我一个做抗体的为什么对CAR-T，TCR-T保持这么热切的关注，答案很简单，因为它们遇到的问题很多地方都相通。入正题。今天来讲这篇文章，“Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity”，发表于《Nature Immunology》。CAR-T目前对实体瘤仍然收效甚微。Although CAR T cell therapy has achieved remarkable clinical efficacy in the treatment of various B cell malignancies, its effectiveness has yet to be successfully recapitulated in solid cancers. This has been attributed to a number of factors, including the immunosuppressive tumor microenvironment, insufficient infiltration of tumors by CAR T cells and tumor antigen heterogeneity.增加一个分泌表达元件，在CAR-T研究中，很是常见，但对于DC细胞方面的关注，却寥寥无几。Whilst these studies have highlighted the importance of engaging antigen-presenting cells (APCs) in engendering host antitumor immunity, none of these approaches have investigated the potential of directly promoting the local proliferation and differentiation of a specialized cross-presenting DC subset, designated conventionaltype 1 DC (cDC1), as a way to promote endogenous antitumor T cell epitope spreading and enhance the overall efficacy of CAR T cells in solid tumors.Given that Flt3L is a critical growth factor for DCs6, we hypothesized that armored T cells engineered to secrete Flt3L can overcome tumor heterogeneity by expanding intratumoral cDC1s that activate endogenous T cell responses, resulting in the induction of epitope spreading.目前，Flt3L融合蛋白，已经有几家在做。感兴趣的可以去看一下。Celldex Therapeutics的CDX-301，就是Flt3L融合蛋白。
主要管线：
Flt3L drives DC proliferation and T cell–dependent rejection of solid tumors.首先验证了Flt3L能够抑制了肿瘤的生长。如图。To study the role of Flt3L in tumor progression, we first engineered murine sarcoma 24JK-Her2 and colon adenocarcinoma MC38 cells to stably express Flt3L (24JK-Her2 Cherry FL and MC38 Cherry FL)
MC38 Cherry FL 图略。很明显的抑瘤效果。Flt3L-secreting CAR T cells and immune adjuvants induce host T cell responses towards non-CAR antigens.结果如图。
注：PIC，即poly (I:C)，一种干扰素诱导剂。别名聚肌胞苷酸，聚肌苷酸，聚胞苷酸，是双链RNA的类似物，一条链是ploy（I），另一条链是poly（C），体内细胞在聚肌胞苷酸诱导下产生干扰素，故有广谱抗病毒和免疫调节功能，用于病毒感染性疾病和肿瘤的辅助治疗。相比起来，效果确实较为明显。Combination of Flt3L-secreting CAR T cells and adjuvants induces host T cell epitope spreading.结果依旧如图。
In this setting, anti-Her2 CAR T cells can effectively target E0771-OVA-Her2 but not E0771-OVA cells lacking the Her2 antigen. Indeed, Flt3L-secreting CAR T cells plus adjuvants exhibited significantly enhanced tumor growth inhibition compared with control CAR T cells, suggesting the development of antitumor responses against Her2-negative tumor cells.效果确实不错。看到联用了anti-41BB，是不是有点想法呢？To determine whether treatment with Flt3L-secreting CAR T cells plus adjuvants generated long-term host memory antitumor responses towards antigens beyond Her2 and OVA, we performed contralateral secondary rechallenge using parental lines lacking both antigens. Indeed, rechallenged mice displayed significantly enhanced tumor growth inhibition compared with naive controls, indicating the presence of host memory antitumor responses recognizing non-Her2 antigens.如图。
作者总结陈词，Whilst Flt3L alone was sufficient to mediate the regression of early-stage tumors, additional adjuvants were required for larger, more established tumors. This suggests that early triggering of host immunity is critical, and approaches that enhance intratumoral Flt3L levels, through stronger promoters, codon optimization or increasing local T cell numbers, may altogether engender a more effective antitumor response. Indeed, local CAR T cell delivery may provide an advantage in solid cancers by circumventing the issue of limited trafficking. As our strategy relies upon local proliferation and activation of DCs, further studies will investigate whether intratumoral delivery of Flt3L-secreting CAR T cells can enhance therapeutic responses.
