Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer.
Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer.
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DOI：
10.1136/jitc-2020-002254
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发表时间：
2021-05
影响因子：
10.9
通讯作者：
Fong L
中科院分区：
文献类型：
--
作者：
Sinha M;Zhang L;Subudhi S;Chen B;Marquez J;Liu EV;Allaire K;Cheung A;Ng S;Nguyen C;Friedlander TW;Aggarwal R;Spitzer M;Allison JP;Small EJ;Sharma P;Fong L
SiPuleucel-T是美国食品和药物管理局批准的一种自体细胞免疫疗法，可提高转移性去势抵抗前列腺癌(MCRPC)患者的生存率。我们研究了在西普鲁尔-T治疗后应用ipilimumab是否可以改变对该治疗的免疫和/或临床反应。共有50名mCRPC患者参加了一项临床试验(NCT01804465，ClinicalTrials.gov)，他们在完成siPuleucel-T治疗后立即或推迟3周接受ipilimumab治疗。在研究的不同时间点采集了血液。分别用Luminex法检测抗前列腺酸性磷酸酶(PAP)和抗PA2024特异性血清免疫球蛋白G(Ig G)，用ELISpot检测抗PAP和PA2024产生干扰素-γ(干扰素-γ)，以评估抗原特异性B细胞和T细胞应答。临床反应被定义为血清前列腺特异性抗原水平与治疗前水平相比下降30%。通过飞行时间分析和统计支架分析，用质量细胞仪测定循环免疫细胞的频率和状态。我们发现这种组合耐受性良好，没有发生意想不到的不良事件。Ipilimumab的使用时间没有显著改变抗原特异性B细胞和T细胞反应率，这是临床试验的主要终点。50例患者中有6例出现临床反应，其中3例持续3个月以上。Ipilimumab的使用时机与临床反应或毒性没有显著相关性。联合治疗确实诱导了CD4和CD8T细胞的激活，这在直接的时间表中最为明显。即使在治疗前，CTLA-4阳性循环T细胞的频率较低也与较好的临床结果相关。有趣的是，CTLA-4表达的这些差异与先前对前列腺或前列腺窝进行局部放射治疗(RT)有关。既往的放射治疗也与提高放射学无进展存活率有关。CTLA-4阻滞剂与西普鲁尔-T联合应用可产生适度的临床活动。阻断CTLA-4的时机不会改变抗原特异性反应。临床反应与表达CTLA-4的T细胞较低的基线频率和RT病史有关。因此，先前的癌症治疗可能会导致长期的免疫变化，从而影响对西普鲁切尔-T和抗CTLA-4免疫治疗的反应性。
Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment. A total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis. We found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival. Combining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.
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影响因子：
64.5
作者：
Levine JH;Simonds EF;Bendall SC;Davis KL;Amir el-AD;Tadmor MD;Litvin O;Fienberg HG;Jager A;Zunder ER;Finck R;Gedman AL;Radtke I;Downing JR;Pe'er D;Nolan GP
通讯作者：
Nolan GP
影响因子：
158.5
作者：
Kantoff, Philip W.;Higano, Celestia S.;Young, J.
通讯作者：
Young, J.
影响因子：
20.3
作者：
Kavanagh, Brian;O'Brien, Shaun;Fong, Lawrence
通讯作者：
Fong, Lawrence
影响因子：
82.9
作者：
Formenti SC;Rudqvist NP;Golden E;Cooper B;Wennerberg E;Lhuillier C;Vanpouille-Box C;Friedman K;Ferrari de Andrade L;Wucherpfennig KW;Heguy A;Imai N;Gnjatic S;Emerson RO;Zhou XK;Zhang T;Chachoua A;Demaria S
通讯作者：
Demaria S
影响因子：
23.4
作者：
Fizazi K;Drake CG;Beer TM;Kwon ED;Scher HI;Gerritsen WR;Bossi A;den Eertwegh AJMV;Krainer M;Houede N;Santos R;Mahammedi H;Ng S;Danielli R;Franke FA;Sundar S;Agarwal N;Bergman AM;Ciuleanu TE;Korbenfeld E;Sengeløv L;Hansen S;McHenry MB;Chen A;Logothetis C;CA184-043, Investigators
通讯作者：
CA184-043, Investigators