BACKGROUND It is widely hoped that personal cancer vaccines will extend the number of patients benefiting from checkpoint and other immunotherapies. However, it is clear creating such vaccines will be challenging. It requires obtaining and sequencing tumor DNA/RNA, predicting potentially immunogenic neoepitopes and manufacturing a one-use vaccine. This process takes time and considerable cost. Importantly, most mutations will not produce an immunogenic peptide and many patient's tumors do not contain enough DNA mutations to make a vaccine. We have discovered that frameshift peptides (FSP) created from errors in the production of RNA rather than from DNA mutations are potentially a rich source of neoantigens for cancer vaccines. These errors are predictable, enabling the production of a FSP microarray. Previously we found that these microarrays can identify both personal and shared neoantigens. Here, we compared the performance of personal cancer vaccines (PCVs) with that of a shared antigen vaccine, termed Frameshift Antigen Shared Therapeutic (FAST) vaccine, using the 4 T1 breast cancer model. Sera from 4 T1-tumor bearing mice were assayed on the peptide microarray containing 200 Fs neoantigens, for the PCV, the top 10 candidates were select and personal vaccines constructed and administrated to the respective mice. For the FAST, we selected the top 10 candidates with higher prevalence among all the mice challenged. Seven to 12 days challenged mice were immunized, combined or not with immune checkpoint inhibitor (ICI) (αPD-L1 and αCTLA-4). Primary and secondary tumor clearance and growth were evaluated as well as cellular and humoral immune response against the vaccine targets by IFN-γ ELISPOT and ELISA. Lastly, we analyzed the immune response of the FAST-vaccinated mice by flow cytometry in comparison to the control group. RESULTS We found that PCVs and FAST vaccines both reduced primary tumor incidence and growth as well as lung metastases when delivered as monotherapies or in combination with ICI. Additionally, the FAST vaccine induces a robust and effective T-cell response. CONCLUSIONS These results suggest that FSPs produced from RNA-based errors are potent neoantigens that could enable production of off-the-shelf shared antigen vaccines for solid tumors with efficacy comparable to that of PCVs.

中文翻译：

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小鼠乳腺癌模型中个人和共享移码新抗原疫苗的比较。

背景技术人们广泛希望，个人癌症疫苗将扩大受益于检查站和其他免疫疗法的患者数量。但是，很显然，创建此类疫苗将具有挑战性。它需要获得肿瘤DNA / RNA并对其进行测序，预测可能具有免疫原性的新表位，并制造一种一次性疫苗。此过程需要时间和大量成本。重要的是，大多数突变不会产生免疫原性肽，而且许多患者的肿瘤都没有足够的DNA突变来制备疫苗。我们已经发现，由于RNA产生错误而不是DNA突变产生的移码肽（FSP）可能是癌症疫苗新抗原的丰富来源。这些错误是可以预测的，从而可以生产FSP微阵列。以前，我们发现这些微阵列可以识别个人和共享的新抗原。在这里，我们使用4 T1乳腺癌模型比较了个人癌症疫苗（PCV）和共享抗原疫苗（称为移码抗原共享治疗（FAST）疫苗）的性能。在含有200 Fs新抗原的肽微阵列上分析了来自4只具有T1肿瘤的小鼠的血清，对于PCV，选择了前10名候选者，并构建了个人疫苗并将其施用于相应的小鼠。对于FAST，我们在所有受攻击的小鼠中选择了患病率最高的前10名候选者。免疫攻击的小鼠7至12天，或不与免疫检查点抑制剂（ICI）（αPD-L1和αCTLA-4）结合。通过IFN-γELISPOT和ELISA评估了原发和继发肿瘤的清除和生长以及针对疫苗靶标的细胞和体液免疫反应。最后，与对照组相比，我们通过流式细胞术分析了FAST疫苗接种小鼠的免疫反应。结果我们发现PCV和FAST疫苗作为单一疗法或与ICI联合使用时，均可降低原发性肿瘤的发生率和生长以及肺转移。此外，FAST疫苗可诱导强大而有效的T细胞反应。结论这些结果表明，由基于RNA的错误产生的FSP是有效的新抗原，可用于生产实体瘤的现成共享抗原疫苗，其功效可与PCV媲美。与对照组相比，我们通过流式细胞术分析了FAST疫苗接种小鼠的免疫反应。结果我们发现PCV和FAST疫苗作为单一疗法或与ICI联合使用时，均可降低原发性肿瘤的发生率和生长以及肺转移。此外，FAST疫苗可诱导强大而有效的T细胞反应。结论这些结果表明，由基于RNA的错误产生的FSP是有效的新抗原，可以使实体瘤的现成共享抗原疫苗的生产与PCV相当。与对照组相比，我们通过流式细胞术分析了FAST疫苗接种小鼠的免疫反应。结果我们发现PCV和FAST疫苗作为单一疗法或与ICI联合使用时，均可降低原发性肿瘤的发生率和生长以及肺转移。此外，FAST疫苗可诱导强大而有效的T细胞反应。结论这些结果表明，由基于RNA的错误产生的FSP是有效的新抗原，可用于生产实体瘤的现成共享抗原疫苗，其功效可与PCV媲美。结果我们发现PCV和FAST疫苗作为单一疗法或与ICI联合使用时，均可降低原发性肿瘤的发生率和生长以及肺转移。此外，FAST疫苗可诱导强大而有效的T细胞反应。结论这些结果表明，由基于RNA的错误产生的FSP是有效的新抗原，可用于生产实体瘤的现成共享抗原疫苗，其功效可与PCV媲美。结果我们发现PCV和FAST疫苗作为单一疗法或与ICI联合使用时，均可降低原发性肿瘤的发生率和生长以及肺转移。此外，FAST疫苗可诱导强大而有效的T细胞反应。结论这些结果表明，由基于RNA的错误产生的FSP是有效的新抗原，可用于生产实体瘤的现成共享抗原疫苗，其功效可与PCV媲美。