Project description:Interventions: 1 cycle is 21days. BBI608: Oral administration at a dose of 240mg or 480 mg BID, every day Pembrolizumab: Administration at a dose of 200 mg/body on Day 1 of each cycle The therapy will be repeated until meeting the discontinuation criteria. [Additional cohort to the Phase II part] BBI608: Oral administration at a dose of 240 mg BID, every day Pembrolizumab: Administration at a dose of 200 mg/body on Day 1 of each cycle.
Primary outcome(s): Immune-related objective response rate (irORR) determined by their Response Evaluation Criteria In Solid Tumors (irRECIST) [Additional cohort to the Phase II part] Objective response rate determined by the RECIST version 1.1
Study Design: Single arm Non-randomized
Project description:Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n=7). Treatment was well tolerated in this small cohort without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9 – 6.0 months) and overall survival of 11.8 months (90 % CI, 9.2 – 14.2 months). We aimed to elucidate reasons for limited efficacy through correlative analyses. Using BBZ qPCR, we found circulating CAR T cells in 5 out of 7 patients at the time of repeat resection, but only in 1 patient in the tumor. However, shared T-cell receptors (TCRs) were found between the infusion product and the relapsed tumors, which could indicate an infiltration but lack of persistence of the CAR T cells. We further compared the tumor microenvironment of the tumors harvested before and after CAR+aPD1 administration using single cell RNA sequencing and observed comparable proportions of the major immune cell subsets. However, the myeloid and T cells infiltrating the tumors significantly evolved, with more exhausted, regulatory, and IFN-stimulated T cells at the relapse. At that time, the amount of IFN-stimulated T cells positively correlated with time from relapse to death. Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.
Project description:Immune checkpoint inhibitors (ICIs) have become a major treatment option for non-small cell lung cancer, but their efficacy is still limited because only a subset of patients responded to ICIs. Bojungikki-Tang (BJIKT), a widely used herbal medicine extracted from 10 medicinal plants, has been largely investigated as a combined treatment with anticancer agents. In this study, we examined the potential anti-tumor effect of co-administration of BJIKT and pembrolizumab in human peripheral blood mononuclear cell (PBMC)-injected H460 tumor-bearing MHC Ⅰ/Ⅱ double knockout NSG mice. We found that combination treatment with BJIKT and pembrolizumab significantly suppressed tumor growth by regulating the activation of immune cells. Immunohistochemistry analysis showed that the combination therapy decreased the exhausted proportion of CD8(+) and CD4(+) T cells expressing PD-1 and LAG-3 markers in the tumor tissues. Our transcriptome analysis indicated that BJIKT strengthened T cell function and TNF signaling and inhibited TGF-β signaling to induce cell cycle arrest and apoptosis. Additionally, BJIKT synergistically exhibited anti-tumor effects along with immune-related pathways when combined with pembrolizumab. Taken together, combination therapy altered immune cells and regulated anti-tumor immune response, paving the way for a more effective understanding of the role of BJIKT in the tumor microenvironment.
Project description:Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200mg IV every 3 weeks) with either weekly paclitaxel (80mg/m2 weekly) or flat-dose capecitabine (2000mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n=4/13, 95% CI: 10-61%) and 43% for pembrolizumab/capecitabine (n=6/14, 95% CI: 18-71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted.
Project description:We evaluated the efficacy of combining pembrolizumab (anti-PD1 antibody), exemestane (nonsteroidal aromatase inhibitor), and leuprolide (gonadotropin-releasing hormone agonist) for 15 patients with ER+/HER2− premenopausal MBC who had failed one to two lines of hormone therapy without chemotherapy.
Project description:Background: Anti-PD-1 therapy has become a cornerstone of tumor immunotherapy. Over a dozen of anti-PD-1/PD-L1 antibodies have currently been marketed. However, these agents exhibit notable disparities in their characteristics and clinical performance. For instance, in the field of small cell lung cancer (SCLC) where the majority of anti-PD-1 antibodies yielded limited success, Serplulimab produced impressive survival improvements and has been approved by NMPA. The marketing authorization application has also been validated by EMA. Nevertheless, the molecular mechanism underpinning Serplulimab’s superiority over its competitors remains elusive. Methods: We characterized the difference of Serplulimab with approved PD-1/PD-L1 inhibitors such as Pembrolizumab and Nivolumab on their antibody binding features and funcations in vitro and anti-tumor activity in vivo. We also investigated the potential cellular pathways underlying the efficacy of Serplulimab in combination with other immune checkpoint inhibitors. Results: In comparison to competitors, Serplulimab robustly induces PD-1 receptor endocytosis while fostering weaker PD-1-CD28 cis interactions. This phenomenon could mitigate the dephosphorylation of CD28 by SHP2, thereby facilitating sustained and robust T cell activation. Notably, Serplulimab and Pembrolizumab exhibited similar performance in both in vitro Mixed Lymphocyte Reaction assays and in vivo efficacy studies. However, upon co-administration with anti-TIGIT or anti-LAG3, the Serplulimab-containing combination consistently demonstrated superior tumor killing efficacy compared to the Pembrolizumab-based combination. Moreover, our mechanistic investigations have unveiled that the Serplulimab combination effectively reduces tumor microenvironment Treg cell populations, augments effector and memory T cell populations, and more potently modulates genes associated with diverse facets of the immune system, surpassing the effects of the Pembrolizumab combination. Conclusions: In summary, our data underscore Serplulimab as a highly differentiated PD-1 monoclonal antibody with best-in-class therapeutic potential
Project description:A single arm, Phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, and identify pathologic and transcriptomic correlates of response to therapy.