多塔利单抗（dostarlimab）在标准治疗根治性放疗基础上用于医学上无法手术的子宫内膜癌患者的外周免疫特征

Upfront surgical staging is considered standard of care for patients with localized endometrial cancer. However, for patients with significant comorbidities surgery may be high risk or inadvisable. These patients can undergo definitive radiation therapy (RT) delivered with brachytherapy (BT) with or without external beam RT (EBRT). The tolerability and potential benefit of immunotherapy in this patient cohort is unknown. We performed a prospective Phase I trial of dostarlimab in conjunction with definitive RT for patients with medically inoperable endometrial cancer. Ten patients were enrolled. Dostarlimab was administered three weeks prior to the start of RT and then concurrently with RT for three cycles. Here we report the dynamics of circulating immune profiles to identify potential treatment-predictive biomarkers. Longitudinal analysis of paired peripheral blood mass cytometry (CyTOF) and soluble protein analytes (ELISA) was performed at baseline, on- and post-treatment timepoints. One cycle of neoadjuvant dostarlimab prior to RT was associated with increased serum type I interferon-induced chemokines (CXCL9, CXCL10, CXCL11) and IL-2 family cytokines (IL15, IL21), pivotal for immune cell activation and adaptive immune response. While the abundance of T cell populations in PBMCs remained mostly unchanged, effector memory CD4 and CD8 T cells had increased expression of Ki-67 and granzyme B, indicating a proliferative and cytotoxic phenotype. Initiation of RT was associated with multiple changes in plasma protein analytes including further increases in CXCL9/10, upregulation in inflammatory cytokines IL-1 and TNF, as well as cytokines with tumor-promoting potential CCL4, CCL7, and G-CSF. T cells expressing granzyme B and activation markers (CD38, HLA-DR) remained elevated, indicating sustained functional potential. CD11c+ DCs, monocytes, and Treg cells were also increased after RT. Notably, patients treated with BT+EBRT (n=3) compared to those with BT (n=7) had higher increase in DCs and monocytes as well as overall changes in cytokine expression during treatments, such as increased IL4 and IL10 associated with T cell function and decreased CCL2 and CXCL13. At 6-week post-treatment, cytokines elevated from baseline persisted in patients treated with BT+EBRT while less variations in cytokine profiles were observed in the group without EBRT. Lastly, we observed a sustained decrease in PD-1+ T cells after 1 cycle of dostarlimab but an increased frequency of LAG-3+ or Tim-3+ T cells at cycle 2 and 3 of dostarlimab with RT. Taken together, the circulating immune profile demonstrated an association between the baseline and on-treatment immune activation signature with dostarlimab in addition to RT, highlighting the potential of this combination regimen to enhance therapeutic efficacy in patients with inoperable endometrial cancer.