Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
StemiRNA Therapeutics Inc., Shanghai, China.
Sci Adv. 2024 Oct 11;10(41):eadn9961. doi: 10.1126/sciadv.adn9961.
mRNA neoantigen cancer vaccine inducing neoantigen-specific T cell responses holds great promise for cancer immunotherapy; however, its clinical translation remains challenging because of suboptimal neoantigen prediction accuracy and low delivery efficiency, which compromise the in vivo therapeutic efficacy. We present a lipopolyplex (LPP)-formulated mRNA cancer vaccine encoding tandem neoantigens as a cancer therapeutic regimen. The LPP-formulated mRNA vaccines elicited robust neoantigen-specific CD8 T cell responses in three syngeneic murine tumor models (CT26, MC38, and B16F10) to suppress tumor growth. Prophylactic cancer vaccine treatment completely prevented tumor development, and long-lasting memory T cells protected mice from tumor cell rechallenge. Combining the vaccine with immune checkpoint inhibitor further boosted the antitumor activity. Of note, LPP-based personalized cancer vaccine was administered in two cancer patients and induced meaningful neoantigen-specific T cell and clinical responses. In conclusion, we demonstrated that the LPP-based mRNA vaccine can elicit strong antitumor immune responses, and the results support further clinical evaluation of the therapeutic mRNA cancer vaccine.
mRNA 肿瘤新生抗原疫苗能够诱导肿瘤新生抗原特异性 T 细胞反应，在癌症免疫治疗中具有广阔的应用前景；然而，由于新生抗原预测准确性差和递呈效率低，其临床转化仍然具有挑战性，这会影响体内治疗效果。我们提出了一种以脂多聚体（LPP）为载体的 mRNA 肿瘤疫苗，该疫苗编码串联肿瘤新生抗原，作为一种癌症治疗方案。LPP 配方的 mRNA 疫苗在三种同种异体小鼠肿瘤模型（CT26、MC38 和 B16F10）中引发了强烈的肿瘤新生抗原特异性 CD8 T 细胞反应，从而抑制肿瘤生长。预防性癌症疫苗治疗可完全阻止肿瘤的发生，而持久的记忆 T 细胞可保护小鼠免受肿瘤细胞再攻击。将疫苗与免疫检查点抑制剂联合使用可进一步增强抗肿瘤活性。值得注意的是，我们在两名癌症患者中使用了基于 LPP 的个体化癌症疫苗，并诱导了有意义的肿瘤新生抗原特异性 T 细胞和临床反应。总之，我们证明了基于 LPP 的 mRNA 疫苗可以引发强烈的抗肿瘤免疫反应，这些结果支持进一步对治疗性 mRNA 癌症疫苗进行临床评估。
