CMVpp65 疫苗增强CD19修饰的CMV特异性T细胞抗肿瘤能力的研究 - 中国病毒学论坛|我们一直在坚持！

CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19-Redirected CMV-Specific T Cells.

T cells engineered with chimeric antigen receptors (CAR) recognizing CD19 can induce complete remission of B-cell malignancies in clinical trials; however, in some disease settings, CAR therapy confers only modest clinical benefit due to attenuated persistence of CAR T cells. The purpose of this study was to enhance persistence and augment the antitumor activity of adoptively transferred CD19CAR T cells by restimulating CAR(+) T cells through an endogenous cytomegalovirus (CMV)-specific T-cell receptor.

CMV-specific T cells from CMV seropositive healthy donors were selected after stimulation with pp65 protein and transduced with clinical-grade lentivirus expressing the CD19R:CD28:ζ/EGFRt CAR. The resultant bispecific T cells, targeting CMV and CD19, were expanded via CD19 CAR-mediated signals using CD19-expressing cells.

The bispecific T cells proliferated vigorously after engagement with either endogenous CMVpp65 T-cell receptors or engineered CD19 CARs, exhibiting specific cytolytic activity and IFNγ secretion. Upon adoptive transfer into immunodeficient mice bearing human lymphomas, the bispecific T cells exhibited proliferative response and enhanced antitumor activity following CMVpp65 peptide vaccine administration.

We have redirected CMV-specific T cells to recognize and lyse tumor cells via CD19CARs, while maintaining their ability to proliferate in response to CMV antigen stimulation. These results illustrate the clinical applications of CMV vaccine to augment the antitumor activity of adoptively transferred CD19CAR T cells in patients with B-cell malignancies.

靶向CD19嵌合抗原受体修饰的T细胞技术在临床试验中能够对B细胞淋巴细胞白血病患者有完全的缓解率。然而，在一些其他疾病中，由于CAR-T细胞持续性的衰减作用，只能带来较少的临床效应。这项研究的目的是通过内源性巨细胞病毒特异性T细胞受体再刺激CAR+ T细胞，从而提高持久性和CD19 CAR- T细胞抗肿瘤活性。

筛选CMV血清阳性健康供者的CMV 特异性T细胞，使用pp65蛋白刺激，后使用临床级别的慢病毒转导使其表达CD19R:CD28:ζ/EGFRt CAR。获得的双特异性T细胞，靶向CMV和CD19，通过CD19 CAR介导信号,从而能够得到扩增。

内源性CMVpp65 T细胞受体或者是修饰后CD19—CAR处理后，双特异性T细胞能够迅速的扩增，具有特异性杀伤活性和分泌IFN-γ。在过继转移到负荷人淋巴瘤的免疫缺陷小鼠模型后，双特异性T细胞展现了强大的反应，并且在CMVpp65 多肽疫苗处理后抗肿瘤活性得到增强。

我们通过CD19 CARs重新诱导CMV-特异性T细胞识别和溶解肿瘤病毒，对于CMV抗原的刺激，它们的增殖活性得以保持。这些结果显示CMV疫苗在临床上的应用，能够增加CD19 CAR-T细胞在B细胞淋巴细胞白血病患者中取得更好的抗肿瘤效果。