Enhancement of PDT Using Biological Response Modifiers

使用生物反应调节剂增强 PDT

• 批准号: 7264564
• 负责人: DAVID A BELLNIER
• 金额: $ 26.68万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264564
• 关键词: Apoptosis; Area; Basal cell carcinoma; Biological Markers; Biological Response Modifiers; Blood Vessels; Cells; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complex; Condition; Cutaneous; Data; Disease; Disease regression; Disruption; Dose; Drug Kinetics; Effectiveness; Endothelial Cells; Experimental Neoplasms; Funding; Future; Generations; Genes; Goals; HPPH; Human; Immune; Immune response; Immunity; Implant; Inflammatory; Injury; Kinetics; Light; Mediating; Mediator of activation protein; Memory; Modeling; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Nitric Oxide; Patients; Pattern; Perivascular Neoplasm; Personal Satisfaction; Photochemotherapy; Photosensitivity; Photosensitizing Agents; Porfimer Sodium; Primary Neoplasm; Principal Investigator; Property; Protocols documentation; Rate; Relative (related person); Reporting; Research Personnel; Role; Schedule; Serotonin; Source; Surrogate Markers; TNFRSF1A gene; Therapeutic; Time; Tissues; Toxic effect; Translating; Translations; Treatment Effectiveness; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tumor Immunity; Tumor Necrosis Factor-alpha; Tumor Tissue; United States Food and Drug Administration; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Endothelium; Work; base; cell injury; clinical application; cytokine; cytotoxicity; design; immunogenicity; improved; inhibitor/antagonist; novel strategies; pre-clinical; pre-clinical research; preclinical study; programs; research study; response; synergism; therapy design; tumor; tumor growth; xanthenone-4-acetic acid

DESCRIPTION (provided by applicant): Well-designed combination therapies can maintain or increase the potency of the antitumor effect while abrogating toxicity. We have shown that the combination of PDT with TNF-a provides outstanding therapeutic efficacy without increasing toxicity. Yet, this combination may not be clinically viable since systemic TNF-a can have significant toxicity in patients. In the previous funding period we confirmed our original hypothesis that the vascular targeting agent DMXAA would strongly enhance the antitumor activity of PDT while maintaining treatment selectivity. This hypothesis was based on the earlier observation that DMXAA selectively induces TNF-a in tumor tissue. Recent studies suggest that TNF-a induction may not be entirely responsible for the therapeutic synergism between PDT and DMXAA, suggesting other compensatory mechanism(s). It has been shown that the antivascular activity of DMXAA can also result from direct effects on the tumor vascular endothelium and indirect effects of other DMXAA-induced cytokines/mediators besides TNF-a. Therefore, we now plan to closely define the roles of TNF-a and direct endothelial cell apoptosis, as well as that of 5-HT/serotonin, NO and VEGF, in the enhancement of PDT by DMXAA; we hypothesize that by understanding the underlying mechanism of the interaction between DMXAA and PDT regimens will be able to identify a biomarker or surrogate marker that will enable us to develop optimal preclinical and clinical treatment designs. The mechanisms that govern the response to PDT are complex and not well understood; it has recently become clear that the choice of PDT regimen, in particular fluence rate, governs the pattern of tissue response (i.e. the relative contributions of vessel damage and direct tumor cytotoxicity, as well as the strength of the induction of innate and adaptive immune responses) as well as treatment outcome. We have described this in an experimental tumor model using the 2nd-generation photodynamic sensitizer HPPH. We believe that the degree and mechanism of interaction between DMXAA and HPPH-PDT will strongly depend on the PDT treatment regimen. We hypothesize that a PDT regimen will be identified that, in combination with DMXAA, achieves high antitumor efficacy, high selectivity and clinically practicable treatment times. Our group has demonstrated that PDT stimulates innate and adaptive immune responses resulting in increased tumor immunogenicity; we have now shown that DMXAA enhances this response; we now hypothesize that low doses of DMXAA can be used to increase the ability of PDT to augment antitumor immune memory and thus provide control of tumors outside the treatment field. Our Specific Aims are to: 1) Characterize the underlying mechanism(s) of interaction for the enhancement of HPPH-PDT by DMXAA; 2) Determine the mechanism by which DMXAA augments the ability of PDT to enhance antitumor immune memory; 3) to bring the preclinical research of the past funding period to clinical fruition we will examine the activity of the combination of DMXAA and Photofrin-PDT against basal cell carcinomas (BCCs).

描述（由申请人提供）：精心设计的联合治疗可以维持或增加抗肿瘤作用的效力，同时消除毒性。我们已经表明，PDT与TNF-α的组合提供了出色的治疗效果而不增加毒性。然而，这种组合可能在临床上不可行，因为全身性TNF-α可能在患者中具有显著的毒性。在之前的资助期间，我们证实了我们最初的假设，即血管靶向药物DMXAA将在保持治疗选择性的同时强烈增强PDT的抗肿瘤活性。该假设基于DMXAA选择性地诱导肿瘤组织中的TNF-α的早期观察。最近的研究表明，TNF-α诱导可能不完全负责PDT和DMXAA之间的治疗协同作用，提示其他代偿机制。已经表明，DMXAA的抗血管活性也可以由对肿瘤血管内皮的直接作用和除TNF-α之外的其他DMXAA诱导的细胞因子/介质的间接作用引起。因此，我们现在计划密切定义TNF-α和直接内皮细胞凋亡的作用，以及5-HT/血清素、NO和VEGF在DMXAA增强PDT中的作用;我们假设通过理解DMXAA和PDT方案之间相互作用的潜在机制，将能够鉴定生物标志物或替代标志物，其将使我们能够开发最佳的临床前和临床治疗设计。控制对PDT的反应的机制是复杂的，并且还没有很好地理解;最近已经清楚的是，PDT方案的选择，特别是注量率，控制组织反应的模式（即血管损伤和直接肿瘤细胞毒性的相对贡献，以及先天性和适应性免疫反应的诱导强度）以及治疗结果。我们已经在使用第二代光动力增敏剂HPPH的实验肿瘤模型中描述了这一点。我们相信DMXAA和HPPH-PDT之间相互作用的程度和机制将强烈依赖于PDT治疗方案。我们假设，PDT方案将被确定，与DMXAA相结合，实现高抗肿瘤疗效，高选择性和临床可行的治疗时间。我们的研究小组已经证明，PDT刺激先天性和适应性免疫反应，导致肿瘤免疫原性增加;我们现在已经证明，DMXAA增强这种反应;我们现在假设，低剂量的DMXAA可用于增加PDT的能力，以增强抗肿瘤免疫记忆，从而提供治疗领域以外的肿瘤控制。我们的具体目标是：1）表征DMXAA增强HPPH-PDT的相互作用的潜在机制; 2）确定DMXAA增强PDT增强抗肿瘤免疫记忆能力的机制; 3）为了使过去资助期的临床前研究取得临床成果，我们将检查DMXAA和Photofrin-PDT组合对基底细胞癌（BCC）的活性。