一个磨蹭很久的PD-1+TGFβ combo / 四六文摘

诺华的PDR001+NIS793组合

PDR001/spartalizumab: A humanized monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1), with immune checkpoint inhibitory and antineoplastic activities. Upon administration, spartalizumab binds to PD-1 expressed on activated T-cells and blocks the interaction with its ligands, programmed cell death 1 ligand 1 (PD-L1, PD-1L1) and PD-1 ligand 2 (PD-L2, PD-1L2). The inhibition of ligand binding prevents PD-1-mediated signaling and results in both T-cell activation and the induction of T-cell-mediated immune responses against tumor cells. PD-1, an immunoglobulin (Ig) superfamily transmembrane protein and inhibitory receptor, negatively regulates T-cell activation.

anti-TGF-beta monoclonal antibody NIS793: A monoclonal antibody directed against human transforming growth factor beta (TGF-beta), with potential antineoplastic activity. Anti-TGF-beta monoclonal antibody NIS793 specifically targets and binds to TGF-beta, thereby preventing the activation of TGF-beta-mediated signaling pathways. TGF-beta, a pro-inflammatory mediator that is mutated and/or overexpressed in a number of cancer cell types, is involved in cancer cell proliferation and migration, and tumor progression.

NIS793来自Xoma授权，以前代码XOMA089，15年10月全球权益授权给诺华

Preclinical data have shown that XOMA089 displays activity against tumor growth in preclinical models of squamous cell head and neck carcinoma and breast cancer (BC). Animal data also suggested that XOMA089 might be synergistic with PD-1 inhibition.

说个题外话，至少在PD-L1+TGFβ的体内实验中，Y-Trap形式比PD-L1+TGFβRII两个分开效果要显著，可能因为有研究显示TGFβ升高是TME针对检查点阻断的应答之一，所以不管是动物模型还是人的试验，TGFβ mono都不会有效；而在PD-L1 mAb上连接结合TGFβ的片段可以更精准的在TME中消除这种免疫抑制，也是Y Trap相比PD-L1+TGFβRII分开的优势。

Y Trap中，现在大家的注意力都在TGFβ上，但是决定efficacy的首要因素应该还是α-PD-L1，毕竟是primary MOA，下图中在接种了TNBC (MDA-MB-231-Luc)的小鼠中也体现了一丝差异的趋势，当然只是一丝。

言归正传：

Phase I/Ib Study of NIS793 in Combination With PDR001 in Patients With Advanced Malignancies.

为什么NIS793还会单独一组?之前XOMA 089似乎没做过临床，看下安全性、PK、PD之类，疗效应该不指望了

再看下入排：扩张阶段只有NSCLC和ccRCC要求对anti-PD-1/PD-L1z治疗抵抗

Escalation: Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by RECIST version 1.1 who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists.

Expansion: Patients with advanced/metastatic solid tumors, with at least one measurable lesion as determined by RECIST version 1.1, who have progressed despite standard therapy following their last prior therapy or are intolerant to standard therapy and fit into one of the following groups: Group 1: NSCLC resistant to anti-PD-1/PD-L1; Group 2: TNBC; Group 3: HCC; Group 4: MSS-CRC; Group 5: pancreatic; Group 6 ccRCC resistant to anti-PD-1/PD-L1.

Resistance to anti-PD-1/PD-L1 therapy is defined as: Documented progressive disease occurring while on/or within 6 months after anti-PD-1 and/or anti-PD-L1 agent (single or combination) received as the last therapy prior to enrollment.

现在这个时代有这种组合倒不新奇，主要是这个研究16年10月份就登记了

一直在磨蹭

https://clinicaltrials.gov/ct2/history/NCT02947165?A=1&B=10&C=Side-by-Side#StudyPageTop