T cell receptor gene therapy of cancer

免疫性T细胞转移在其他疗法中脱颖而出，能够根除大型和长期存在的人类癌症，即使它们不再能通过手术治愈。最近的临床经验支持突变特异性T细胞在抑制T细胞检查点或使用肿瘤浸润淋巴细胞的过继治疗在治疗上有效时用于癌症免疫治疗的重要性。不幸的是，迄今为止，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非活性状态。为了克服这一缺点，我们提出将编码突变特异性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，因此在每种癌症中都发现了突变抗原，为治疗干预提供了恒定的T细胞靶点来源-称为TCR基因治疗。本提案的长期目标是确定选择突变特异性TCR的基本标准和方法，其将有效用于临床TCR基因治疗，从而克服当前的命中或失误方法。目的1集中于受TCR亲和力影响并决定TCR工程化T细胞的体内功能的参数的定义。目标2中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TCR的可靠来源，或者突变特异性TCR是否必须从无抗原环境中分离以实现高治疗功效。本申请中的所有实验将集中于人TCR和人肿瘤抗原，最终目标是鉴定用于临床应用的TCR。

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.