T cell receptor gene therapy of cancer

在其他疗法中，过继T细胞转移在能够根除大型和长期存在的人类癌症方面脱颖而出，即使它们不能再通过手术治愈。最近的临床经验支持，当抑制T细胞检查点或当使用肿瘤浸润性淋巴细胞的过继治疗在治疗上有效时，突变特异性T细胞对于癌症免疫治疗的重要性。不幸的是，到目前为止，这种免疫疗法的成功仅限于相对较少的病例。疗效可能是有限的，因为治疗通常依赖于刺激耐受性T细胞，这些细胞在短暂激活后恢复到不活跃状态。为了克服这一缺陷，我们建议将编码突变特异性T细胞受体(TCR)的基因转移到从患者外周血中分离出来的新鲜、无偏见的T细胞中，可以为过继治疗提供更有效的T细胞。突变通常是肿瘤发展的原因，因此在每一种癌症中都发现了突变抗原，为治疗干预提供了持续的T细胞靶点--被称为TCR基因治疗。这项建议的长期目标是确定选择突变特异性TCR的基本标准和方法，这些TCR将有效地用于临床TCR基因治疗，从而克服目前随机或未命中的方法。目的1重点介绍TCR亲和力影响和决定TCR工程T细胞体内功能的参数。AIM 2的实验将确定患者来源的T细胞是否可以用作突变特异性TCRs的可靠来源，或者是否必须从无抗原环境中分离突变特异性TCRs以实现高疗效。这一应用中的所有实验都将集中在人类TCRs和人类肿瘤抗原上，最终目标是识别TCRs用于临床应用。

Adoptive T cell transfer stands out among other therapies in being able to eradicate large and long-established human cancers even when they can no longer be cured surgically. Recent clinical experience supports the importance of mutation-specific T cells for cancer immunotherapy when inhibiting T cell checkpoints or when adoptive therapy using tumor-infiltrating lymphocytes was therapeutically effective. Unfortunately, the success of such immunotherapies has so far been restricted to relatively few cases. The efficacy might be limited because treatments often rely on stimulating tolerant T cells, which revert into an inactive state after transient activation. To circumvent this shortcoming, we propose that the transfer of genes encoding mutation-specific T cell receptors (TCRs) into fresh, unbiased T cells isolated from the patient`s peripheral blood could provide more effective T cells for adoptive therapy. Mutations are usually the cause of tumor development and mutant antigens are therefore found in every cancer, providing a constant source of T cell targets for therapeutic intervention - designated as TCR gene therapy. The long-term objective of this proposal is to identify the fundamental criteria and approaches to select mutation- specific TCRs that will be effective for clinical TCR gene therapy and thereby to overcome the current hit-or-miss approach. Aim 1 focuses on the definition of parameters that are impacted by TCR affinity and that determine the in vivo function of TCR-engineered T cells. Experiments in Aim 2 will determine whether patient-derived T cells can be used as reliable source for mutation-specific TCRs or whether mutation-specific TCRs must be isolated from antigen-free environments to achieve high therapeutic efficacy. All experiments in this application will focus on human TCRs and human tumor antigens with the ultimate goal to identify TCRs for clinical application.