Biokinetic Modeling and Dosimetry for Optimizing Intraperitoneal Radioimmunotherapy of Ovarian Cancer Microtumors

Abstract

A biokinetic model was constructed to evaluate and optimize various intraperitoneal radioimmunotherapies for micrometastatic tumors. The model was used to calculate the absorbed dose to both anticipated microtumors and critical healthy organs and demonstrated how intraperitoneal targeted radiotherapy can be optimized to maximize the ratio between them. Methods: The various transport mechanisms responsible for the biokinetics of intraperitoneally infused radiolabeled monoclonal antibodies (mAbs) were modeled using a software package. Data from the literature were complemented by pharmacokinetic data derived from our clinical phase I study to set parameter values. Results using the β-emitters 188 Re, 177 Lu, and 90 Y and the α-emitters 211 At, 213 Bi, and 212 Pb were compared. The effects of improving the specific activity, prolonging residence time by introducing an osmotic agent, and varying the activity concentration of the infused agent were investigated. Results: According to the model, a 1.7-L infused saline volume will decrease by 0.3 mL/min because of lymphatic drainage and by 0.7 mL/min because of the transcapillary convective component. The addition of an osmotic agent serves to lower the radiation dose to the bone marrow. Clinically relevant radioactivity concentrations of α-and β-emitters bound to mAbs were compared. For α-emitters, microtumors receive high doses (.20 Gy or 100 Sv [relative biological effect 5 5]). Since most of the tumor dose originates from cell-bound radionuclides, an increase in the specific activity would further increase the tumor dose without affecting the dose to peritoneal fluid or bone marrow. For β-emitters, tumors will receive almost entirely nonspecific irradiation. The dose from cell-bound radiolabeled mAbs will be negligible by comparison. For the long-lived 90 Y, tumor doses are expected to be low at the maximum activity concentration delivered in clinical studies. Conclusion: According to the presented model, α-emitters are needed to achieve radiation doses high enough to eradicate microscopic tumors. Atdi agnosis, ovarian cancer has often spread within the peritoneum. Treatment with advanced surgery and consolidated chemotherapy can appear successful, as many patients are declared tumor-free after a second laparoscopy. However, most of these patients will relapse and eventually die. To increase treatment success, adjuvant or consolidating therapies involving radionuclides have been attempted. Intraperitoneal radioimmunotherapy has the potential to irradiate micro-or subclinical tumors that have spread within the peritoneum. (2), complete remission at third-look evaluation (3), and prolonged time to intraperitoneal recurrence (4).The high-linear-energy transfer and short range of a-particles (50-100 mm) facilitates more concentrated irradiation of microscopic tumors. Various a-emitters have thus been evaluated for several cancer types (5). Our group used preclinical experiments to study the therapeutic effect and toxicity of the a-emitters 211 At and 213 Bi for intr...

B7-H3-targeted 212Pb radioimmunotherapy of ovarian cancer in preclinical models

“…The significantly greater sensitivity of the cells (three- to forty-fold) to a targeted RIC relative to a control RIC in these studies is equivalent to or greater than those reported for other cancer cells and radionuclides [16, 42-45]. The in vitro IC 50 concentrations of 212 Pb-376.96 against adherent ovarian cancer cells and CICs (1.6-33 kBq/mL) were lower than the maximum concentrations of alternative α-particle RICs calculated to be present in the peritoneum of ovarian cancer patients (42-100 kBq/mL) during clinical trials [15, 19, 21]. This demonstrates the utility of 212 Pb-376.96 at clinically achievable concentrations to kill both differentiated cells and CICs that promote metastases, chemoresistance, and recurrent disease.…”

“…The trend of prolonged mouse survival with higher doses of 212 Pb-376.96, coupled with the finding that all mice eventually succumbed to disease burden, suggests that in vivo saturation of the target epitope had not occurred with the doses used here [47]. Microdosimetry calculations and experimental results indicate that administering α-particle RICs in high specific activity at doses that saturate the target epitope in vivo is a viable strategy to maximize the absorbed dose to tumors without significantly increasing the dose to normal tissues [15, 49]. The significantly prolonged survival of mice that received 212 Pb-376.96 relative to a comparable dose of 212 Pb-F3-C25 demonstrates the advantage of targeting the mAb-defined B7-H3 epitope.…”

“…targeted radioimmunotherapy (RIT) with β-particles to enhance therapeutic efficacy against ovarian cancer [11-13]. These applications have failed to produce significant clinical responses in patients, possibly due to inadequate absorbed radiation doses from low linear energy transfer (LET) β-particles (0.1-1 keV/μm) [14, 15] and survival of ovarian CICs at doses that do not cause normal organ toxicities. Replacement of β-particle emitters with α-particle emitting radionuclides for targeted RIT offers greater potential for effective cell death because of the short path length (50-80 μm), high LET (100 keV/μm), and high relative biological effectiveness of α-particles [14-16].…”

Therapeutic efficacy of α-radioimmunotherapy with different activity levels of the 213Bi-labeled monoclonal antibody MX35 in an ovarian cancer model

“…Successful preclinical studies with 211 At have already led to a clinical phase I study [10, 11], and additional clinical trials are planned. While most of our efforts have been spent on development and evaluation of 211 At radiopharmaceuticals, model calculations [12] show that 213 Bi might be preferential for intraperitoneal (i.p.) radioimmunotherapy (RIT) of disseminated ovarian cancer.…”

A dosimetric model for the heterogeneous delivery of radioactive nanoparticles In vivo: a feasibility study

“…Because of this, a huge amount of effort has been invested in the creation of dosimetric algorithms to analyze dose deposition and dose–response in clinical and preclinical models. Some of these models are based on theoretical calculations that make educated assumptions about source deposition [8–11], while others use nuclear imaging methods such as single photon emission computed tomography (SPECT) to approximate the source distribution [4, 5, 12]. Although theoretical models can help one quickly change parameters and estimate outcomes, the calculated distributions do not represent the actual heterogeneity of source and dose distribution in a tumor.…”