Moving TIL Therapy Past the Valley of Death

描述（由申请人提供）：研究领域：转移性黑色素瘤最有效的治疗方法是肿瘤浸润淋巴细胞（TIL）疗法，该疗法从患者的肿瘤片段中获得TIL，在体外培养大量TIL，然后再输注回患者体内（1-4）。问题：尽管它能够提供完全缓解，但培养治疗性细胞剂量的过程是如此低效和复杂，以至于TIL治疗无法逃脱死亡之谷。建议的解决方案：在先前的II期SBIR GM058978下，我们创造了细胞培养设备技术的范式转变，该技术已被广泛研究用于TIL生产。结果表明，可以创建一个大大简化的过程，使TIL治疗走出死亡之谷，走上商业道路。关键是要让TILs驻留在一个高度气体渗透性，液体不渗透性的膜上，浸没在非常规高水平的介质下。我们称这种方法为“G-Rex”。在这个位置上，他们可以获得所需的氧气和营养，而不需要昂贵和复杂的辅助设备。使用这种设备配置，我们打算将TIL生产过程从多达60个传统设备和30L介质减少到只有2个G-Rex设备和4L到5L介质。许多其他生产优势是这种程度的流程简化所固有的。由于这个项目，应用TIL疗法的盈利潜力将存在，商业实体将受到刺激，利用TIL疗法的强大成果。研究：我们的研究将通过优化G-Rex协议和设备来提供最有效的TIL生产：目标1：确定最佳TIL表面密度，以最大限度地减少TIL快速膨胀过程的持续时间。目标2：确定G-Rex的最佳高度，以最大限度地减少TIL快速膨胀过程（REP）中的进料频率。目标3：定义全尺寸G-Rex设备允许的透气膜厚度的变化。目标4：全面验证优化的G-Rex TIL培养标准操作规程和G-Rex设备规格。项目完成后TIL治疗情况：在优化项目之外，G-Rex在非优化状态下的临床应用已经开始。在这项研究完成后，优化的G-Rex将过渡到一项多中心可比性研究，随后是一项随机研究，FDA批准和商业化的TIL治疗。

DESCRIPTION (provided by applicant): The Field: The most effective treatment for metastatic melanoma is Tumor Infiltrating Lymphocyte (TIL) therapy, in which TILs are obtained from a patient's tumor fragments, grown to an immense quantity in vitro, and infused back into the patient (1-4). The Problem: Despite its ability to provide complete remission, the process of growing a therapeutic cell dose is so inefficient and complicated that TIL therapy cannot escape the Valley of Death. The Proposed Solution: Under prior Phase II SBIR GM058978, we created a paradigm shift in cell culture device technology that has been extensively studied for TIL production. The results demonstrate a greatly simplified process can be created that will allow TIL therapy to move beyond the Valley of Death and onto a commercial path. The key is to allow TILs to reside on a highly gas permeable, liquid impermeable membrane submerged under an unconventionally high level of medium. We call this approach "G-Rex". With TILs in this position, they have access to oxygen and nutrients on demand without need of expensive and complicated ancillary equipment. Using this device configuration, we intend to reduce the TIL production process from up to 60 conventional devices and 30L of medium to just 2 G-Rex devices and as little as 4L to 5L of medium. Many other production advantages are inherent to this level of process simplification. As a result of this program, the potential for profit by applying TIL therapy will exist and commercial entities will be spurred to capitalize on the powerful outcomes of TIL therapy. The Investigation: Our investigation will provide the most efficient TIL production possible by optimizing G- Rex Protocols and devices: Aim 1: Determine the optimal TIL surface density that minimizes the duration of TIL Rapid Expansion Process Aim 2: Determine the optimal height of the G-Rex that will minimize the feeding frequency during the TIL Rapid Expansion Process (REP). Aim 3: Define the variance of gas permeable membrane thickness allowed in full scale G-Rex devices. Aim 4: Full scale validation of optimized G-Rex TIL culture S.O.P.s and G-Rex device specifications. The status of TIL therapy upon completion of this program: Separate from this optimization program, clinical application of G-Rex in the non-optimized state is already occurring. Upon completion of this investigation, the optimized G-Rex will transition into a multi-center comparability study followed by a randomized study, FDA approval, and commercially available TIL therapy.