Dose-Response in Radionuclide Therapy

放射性核素治疗中的剂量效应 项目摘要 在这个相互竞争的续签申请中，我们的总体目标仍然是前面描述的-使患者能够- 通过建立提供放射性药物治疗(RPT)的具体治疗计划方法 方法和开发计算工具，以更好地预测组织毒性和肿瘤反应。在 在之前的赠款期间，我们解决了与Beta排放者的RPT问题，并建立了计划组合的方法 使用β发射体RPT的体外放射治疗。在这份续期申请中，我们建议解决 阿尔法粒子发射体的剂量学。α粒子发射器已被公认为高度有效的疗法 从根本上说，它们的机制是新颖的，基本上不受耐药性的影响。FDA最近批准了 一种这样的试剂已经导致了许多努力，将更多的阿尔法发射体RPT(αRPT)带到临床。α粒子 是短程(50至100微米)高线性能量转移(LET)粒子，导致优势双 搁浅对DNA造成断裂伤害。虽然有一种成熟的剂量学形式用于风险评估 这些，没有剂量学形式主义能够解释这些的高LET和短范围来评估 毒性和疗效--治疗终点。我们建议开发一种解决这一问题的方法 这些制剂的范围和高效性。具体目标是：1.测量相对生物学 正常组织对α粒子发射体放射性药物(αRPTS)的有效性。没有系统性的 对正常组织的RBE进行了评估。当前可用的值主要源自 体外细胞研究。由于生物效应=吸收剂量(AD)×RBE，因此需要避免正常组织的RBE 毒性，计划治疗，并安全地执行αRPT的I期AD升级试验。在体内测量肿瘤的RBE 对于3种肿瘤类型，在体外与RBE比较。肿瘤随机对照试验不仅用于疗效评估，也用于治疗 优化治疗，避免患者过度治疗。开发并整合用于α的宏微观建模- 将粒子发射器剂量测量转换为3D-RD。在以前的支持下开发的从宏观到微观的方法是 用于完整抗体的肾脏剂量测定，标记了不同的阿尔法发射体。这一目标将延伸到 本工作以多肽和小分子为基础，将该方法融入到3D-RD平台中，建立 新版3D-RD(α3D-RD)。建立可将外部梁RT(XRT)与 αRpt.将XRT与αRPT相结合是有充分理由的。这样的待遇还没有实施 因为一种结合剂量图中微尺度RBE加权剂量分布和剂量的方法- 不存在可在XRT计划软件中使用的体积直方图。我们将在XRT-RPT的基础上 我们以前开发的方法，目前正在与Sm-153(一种β粒子发射器)一起使用 霍普金斯大学正在进行的一项针对骨肉瘤患者的临床试验，以建立一种可以 整合到α3D-RD中。这些目标的成功完成将使剂量学驱动的治疗成为可能 实施这一新颖而高效的治疗方式的规划方法。

Dose-Response in Radionuclide Therapy Project Summary In this competing renewal application, our overall objective remains as previously described - to enable a patient- specific treatment planning approach to delivering radiopharmaceutical therapy (RPT) by establishing methodologies and developing computational tools that better predict tissue toxicity and tumor response. In the prior grant period we addressed RPT with beta-emitters and established a methodology to plan combination external beam radiotherapy with beta-emitter RPT. In this renewal application we propose to address the dosimetry of alpha-particle emitters. α-particle emitters have been recognized as highly potent therapeutics that are fundamentally novel in their mechanism and largely impervious to resistance. The recent FDA approval of one such agent has led to numerous efforts to bring more alpha-emitter RPTs (αRPT) to the clinic. α-particles are short-range (50 to 100 µm,) high linear energy transfer (LET) particles which cause preponderant double- stranded break damage to DNA. Although there is a well-established dosimetry formalism for risk evaluation of these, there is no dosimetry formalism able to account for the high LET and the short range of these to evaluate toxicity and efficacy – therapeutic endpoints. We propose to develop a methodology that accounts for the short range and high potency of these agents. The specific aims to do this are: 1. Measure the Relative Biological Effectiveness (RBE) of normal tissue for α-particle emitter radiopharmaceuticals (αRPTs). No systematic evaluation of RBE for normal tissues has been undertaken. Currently available values are largely derived from in vitro cell studies. Since biological effect = Absorbed Dose (AD) x RBE, normal tissue RBE is needed to avoid toxicity, plan therapy, and safely execute phase I AD escalation trials for αRPT.2. Measure tumor RBE, in vivo for 3 tumor types, compare to RBE, in vitro. Tumor RBE is needed to assess efficacy as well as for treatment optimization to avoid over-treating patients.3. Develop and incorporate macro to micro modeling for α- particle emitter dosimetry into 3D-RD. The macro to micro approach developed with prior support has been implemented for kidney dosimetry of intact antibodies, labeled with different alpha-emitters. This aim will extend this work to peptides and small molecules and incorporate the method into the 3D-RD platform to establish a new version of 3D-RD (α3D-RD).4. Establish models that enable combined external beam RT (XRT) with αRPT. There is a strong rationale for combining XRT with αRPT. Such treatment has not been implemented because a methodology that incorporates micro-scale RBE-weighted dose distribution in dose maps and dose- volume histograms that can be used in XRT planning software does not exist. We will build upon the XRT-RPT method that we developed previously and that is currently being used with Sm-153, (a beta-particle emitter) in an ongoing clinical trial at Hopkins in patients with osteosarcoma to establish a formalism that can be incorporated into α3D-RD. Successful completion of these aims will enable a dosimetry-driven, treatment planning approach to implementing this novel and highly potent therapeutic modality.