Project description:Many cancer patients don’t benefit from currently-approved immune checkpoint inhibitors (ICI), suggesting that additional immunomodulation of the immunosuppressive tumour microenvironment (TME) is required. MTL-CEBPA specifically upregulates expression of master myeloid transcription factor, CEBPA, relieving myeloid-driven immunosuppression. Here, we report the safety, tolerability, pharmacokinetics, and efficacy of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumours that typically show ICI resistance. Multimodal exploratory analyses of paired patient biopsies demonstrate biological changes associated with combination treatment of MTL-CEBPA and pembrolizumab, including increased infiltration of T cell and antigen-presenting cells supporting conversion from an immune desert towards a more immune-inflamed TME. Patients with disease stabilisation demonstrate reductions in immunosuppressive myeloid cells post-treatment. Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335). This manuscript also reports proteomic data from patients treated with MTL-CEBPA in combination with sorafenib from clinical trial, OUTREACH, accessible at ClinicalTrials.gov, number NCT02716012 and reported. Stored plasma from patients from this clinical trial were analysed using OLINK as described below.
Project description:Background: This study evaluated the safety, tolerability and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Patients and Methods: Patients with MSS/pMMR mCRC with stable or progressive disease on prior fluoropyrimidine-based therapy received capecitabine 1000 mg/m2 by mouth twice daily days 1-14, bevacizumab 7.5 mg/kg day 1, and pembrolizumab 200 mg day 1 every 3 weeks. The primary endpoint was overall response rate by RECIST 1.1. Secondary endpoints were safety, duration of response, progression-free survival (PFS), and overall survival (OS). Results: Forty-four patients were enrolled between April 2018 and October 2021. Median follow up time was 9.3 months, while median time on treatment was 6 months. Overall response rate for 40 evaluable patients was 5% with median duration of response of 13.5 months. Median PFS was 4.1 months and median OS was 10.1 months. Grade ≥3 treatment-related adverse events occurred in 13 patients (30%); none were classified as immune-related. Grade 1-2 immune-related adverse events occurred in 8 patients (18%). Dose modifications occurred in 27 patients (61%), most commonly for palmar-plantar erythrodysesthesia. Single cell RNA sequencing on a subset of tumor biopsies demonstrated that the frequency of dendritic cells and tumor-infiltrating activated T cells correlated with time on treatment. Conclusions: The combination of pembrolizumab with capecitabine and bevacizumab was tolerable with an expected toxicity profile in MSS/pMMR mCRC patients. The overall response rate of 5% did not meet the prespecified target of ≥15%;, however, 55% patients remained on treatment >6 months.
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:To investigate the effect of Napabucasin (BBI608) on liver microenvironment, mice were pretreated with Napabucasin or vehicle control (1% NaCMC) via daily gavage for one week.
Project description:Immune checkpoint inhibitors have limited activity as monotherapy in biliary cancers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic immune cell growth factor which resulted in prolonged survival when combined with ipilimumab in melanoma. We conducted a single-center, phase II trial to evaluate the efficacy and safety of combining GM-CSF with pembrolizumab in patients with advanced biliary cancers after prior standard chemotherapy but no prior immune checkpoint inhibitor. Pembrolizumab 200 mg was administered intravenously in 21-day cycles, along with two cycles of GM-CSF 250 µg subcutaneously days 1 through 14. The primary endpoint was objective response rate. Among 42 patients enrolled, the median age was 61 years, 67% had intrahepatic cholangiocarcinoma, 90% had stage IV disease, and 24% had underlying viral hepatitis. The confirmed objective response rate was 12% (95% confidence interval: 4, 26), including two patients with complete response, and 26% of patients had progression-free survival ongoing at 6 months. Treatment was well-tolerated with treatment-related grade 3-4 events in 7% and treatment-related serious adverse events in 10%. Tumor PD-L1 expression was present in 46% and was associated with a higher rate of 6-month progression-free survival. Paired tumor biopsies showed upregulation of CD8+ T cell populations and antigen processing pathways after the addition of GM-CSF. In conclusion, the addition of GM-CSF to pembrolizumab was well-tolerated but did not meet the pre-specified response rate for efficacy. A subset of patients experienced deep responses and prolonged stable disease. GM-CSF elicited changes in the tumor immune microenvironment that could guide future combination approaches.
Project description:Immune checkpoint inhibitors have limited activity as monotherapy in biliary cancers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic immune cell growth factor which resulted in prolonged survival when combined with ipilimumab in melanoma. We conducted a single-center, phase II trial to evaluate the efficacy and safety of combining GM-CSF with pembrolizumab in patients with advanced biliary cancers after prior standard chemotherapy but no prior immune checkpoint inhibitor. Pembrolizumab 200 mg was administered intravenously in 21-day cycles, along with two cycles of GM-CSF 250 µg subcutaneously days 1 through 14. The primary endpoint was objective response rate. Among 42 patients enrolled, the median age was 61 years, 67% had intrahepatic cholangiocarcinoma, 90% had stage IV disease, and 24% had underlying viral hepatitis. The confirmed objective response rate was 12% (95% confidence interval: 4, 26), including two patients with complete response, and 26% of patients had progression-free survival ongoing at 6 months. Treatment was well-tolerated with treatment-related grade 3-4 events in 7% and treatment-related serious adverse events in 10%. Tumor PD-L1 expression was present in 46% and was associated with a higher rate of 6-month progression-free survival. Paired tumor biopsies showed upregulation of CD8+ T cell populations and antigen processing pathways after the addition of GM-CSF. In conclusion, the addition of GM-CSF to pembrolizumab was well-tolerated but did not meet the pre-specified response rate for efficacy. A subset of patients experienced deep responses and prolonged stable disease. GM-CSF elicited changes in the tumor immune microenvironment that could guide future combination approaches.
Project description:Single-agent anti-PD-1 antibodies lack clinical efficacy in patients with chronic lymphocytic leukemia (CLL). Here, we study the peripheral blood samples from high-risk or relapsed/refractory CLL before and after combination therapy of ibrutinib, fludarabine, and pembrolizumab (IFP). We performed bulk RNA-sequencing (bulk RNA-seq) to detect the transcriptomic changes of CLL and T cells during treatment, and demonstrated the immune responses of CD8 T cells to pembrolizumab by single-cell RNA sequencing (scRNA-Seq).
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.