Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
Department of Biology, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
Cancer Immunol Immunother. 2021 Nov;70(11):3183-3197. doi: 10.1007/s00262-021-02912-9. Epub 2021 Apr 1.
There is a growing interest in the use of patient-derived T cells for the treatment of various types of malignancies. The expansion of a polyclonal and polyspecific population of tumor-reactive T cells, with a subsequent infusion into the same donor patient, has been implemented, sometimes with positive results. It is not known, however, whether a set of T cells with a single antigen specificity may be sufficient for an effective therapy. To gain more insights in this matter, we used naturally occurring T cells recognizing a retroviral peptide (AH1), which is endogenous in many tumor cell lines of BALB/c origin and which serves as potent tumor rejection antigen. We were able to isolate and expand this rare population of T cells to numbers suitable for therapy experiments in mice (i.e., up to 30 × 10 cells/mouse). After the expansion process, T cells efficiently killed antigen-positive tumor cells in vitro and demonstrated tumor growth inhibition in two syngeneic murine models of cancer. However, AH1-specific T cells failed to induce complete regressions of established tumors. The incomplete activity was associated with a failure of injected T cells to survive in vivo, as only a very limited amount of T cells was found in tumor or secondary lymphoid organs 72 h after injection. These data suggest that future therapeutic strategies based on autologous T cells may require the potentiation of tumor-homing and survival properties of cancer-specific T cells.
人们越来越关注利用患者来源的 T 细胞治疗各种类型的恶性肿瘤。已经实施了扩增多克隆和多特异性肿瘤反应性 T 细胞群体，然后将其输注回同一供体患者中，有时会取得阳性结果。然而，尚不清楚是否具有单一抗原特异性的一组 T 细胞就足以进行有效的治疗。为了更深入地了解这一问题，我们使用了识别逆转录病毒肽 (AH1) 的天然存在的 T 细胞，该肽在许多源自 BALB/c 的肿瘤细胞系中内源性存在，并且是有效的肿瘤排斥抗原。我们能够分离和扩增这种稀有 T 细胞群体，使其数量适合在小鼠中进行治疗实验（即，每只小鼠高达 30×10 个细胞）。在扩增过程之后，T 细胞在体外有效地杀死了抗原阳性的肿瘤细胞，并在两种同源的小鼠癌症模型中显示出肿瘤生长抑制作用。然而，AH1 特异性 T 细胞未能诱导已建立的肿瘤完全消退。不完全的活性与注入的 T 细胞在体内无法存活有关，因为在注入后 72 小时，仅在肿瘤或次级淋巴器官中发现非常有限数量的 T 细胞。这些数据表明，基于自体 T 细胞的未来治疗策略可能需要增强肿瘤归巢和癌症特异性 T 细胞的存活特性。
