Enhancement of PDT Using Biological Response Modifiers

使用生物反应调节剂增强 PDT

• 批准号: 7142856
• 负责人: DAVID A BELLNIER
• 金额: $ 27.15万
• 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/7142856
• 关键词: antigen antibody reaction; apoptosis; biological response modifiers; blood vessels; cancer prevention; combination cancer therapy; immunoregulation; laboratory mouse; metastasis; neoplasm /cancer; neoplasm /cancer immunotherapy; neoplasm /cancer photoradiation therapy; neoplastic cell; nonhuman therapy evaluation; tumor necrosis factor alpha; xenotransplantation

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）：设计良好的联合疗法可以在消除毒性的同时保持或增加抗肿瘤效果的效力。我们已经证明，PDT与TNF-a的组合提供了突出的治疗效果，而不增加毒性。然而，这种组合在临床上可能不可行，因为全身性TNF-a对患者具有显著的毒性。在之前的资助期内，我们证实了我们最初的假设，即血管靶向剂DMXAA会在保持治疗选择性的同时，强烈增强PDT的抗肿瘤活性。这一假设是基于DMXAA在肿瘤组织中选择性诱导TNF-a的早期观察。最近的研究表明，TNF-a诱导可能并不完全负责PDT和DMXAA之间的治疗协同作用，提示其他补偿机制。研究表明，DMXAA的抗血管活性还可能来自于DMXAA对肿瘤血管内皮的直接作用和除TNF-a外的其他细胞因子/介质的间接作用。因此，我们现在计划密切确定TNF-a和直接内皮细胞凋亡，以及5-HT/ 5-羟色胺，NO和VEGF在DMXAA增强PDT中的作用；我们假设，通过了解DMXAA和PDT方案之间相互作用的潜在机制，将能够识别生物标志物或替代标志物，使我们能够开发最佳的临床前和临床治疗设计。控制PDT反应的机制是复杂的，并没有得到很好的理解；最近已经很清楚，PDT方案的选择，特别是影响率，决定了组织反应的模式（即血管损伤和直接肿瘤细胞毒性的相对贡献，以及诱导先天和适应性免疫反应的强度）以及治疗结果。我们在使用第二代光动力敏化剂HPPH的实验性肿瘤模型中描述了这一点。我们认为DMXAA和hphh -PDT之间相互作用的程度和机制将强烈依赖于PDT治疗方案。我们假设将确定一种PDT方案，该方案与DMXAA联合使用，具有高抗肿瘤疗效，高选择性和临床可行的治疗时间。我们的团队已经证明PDT刺激先天和适应性免疫反应，导致肿瘤免疫原性增加；我们现在已经证明DMXAA增强了这种反应；我们现在假设，低剂量的DMXAA可以用来增加PDT增强抗肿瘤免疫记忆的能力，从而提供对治疗领域外肿瘤的控制。我们的具体目标是：1)表征DMXAA增强hphh - pdt的相互作用的潜在机制；2)确定DMXAA增强PDT抗肿瘤免疫记忆能力的机制；3)为了将过去资助期的临床前研究转化为临床成果，我们将研究DMXAA和Photofrin-PDT联合治疗基底细胞癌（bcc）的活性。