Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

Du, Yong; Honeychurch, Jamie; Glennie, Martin J.; Johnson, Peter; Illidge, Tim

doi:10.1158/0008-5472.can-06-2495

Cited by 8 publications

(6 citation statements)

References 33 publications

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“…An extreme case of such non-uniformity is a tumor with a highly metabolic surface and a necrotic core with no uptake. However, in non-Hodgkin lymphoma this level of non-uniformity is rare as tumors are generally well perfused with relatively uniform uptake (Du et al 2007). When necrosis is evident on SPECT, it is sometimes also evident on CT as a low attenuation dark region.…”

Section: Discussionmentioning

confidence: 99%

Post-reconstruction non-local means filtering methods using CT side information for quantitative SPECT

2013

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Quantitative SPECT techniques are important for many applications including internal emitter therapy dosimetry where accurate estimation of total target activity and activity distribution within targets are both potentially important for dose-response evaluations. We investigated non-local means (NLM) post-reconstruction filtering for accurate I-131 SPECT estimation of both total target activity and the 3D activity distribution. We first investigated activity estimation versus number of ordered-subsets expectation-maximization (OSEM) iterations. We performed simulations using the XCAT phantom with tumors containing a uniform and a non-uniform activity distribution, and measured the recovery coefficient (RC) and the root mean squared error (RMSE) to quantify total target activity and activity distribution, respectively. We observed that using more OSEM iterations is essential for accurate estimation of RC, but may or may not improve RMSE. We then investigated various post-reconstruction filtering methods to suppress noise at high iteration while preserving image details so that both RC and RMSE can be improved. Recently, NLM filtering methods have shown promising results for noise reduction. Moreover, NLM methods using high-quality side information can improve image quality further. We investigated several NLM methods with and without CT side information for I-131 SPECT imaging and compared them to conventional Gaussian filtering and to unfiltered methods. We studied four different ways of incorporating CT information in the NLM methods: two known (NLM CT-B and NLM CT-M) and two newly considered (NLM CT-S and NLM CT-H). We also evaluated the robustness of NLM filtering using CT information to erroneous CT. NLM CT-S and NLM CT-H yielded comparable RC values to unfiltered images while substantially reducing RMSE. NLM CT-S achieved −2.7 to 2.6% increase of RC compared to no filtering and NLM CT-H yielded up to 6% decrease in RC while other methods yielded lower RCs than them: Gaussian filtering (up to 11.8% decrease in RC), NLM method without CT (up to 9.5% decrease in RC), and NLM CT-M and NLM CT-B (up to 19.4% decrease in RC). NLM CT-S and NLM CT-H achieved 8.2 to 33.9% and −0.9 to 36% decreased RMSE on tumors compared to no filtering respectively while other methods yielded less reduced or increased RMSE: Gaussian filtering (up to 7.9% increase in RMSE), NLM method without CT (up to 18.3% increase in RMSE), and NLM CT-M and NLM CT-B (up to 31.5% increase in RMSE). NLM CT-S and NLM CT-H also yielded images with tumor shapes that better-matched the true shapes than other methods. All NLM methods using CT information were robust to small misregistration between SPECT and CT, but NLM CT-S and NLM CT-H were more sensitive than NLM CT-M and NLM CT-B to missing CT information.

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Section: Discussionmentioning

confidence: 99%

Post-reconstruction non-local means filtering methods using CT side information for quantitative SPECT

2013

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“…This hinders the uniform distribution of radiolabeled mAbs throughout the tumor unless the dose of mAbs administered is at a concentration that can saturate all antigens on the tumor cells. Nonuniform microdistribution of mAb leads to a marked difference in individual cell survival across the tumor [ 71 ]. Therefore, although RIT was shown to be effective against hematological tumors, solid tumors were less responsive due to insufficient dose delivery and radiation resistance [ 72 ].…”

