Treos Bio Ltd., London W1W6XB, UK.
Treos Bio Zrt, 8200 Veszprém, Hungary.
Cells. 2021 Nov 5;10(11):3048. doi: 10.3390/cells10113048.
Over 30 years after the first cancer vaccine clinical trial (CT), scientists still search the missing link between immunogenicity and clinical responses. A predictor able to estimate the outcome of cancer vaccine CTs would greatly benefit vaccine development. Published results of 94 CTs with 64 therapeutic vaccines were collected. We found that preselection of CT subjects based on a single matching HLA allele does not increase immune response rates (IRR) compared with non-preselected CTs (median 60% vs. 57%, = 0.4490). A representative in silico model population (MP) comprising HLA-genotyped subjects was used to retrospectively calculate in silico IRRs of CTs based on the percentage of MP-subjects having epitope(s) predicted to bind ≥ 1-4 autologous HLA allele(s). We found that in vitro measured IRRs correlated with the frequency of predicted multiple autologous allele-binding epitopes (AUC 0.63-0.79). Subgroup analysis of multi-antigen targeting vaccine CTs revealed correlation between clinical response rates (CRRs) and predicted multi-epitope IRRs when HLA threshold was ≥ 3 ( = 0.7463, = 0.0004) but not for single HLA allele-binding epitopes ( = 0.2865, = 0.2491). Our results suggest that CRR depends on the induction of broad T-cell responses and both IRR and CRR can be predicted when epitopes binding to multiple autologous HLAs are considered.
在首次癌症疫苗临床试验 (CT) 开展 30 多年后，科学家们仍在探寻免疫原性和临床反应之间缺失的联系。如果有一种能够预测癌症疫苗 CT 结果的方法，将极大地促进疫苗的开发。我们收集了 94 项含 64 种治疗性疫苗的 CT 研究的已发表结果。我们发现，与非预选 CT 相比，基于单一匹配 HLA 等位基因对 CT 受试者进行预选并不能提高免疫反应率 (IRR)（中位数分别为 60%和 57%， = 0.4490）。使用包含 HLA 基因分型受试者的代表性计算模型人群 (MP)，根据预测与≥1-4 个自体 HLA 等位基因结合的表位的 MP 受试者的百分比，回顾性计算 CT 的计算 IRR。我们发现，体外测量的 IRR 与预测的多个自体等位基因结合表位的频率相关（AUC 为 0.63-0.79）。对多抗原靶向疫苗 CT 的亚组分析表明，当 HLA 阈值≥3 时，临床反应率 (CRR) 与预测的多表位 IRR 相关（ = 0.7463， = 0.0004），而与单个 HLA 等位基因结合表位无关（ = 0.2865， = 0.2491）。我们的结果表明，CRR 取决于广谱 T 细胞反应的诱导，当考虑到与多个自体 HLA 结合的表位时，可以预测 IRR 和 CRR。
