Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Transl Med. 2020 Apr 1;12(537). doi: 10.1126/scitranslmed.aaz3577.
Tumors with high mutational burden (TMB) tend to be responsive to immune checkpoint blockade (ICB) because there are neoantigens available for targeting by reinvigorated T cells, whereas those with low TMB demonstrate limited clinical responses. To determine whether antigen-specific T cell responses can be elicited after treatment with ICB in cancers that have a low TMB, we conducted a clinical trial with ipilimumab in 30 patients with metastatic castration-resistant prostate cancer. We identified two distinct cohorts by survival and progression times: "favorable" ( = 9) and "unfavorable" ( = 10). Patients in the favorable cohort had high intratumoral CD8 T cell density and IFN-γ response gene signature and/or antigen-specific T cell responses. Two patients with a relatively low TMB had T cell responses against unique neoantigens. Moreover, six of nine patients in the favorable group are still alive at the time of analysis, with survival ranging from 33 to 54 months after treatment. All 10 patients in the unfavorable cohort have succumbed to their disease and had survival ranging from 0.6 to 10.3 months. Collectively, our data indicate that immunological correlates associated with effector T cell responses are observed in patients with metastatic prostate cancer who benefit from ICB.
高突变负担（TMB）的肿瘤往往对免疫检查点阻断（ICB）有反应，因为有新抗原可供重新激活的 T 细胞靶向，而 TMB 低的肿瘤则表现出有限的临床反应。为了确定在 TMB 低的癌症中接受 ICB 治疗后是否可以引发抗原特异性 T 细胞反应，我们对 30 名转移性去势抵抗性前列腺癌患者进行了伊匹单抗临床试验。我们根据生存和进展时间确定了两个不同的队列：“有利”（=9）和“不利”（=10）。有利队列的患者肿瘤内 CD8 T 细胞密度高，IFN-γ 反应基因特征和/或抗原特异性 T 细胞反应高。两名 TMB 相对较低的患者对独特的新抗原产生了 T 细胞反应。此外，有利组的 9 名患者中有 6 名仍存活，治疗后生存时间从 33 个月到 54 个月不等。不利组的 10 名患者均死于疾病，生存时间从 0.6 个月到 10.3 个月不等。总的来说，我们的数据表明，在从 ICB 中获益的转移性前列腺癌患者中观察到与效应 T 细胞反应相关的免疫相关性。