Section: Introductionmentioning

confidence: 99%

Combination Radioimmunotherapy Approaches and Quantification of Immuno-PET

Kim

2016

Nucl Med Mol Imaging

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Monoclonal antibodies (mAbs), which play a prominent role in cancer therapy, can interact with specific antigens on cancer cells, thereby enhancing the patient’s immune response via various mechanisms, or mAbs can act against cell growth factors and, thereby, arrest the proliferation of tumor cells. Radionuclide-labeled mAbs, which are used in radioimmunotherapy (RIT), are effective for cancer treatment because tumor associated-mAbs linked to cytotoxic radionuclides can selectively bind to tumor antigens and release targeted cytotoxic radiation. Immunological positron emission tomography (immuno-PET), which is the combination of PET with mAb, is an attractive option for improving tumor detection and mAb quantification. However, RIT remains a challenge because of the limited delivery of mAb into tumors. The transport and uptake of mAb into tumors is slow and heterogeneous. The tumor microenvironment contributed to the limited delivery of the mAb. During the delivery process of mAb to tumor, mechanical drug resistance such as collagen distribution or physiological drug resistance such as high intestinal pressure or absence of lymphatic vessel would be the limited factor of mAb delivery to the tumor at a potentially lethal mAb concentration. When α-emitter-labeled mAbs were used, deeper penetration of α-emitter-labeled mAb inside tumors was more important because of the short range of the α emitter. Therefore, combination therapy strategies aimed at improving mAb tumor penetration and accumulation would be beneficial for maximizing their therapeutic efficacy against solid tumors.

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“…2,3 This difference is partly explained by difficulty in delivering the antibody to all parts of the tumor. 4,5 The reasons for such nonuniform microdistribution have been extensively evaluated in animal models, and relate to large tumor size, increased central interstitial pressure, and mechanical barriers (e.g. collagen and tight-junction).…”

Section: Introdcutionmentioning

confidence: 99%

Microdistribution of fluorescently-labeled monoclonal antibody in a peritoneal dissemination model of ovarian cancer

et al. 2010

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The microdistribution of therapeutic monoclonal antibodies within a tumor is important for determining clinical response.Nonuniform microdistribution predicts therapy failure. Herein, we developed a semiquantitative method for measuring microdistribution of an antibody within a tumor using in situ fluorescence microscopy and sought to modulate the microdistribution by altering the route and timing of antibody dosing. The microdistribution of a fluorescently-labeled antibody, trastuzumab (50-µg and 150-µg intraperitoneal injection (i.p.), and 100-µg intravenous injection (i.v.)) was evaluated in a peritoneal dissemination mouse model of ovarian cancer. In addition, we evaluated the microdistribution of concurrently-injected (30-µg i.p. and 100-µg i.v.) or serial (two doses of 30-µg i.p.) trastuzumab using in situ multicolor fluorescence microscopy. After the administration of 50-µg i.p. and 100-µg i.v. trastuzumab fluorescence imaging showed no significant difference in the central to peripheral signal ratio (C/P ratio) and demonstrated a peripheral-dominant accumulation, whereas administration of 150-µg i.p. trastuzumab showed relatively uniform, central dominant accumulation. With concurrent-i.p.-i.v. injections trastuzumab showed slightly higher C/P ratio than concurrently-injected i.p. trastuzumab. Moreover, in the serial injection study, the second injection of trastuzumab distributed more centrally than the first injection, while no difference was observed in the control group. Our results suggest that injection routes do not affect the microdistribution pattern of antibody in small peritoneal disseminations.However, increasing the dose results in a more uniform antibody distribution within peritoneal nodules. Furthermore, the serial i.p. injection of antibody can modify the microdistribution within tumor nodules. This work has implications for the optimal delivery of antibody based cancer therapies.

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Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

Cited by 8 publications

References 33 publications

Post-reconstruction non-local means filtering methods using CT side information for quantitative SPECT

Post-reconstruction non-local means filtering methods using CT side information for quantitative SPECT

Combination Radioimmunotherapy Approaches and Quantification of Immuno-PET

Microdistribution of fluorescently-labeled monoclonal antibody in a peritoneal dissemination model of ovarian cancer

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