Safety Assessment of Laser Activated NanoTherapy (LANT) as a Potential Treatment for Veterans with Cutaneous Squamous Cell Carcinomas

激光激活纳米疗法 (LANT) 作为皮肤鳞状细胞癌退伍军人潜在治疗方法的安全性评估

• 批准号: 10483631
• 负责人: Hadiyah-Nicole Green
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483631
• 关键词: 3D ultrasound; Address; Age; Appearance; Area; Arsenic; Biodistribution; Biological; Biopsy; Burn injury; Cell Death; Cessation of life; Chemical Warfare Agents; Cicatrix; Clinical; Connective Tissue; Control Groups; Data; Dermis; Diagnosis; Domestic Pig; Dose; Effectiveness; Ensure; Epidermis; Evaluation; Excision; Generations; Gold; Hematology; Histologic; Histology; Histopathology; Human; Image; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Infection; Injections; Injury; Institutional Review Boards; Lasers; Local anesthesia; Malignant Neoplasms; Measures; Medical Technology; Methods; Modeling; Morphology; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Output; Pain; Pilot Projects; Process; Prognosis; Publications; Publishing; Radiation; Recurrence; Research Design; Risk; Safety; Serology; Site; Skin; Skin Cancer; Squamous cell carcinoma; Subcutaneous Tissue; Surface; Technology; Testing; The Sun; Thermal Ablation Therapy; Time; Tissues; Toxic effect; Translating; Ulcer; Ultrasonography; Ultraviolet Rays; United States; Veterans; Work; Xenograft procedure; base; bench to bedside; cancer therapy; comorbidity; design; digital; effective therapy; first-in-human; high risk; immunosuppressed; in vivo; innovation; insight; interest; lewisite; melanocyte; melanoma; minimally invasive; mouse model; nanoparticle; nanorod; nanotherapy; new technology; novel; pharmacokinetics and pharmacodynamics; porcine model; recruit; safety assessment; side effect; skin regeneration; skin squamous cell carcinoma; standard of care; subcutaneous; therapeutically effective; therapy outcome; tumor

Cutaneous squamous cell carcinomas (cSCC) are responsible for more than twice the number of skin cancer deaths than melanoma, representing up to 50% of all skin cancers. Approximately 700,000 cases are diagnosed annually in the United States, but Veterans have a higher risk for cSCC because of age and extensive exposures during the line of duty to UV radiation and arsenic-based chemical warfare agents. Most cSCC can be successfully treated by surgical excision or Mohs Micrographic Surgery (Mohs); however, a subset of cSCC cases result in locoregional recurrence, metastases, and death. The poor prognoses for many Veterans with cSCC result in a substantial unmet need for better treatment options, especially for those who request a non-surgical treatment option or who are not a candidate for surgery because they are immunosuppressed or have other comorbidities. The novel technology in this proposal, Laser-Activated NanoTherapy (LANT), can meet this unmet need for an alternative to radiation when surgery is not an option. LANT is a thermal ablation platform therapy using near-infrared laser excitation of gold nanorods (AuNRs) that generates enough heat to induce site-specific cellular death. The innovation of our technology is the nanoparticle design and the resulting therapeutic outcomes. In our preliminary studies, LANT demonstrated (a) 100% SCC cell death at the highest concentration on our dose-escalation curve in vitro, and (b) complete tumor regression after one treatment iteration with clear tumor margins in subcutaneously-xenografted squamous cell carcinoma in mice, compared to three control groups, no-treatment, laser-only, and AuNRs- only. Based on these findings, we propose a study designed to demonstrate that LANT is safe and translate LANT from bench to bedside with three aims. For Aim 1, we will demonstrate the biodistribution, clearance, and safety of AuNRs in a murine tumor model and a domestic swine model to acquire PK/PD data using ICP- MS, hematology/serology, and histology. We will verify the distribution of AuNRs, heat generation, and LANT- induced injury to the tumor, tumor margins, and surrounding tissues using 3D ultrasound imaging, K-type thermocouples, and IR thermographic cameras. We will also validate LANT safety at different laser output powers by capturing gross appearance changes with photographic imaging and analyzing morphological changes with histological evaluation of tumors, tumor margins, and surrounding tissues. We will work with our FDA consultant and seven (7) clinical partners to obtain FDA and IRB approvals before beginning the pilot study. For Aim 2, we will recruit Veterans (n = 10) who have biopsy-confirmed local, low-risk cSCC. Veterans will receive 3-D ultrasound-guided injections of AuNRs during LANT. Veterans will also receive the standard of care Mohs Micrographic Surgery to confirm clear tumor margins 21 days after LANT. We will employ an adaptive Bayesian Continual Reassessment Method (CRM) to determine and adjust the LANT dose, measured by local skin toxicities and tumor regression measured by 3-D ultrasound imaging and digital calipers. For Aim 3, we will evaluate the morphological and histopathological changes of the tumor, tumor margin, and surrounding tissue before and after LANT. Histopathological evaluation of the locoregional biopsies and treated tumors will be used to characterize the appearance of melanocytes, the epidermis, dermis, hypodermis, and subcutis of the tumor, tumor margin, and surrounding tissue before and after LANT. We will gain biological, morphological, and histopathological insight into LANT's cellular and gross impact, demonstrating that LANT is a safe and effective treatment option for cSCC.

