Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer
Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer
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DOI：
10.1126/scitranslmed.aaz3577
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发表时间：
2020-04-01
影响因子：
17.1
通讯作者：
Sharma, Padmanee
中科院分区：
文献类型：
--
作者：
Subudhi, Sumit K.;Vence, Luis;Sharma, Padmanee
高突变负荷(TMB)的肿瘤往往对免疫检查点阻断(ICB)有反应，因为有新的抗原可供活化的T细胞靶向，而低TMB的肿瘤表现出有限的临床反应。为了确定ICB治疗后是否可以在TMB低的癌症患者中激发抗原特异性T细胞反应，我们对30名转移性去势抵抗前列腺癌患者进行了伊普利单抗的临床试验。我们通过生存和进展时间确定了两个不同的队列：“有利”(n=9)和“不利”(n=10)。有利队列中的患者有较高的肿瘤内CD8 T细胞密度和干扰素-γ反应基因特征和/或抗原特异性T细胞反应。两名TMB相对较低的患者对独特的新抗原有T细胞应答。此外，在分析时，有利组的9名患者中有6名仍然活着，治疗后存活期从33个月到54个月不等。在不利的队列中，所有10名患者都死于自己的疾病，存活时间从0.6个月到10.3个月不等。总之，我们的数据表明，在从ICB受益的转移性前列腺癌患者中，观察到了与效应T细胞反应相关的免疫学相关性。
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" (n = 9) and "unfavorable" (n = 10). Patients in the favorable cohort had high intratumoral CD8 T cell density and IFN-gamma 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.