunotherapy might be related to the tumor pO2 at the time that radioimmunotherapy was administered. We evaluated the growth of xenografts of CALU-3 tumors, a non-small cell lung carcinoma, in response to an 8.9-MBq dose of 131I-RS-7-anti-EGP-1 and correlated tumor growth rate with initial tumor pO2 measured by EPR oximetry. The greatest growth delay in response to radioimmunotherapy had the highest initial pO2, and the fastest-growing tumors had the lowest initial pO2. We then determined the dynamic effect of radioimmunotherapy on tumor pO2 by serial measurements of pO2 for 35 days after radioimmunotherapy. This information could be important for ascertaining the likelihood that a tumor will respond to additional doses as part of a multiple dose scheme. Serial tumor pO2 measurements may help identify a window of opportunity when the surviving tumor regions will be responsive to a second round of radioimmunotherapy or a second therapeutic modality such as chemotherapy or an anti-vascular agent. After radioimmunotherapy, there was an increase in tumor pO2 followed by a decrease below initial levels in most mice. Thus defined times may exist when a tumor is more or less radiosensitive after radioimmunotherapy.
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Despite the advances in the management of ovarian cancer, the disease remains the leading cause of death from gynecological malignancies. As it generally remains confined to the peritoneal cavity, ovarian cancer is an attractive target for radioimmunotherapy via the intraperitoneal route of administration. Several clinical trials have been carried out investigating radiolabeled monoclonal antibodies and the results seem promising, especially in patients with small-volume residual disease after conventional therapy. Intraperitoneal radioimmunotherapy has yet to prove itself as an important part of the treatment of ovarian cancer.
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A phase I/II study found that radioimmunotherapy with 177Lu and the anti-CD20 antibody rituximab along with the chelator DOTA is safe and feasible for treatment of relapsed follicular, mantle cell, or other indolent lymphomas.
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Supplementary Figure 1 from Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma
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A comparative study of multiple modalities, radioimmunotherapy combined with cisplatin and MBV was made. The tumor size and macrophage activity (acid phosphatase) were measured after treatment. The results showed that the tumor inhibition rates were 48, 55, 74, 76, 79% in radioimmunotherapy, cisplatin, radioimmunotherapy + MBV, radioimmunotherapy + cisplatin and radioimmunotherapy + MBV + cisplatin groups, respectively. Radioimmunotherapy was effective in controlling tumor growth, especially in sequential treatment by two injections. Both cisplatin and MBV could increase therapeutic effect of radioimmunotherapy. Therefore, combination of the three modalities is the best choice for tumor growth control. The effectiveness of MBV may be related to the increase of macrophage activity. Preliminary clinical results were satisfactory. Decline in serum AFP level and shrinkage of tumor were observed in 80% (12/15) and 65% (13/20) of the patients. It is suggested that combination of multiple treatment modalities may provide an important approach to treat moderately advanced liver cancer.
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This paper describes in detail the advances in monoclonal antibodies for radioimmunotherapy since 1990. It introduces the radionuclides, monoclonal antibodies including their dosimetry, toxicity and radiobiological characteristics in radioimmunotherapy. Finally it discusses the problems, potential solutions and future directions in developing monoclonal antibodies for radioimmunotherapy.
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We retrospectively evaluated 18F-FDG PET/CT for monitoring the response of non-Hodgkin9s lymphoma to radioimmunotherapy. Methods: A total of 33 clinical patients received 131I-tositumomab (n = 23) or 90Y-ibritumomab tiuxetan (n = 10) and underwent 18F-FDG PET/CT scans before radioimmunotherapy and at 12 wk after radioimmunotherapy. A third scan was performed on 13 patients at 24 wk after radioimmunotherapy, 12 of whom did not receive interval therapy. Tumor metabolic activity was assessed before and after radioimmunotherapy visually and quantitatively by lean maximum standardized uptake value (SUVlean max). Response was assessed by the International Workshop Criteria (IWC) and Revised IWC, which includes 18F-FDG PET (IWC-PET). Results: Mean SUVlean max decreased from baseline in 244 target lesions 12 wk after radioimmunotherapy (from 6.51 ± 4.05 to 3.94 ± 4.41; P < 0.01), regardless of response at 12 wk after radioimmunotherapy (P ≤ 0.02). After radioimmunotherapy, SUVlean max was lower for responders than for nonresponders (P ≤ 0.01). Median percentage change in SUVlean max of target lesions per patient was −51% (−95% to 97%). No significant difference in decline in SUVlean max between patients who received 131I-tositumomab and those who received 90Y-ibritumomab tiuxetan was demonstrated (−31% ± 51% vs. −47% ± 46%; P = 0.38). Patients with greater than a 52% decline in SUVlean max tended toward longer survival (P = 0.09) than those with lesser declines. The 12-wk overall response rate to radioimmunotherapy based on IWC was 42% (14/33); complete response rate was 15% (5/33). Eleven of 12 patients with progression at 12 wk had new disease sites, and in 4 patients, new disease sites were the only sites of progression. Of 108 lesions evaluated at 12 and 24 wk after radioimmunotherapy, 49 resolved at 12 wk and remained resolved at 24 wk, 17 gradually declined in SUV over 24 wk, and 37 initially decreased at 12 wk but increased at 24 wk. PET showed disease progression at 24 wk in 10 of 13 patients; 7 patients had new lesions and 1 was reclassified from partial response to complete response. Conclusion: In non-Hodgkin9s lymphoma, 18F-FDG uptake in tumors typically drops significantly after radioimmunotherapy. A continued decline in tumor SUVlean max between 12 and 24 wk without additional therapy can occur, suggesting a need for delayed-response assessment. In patients who progress after radioimmunotherapy, new sites of disease commonly develop, rather than recurrence or progression at previous disease sites. Large declines in 18F-FDG uptake tend to be seen in those with the longest progression-free survival.
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Cancers of the immune system (lymphomas) are extremely sensitive to radiation. Medical research over the last decade has lead to the development of monoclonal antibodies that can target lymphoma cells being attached to radioactive isotopes that help destroy those cells. Such treatment is known as radioimmunotherapy and this article describes its use for non-Hodgkin’s lymphoma. Nurses need to become familiar with how radioimmunotherapy differs from conventional chemotherapy.
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