Parthenon Therapeutics, Boston, Massachusetts, USA
Consultant, Parthenon Therapeutics, Boston, Massachusetts, USA.
J Immunother Cancer. 2023 Jun;11(6). doi: 10.1136/jitc-2023-006773.
Checkpoint inhibitors represent an effective treatment approach for a variety of cancers through their inhibition of immune regulatory pathways within the tumor microenvironment (TME). Unfortunately only a minority of patients with cancer achieve clinical benefit from immunotherapy, with the TME emerging as an important predictor of outcomes and sensitivity to therapy. The extent and pattern of T-cell infiltration can vary prominently within/across tumors and represents a biological continuum. Three immune profiles have been identified along this continuum: 'immune-desert' or 'T-cell cold' phenotype, 'immune-active', 'inflamed', or 'T-cell hot' phenotype, and 'immune excluded' phenotype. Of the three profiles, immune excluded remains the most ill-defined with no clear, universally accepted definition even though it is commonly associated with lack of response to immune checkpoint inhibitors and poor clinical outcomes. To address this, 16 multidisciplinary cancer experts from around the world were invited to participate in a symposium using a three-round modified Delphi approach. The first round was an open-ended questionnaire distributed via email and the second was an in-person discussion of the first round results that allowed for statements to be revised as necessary to achieve a maximum consensus (75% agreement) among the rating committee (RC). The final round questionnaire was distributed to the RC via email and had a 100% completion rate. The Delphi process resulted in moving us closer to a consensus definition for immune exclusion that is practical, clinically pertinent, and applicable across a wide range of cancer histologies. A general consensus of the role of immune exclusion in resistance to checkpoint therapy and five research priorities emerged from this process. Together, these tools could help efforts designed to address the underlying mechanisms of immune exclusion that span cancer types and, ultimately, aid in the development of treatments to target these mechanisms to improve patient outcomes.
检查点抑制剂通过抑制肿瘤微环境 (TME) 中的免疫调节途径，代表了一种针对多种癌症的有效治疗方法。不幸的是，只有少数癌症患者从免疫疗法中获得临床获益，TME 成为结局和对治疗敏感性的重要预测因素。T 细胞浸润的程度和模式在肿瘤内/间可能有很大差异，代表了一个生物学连续体。沿着这个连续体已经确定了三种免疫特征：“免疫荒漠”或“T 细胞冷”表型、“免疫活跃”、“炎症”或“T 细胞热”表型，以及“免疫排斥”表型。在这三种表型中，免疫排斥仍然是最不明确的，即使它通常与缺乏对免疫检查点抑制剂的反应和不良临床结局相关，但仍没有明确的、普遍接受的定义。为了解决这个问题，来自世界各地的 16 名多学科癌症专家应邀参加了一次研讨会，采用三轮改良 Delphi 方法。第一轮是通过电子邮件分发的开放式问卷，第二轮是对第一轮结果进行面对面讨论，以便在必要时对陈述进行修订，以实现评分委员会 (RC) 之间的最大共识 (75%的一致性)。最后一轮问卷通过电子邮件分发给 RC，并达到了 100%的完成率。德尔菲过程使我们更接近于一个实用的、临床相关的、适用于广泛癌症组织学的免疫排斥共识定义。这一过程产生了对免疫排斥在抵抗检查点治疗中的作用的普遍共识，以及五个研究重点。这些工具共同作用，可以帮助努力解决跨越癌症类型的免疫排斥的潜在机制，并最终有助于开发针对这些机制的治疗方法，以改善患者的治疗效果。