皮肤鳞状细胞癌 (cSCC) 造成的皮肤癌数量是皮肤癌的两倍以上 死亡人数超过黑色素瘤，占所有皮肤癌的 50%。大约 700,000 例 在美国每年都会诊断出鳞状细胞癌，但由于年龄和退伍军人的年龄和年龄，退伍军人患鳞状细胞癌的风险更高 在执勤期间大量暴露于紫外线辐射和砷基化学战剂。最多 cSCC可以通过手术切除或莫氏显微手术（Mohs）成功治疗；然而，一个 部分 cSCC 病例会导致局部复发、转移和死亡。许多人的预后不佳 患有鳞状细胞癌的退伍军人对更好的治疗选择的需求大量未得到满足，特别是对于那些 请求非手术治疗方案或因以下原因不适合手术的人 免疫抑制或有其他合并症。该提案中的新技术是激光激活 当无法进行手术时，纳米疗法 (LANT) 可以满足放射替代方案的未满足需求。 LANT 是一种利用近红外激光激发金纳米棒 (AuNR) 的热消融平台疗法 产生足够的热量来诱导特定位点的细胞死亡。我们技术的创新在于 纳米粒子设计和由此产生的治疗结果。在我们的初步研究中，LANT 证明了 (a) 在我们的体外剂量递增曲线上的最高浓度下，SCC 细胞死亡 100%，以及 (b) 完成 一次治疗迭代后肿瘤消退，皮下异种移植的肿瘤边缘清晰 小鼠鳞状细胞癌，与三个对照组（未治疗组、仅激光组和 AuNRs 组）相比 仅有的。基于这些发现，我们提出了一项研究，旨在证明 LANT 是安全的并可转化为 LANT 从板凳到床边，具有三个目标。对于目标 1，我们将演示生物分布、清除、 AuNRs 在小鼠肿瘤模型和家养猪模型中的安全性和安全性 获取 PK/PD 数据 使用 ICP- MS、血液学/血清学和组织学。我们将验证 AuNR 的分布、热量产生和 LANT- 使用 3D 超声成像 K 型对肿瘤、肿瘤边缘和周围组织造成损伤 热电偶和红外热像仪。我们还将验证不同激光输出下的 LANT 安全性 通过摄影成像捕捉总体外观变化并分析形态 随着肿瘤、肿瘤边缘和周围组织的组织学评估而变化。我们将与我们的 FDA 顾问和七 (7) 名临床合作伙伴在开始试点之前获得 FDA 和 IRB 批准 学习。对于目标 2，我们将招募经活检证实患有局部低风险 cSCC 的退伍军人 (n = 10)。退伍军人 将在 LANT 期间接受 3D 超声引导的 AuNR 注射。退伍军人也将获得标准 LANT 后 21 天进行 Mohs 显微手术以确认清晰的肿瘤边缘。我们将聘请一名 自适应贝叶斯持续重新评估方法 (CRM) 来确定和调整 LANT 剂量， 通过局部皮肤毒性和肿瘤消退进行测量，通过 3D 超声成像和数字技术测量 卡尺。对于目标3，我们将评估肿瘤的形态学和组织病理学变化，肿瘤 LANT 前后的边缘和周围组织。局部区域的组织病理学评估 活组织检查和治疗的肿瘤将用于表征黑素细胞、表皮、 LANT前后肿瘤的真皮、皮下组织和皮下组织、肿瘤边缘和周围组织。 我们将从生物学、形态学和组织病理学角度深入了解 LANT 的细胞和总体影响， 证明 LANT 是治疗 cSCC 的安全有效的选择。