Moving TIL Therapy Past the Valley of Death

描述（由申请人提供）：领域：转移性黑色素瘤的最有效治疗是肿瘤浸润淋巴细胞（TIL）疗法，其中TIL从患者的肿瘤碎片获得，在体外生长至大量，并输注回患者体内（1-4）。问题：尽管它能够提供完全缓解，但增加治疗性细胞剂量的过程是如此低效和复杂，以至于TIL疗法无法逃脱死亡谷。建议的解决方案：在先前的II期SBIR GM 058978中，我们在细胞培养装置技术中创造了一种范式转变，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疗法超越死亡谷，走上商业化道路，关键是让TIL驻留在一个高度透气、液体不可渗透的膜上，浸没在一个非常规的高水平培养基下。我们称这种方法为“G-Rex”。在这种情况下，TILs可以根据需要获得氧气和营养物质，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个常规设备和30 L培养基减少到仅2个G-Rex设备和少至4 L至5 L培养基。许多其他生产优势是这种工艺简化水平所固有的。作为该计划的结果，通过应用TIL疗法获得利润的潜力将存在，并且将刺激商业实体利用TIL疗法的强大结果。调查：我们的研究将通过优化G-雷克斯方案和装置提供可能的最有效的TIL生产：目标1：确定使TIL快速扩增过程的持续时间最小化的最佳TIL表面密度目标2：确定将使TIL快速扩增过程（REP）期间的进料频率最小化的G-雷克斯的最佳高度。目的3：定义全尺寸G-Rex器械中允许的透气膜厚度的方差。目的4：优化的G-Rex TIL培养S. O. P. s和G-Rex器械质量标准的全规模验证。完成该项目后的TIL治疗状态：与该优化项目无关，G-Rex在非优化状态下的临床应用已经开始。完成这项研究后，优化的G-Rex将过渡到多中心可比性研究，然后进行随机研究、FDA批准和市售的TIL疗法。

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.