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

皮肤鳞状细胞癌（cSCC）是皮肤癌数量的两倍多 黑色素瘤占所有皮肤癌的50%。约70万例 在美国，每年诊断一次，但退伍军人由于年龄和 在执行任务期间大量暴露于紫外线辐射和砷基化学战剂。最 cSCC可以通过手术切除或Mohs显微手术（Mohs）成功治疗;然而， 一部分cSCC病例导致局部复发、转移和死亡。穷人替许多人受苦 患有cSCC的退伍军人对更好的治疗方案的需求大量未得到满足，特别是对于那些 要求非手术治疗方案或不适合手术的患者，因为他们 免疫抑制或有其他合并症。该提案中的新技术，激光激活 纳米疗法（LANT）可以满足这种未满足的需求，当手术不是一种选择时，可以替代放射治疗。 LANT是一种使用近红外激光激发金纳米棒（AuNRs）的热消融平台疗法 产生足够的热量导致特定部位的细胞死亡我们的技术创新是 纳米颗粒设计和由此产生的治疗结果。在我们的初步研究中， (a)在我们的体外剂量递增曲线上，在最高浓度下100% SCC细胞死亡，以及（B）完全 在皮下异种移植中，一次治疗迭代后肿瘤消退，肿瘤边缘清晰 与三个对照组（未处理组、仅激光组和AuNRs组）相比， 只.基于这些发现，我们提出了一项研究，旨在证明LANT是安全的， 从板凳到床边，有三个目标。对于目标1，我们将证明生物分布、清除率， AuNR在小鼠肿瘤模型和家猪模型中的安全性 采集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、产热和LANT- 使用3D超声成像对肿瘤、肿瘤边缘和周围组织诱导损伤，K型 热电偶和红外热成像相机。我们还将验证LANT在不同激光输出下的安全性 通过摄影成像捕捉总体外观变化并分析形态学 肿瘤、肿瘤边缘和周围组织的组织学评价变化。我们将与我们的 FDA顾问和七（7）个临床合作伙伴在开始试点之前获得FDA和IRB批准 study.对于目标2，我们将招募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 在LANT后21天进行Mohs显微外科手术以确认清晰的肿瘤边缘。我们将雇用一名 自适应贝叶斯连续再评估方法（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超声成像和数字成像进行测量 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 LNT前后的边缘和周围组织。局部区域的组织学评价 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cSCC的安全有效的治疗选择。

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.