医学
彭布罗利珠单抗
FOXP3型
免疫疗法
肿瘤微环境
内科学
肺癌
肿瘤科
免疫系统
癌症
免疫学
癌症研究
作者
Dirk G. Brockstedt,Adam Grant,Juraj Adamik,Damian Trujillo,Rakesh K. Goyal,William W. Ho,Shoji Ikeda,Qingfeng Zhu,Robert A. Anders,M. Sabouri,Paul D. Kassner
标识
DOI:10.1200/jco.2023.41.16_suppl.2625
摘要
2625 Background: FLX475 is a potent and selective CCR4 antagonist, designed to block the recruitment of immunosuppressive regulatory T cells (T reg ) into tumors without affecting healthy tissues. Blocking migration of T reg into the tumor microenvironment (TME) has the potential to restore antitumor immunity and synergize with a variety of conventional and immunotherapy-based approaches to overcome immune resistance and broaden clinical efficacy. In a recent interim clinical update from the ongoing FLX475-02 Phase 1/2 trial, evidence of monotherapy and combination activity were reported. FLX475 monotherapy induced complete responses in two of the six evaluable subjects enrolled with EBV+ NK/T cell lymphoma. In checkpoint inhibitor naïve non-small-cell lung cancer (NSCLC), 4/13 subjects (31%) had confirmed partial responses (PRs) following treatment with the combination of FLX475 and pembrolizumab. In this analysis we present biomarker data from patients with broad range of tumor types treated with FLX475 monotherapy. We provide evidence to substantiate the mechanism of action and support the combination of FLX475 with pembrolizumab. Methods: Flow cytometry was used to measure relative proportions of T reg in the periphery. CD8 and FOXP3 positive cells in tumor biopsies were quantified by immunohistochemistry (IHC).Gene set enrichment analysis and immune deconvolution methods were used to interrogate RNAseq data derived from tumor biopsies. Results: FLX475 monotherapy results in a small but significant increase in proportion of circulating CD25+CD127-/low CD4+ T reg by day 8 of treatment. IHC analysis revealed a trend towards increased CD8:FOXP3 ratio in the TME of patient biopsies. Transcriptomic profiles from tumor biopsies of FLX475 monotherapy treated patients exhibited significant changes in immune pathways likely to benefit the antitumor response. Using global gene expression analyses we identified that FLX475 monotherapy altered the transcriptome of tumors to resemble those from patients with favorable clinical outcome to anti-PD(L)-1 treatment. Consistent with the proposed mechanism of action, immune deconvolution identified that FLX475-treated patients experienced a decrease in T reg cell populations. Conclusions: FLX475 monotherapy results in beneficial changes in the TME consistent with our proposed mechanism of action. FLX475 monotherapy is modifying the tumor microenvironment toward a phenotype associated with response to anti-PD-1/anti-PD-L1. Clinical trial information: NCT03674567 .
科研通智能强力驱动
Strongly Powered by AbleSci AI