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QUILT-3.055: A Study of Combination Immunotherapies in Patients Who Have Previously Received Treatment With Immune Checkpoint Inhibitors

ABSTRACT: This is a Phase IIb, multicohort, open-label multicenter study of combination immunotherapies in patients who have previously received treatment with PD-1/PD-L1 immune checkpoint inhibitors. All patients in Cohorts 1-4 will receive the combination treatment of PD-1/PD-L1 checkpoint inhibitor plus N-803 for up to 17 cycles. Each cycle is six weeks in duration. Some patients who experience disease progression while on study in Cohorts 1-4 may roll over into Cohort 5 and receive combination therapy with a PD-1/PD-L1 checkpoint inhibitor, N-803, and PD-L1 t-haNK cellular therapy for up to an additional 17 cycles. Each cycle is six weeks in duration. All patients will receive N-803 once every 3 weeks. Patients will also receive the same checkpoint inhibitor that they received during their previous therapy. Radiologic evaluation will occur at the end of each treatment cycle. Treatment will continue for up to 2 years, or until the patient experiences confirmed progressive disease or unacceptable toxicity, withdraws consent, or if the Investigator feels it is no longer in the patient’s best interest to continue treatment. Patients will be followed for disease progression, post-therapies, and survival through 24 months past administration of the first dose of study drug.

DISEASE(S): Uterine Cervical Neoplasms,Microsatellite Instability,Carcinoma,Carcinoma, Transitional Cell,Small Cell Lung Cancer,Colorectal Cancer,Urothelial Carcinoma,Mismatch Repair Deficiency,Carcinoma, Merkel Cell,Lung Neoplasms,Gastric Cancer,Carcinoma, Renal Cell,Colorectal Neoplasms,Carcinoma, Non-small-cell Lung,Renal Cell Carcinoma,Stomach Neoplasms,Head And Neck Squamous Cell Carcinoma,Hepatocellular Carcinoma,Cervical Cancer,Melanoma,Small Cell Lung Carcinoma,Merkel Cell Carcinoma,Non-small Cell Lung Cancer (nsclc),Carcinoma, Squamous Cell,Squamous Cell Carcinoma Of Head And Neck,Non-small Cell Lung Cancer,Carcinoma, Hepatocellular

PROVIDER: 2250175 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:PD-L1 Inhibitor Regulates the miR-33a-5p/PTEN Signaling Pathway and Can Be Targeted to Sensitize Glioblastomas to Radiation. Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.

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QUILT-3.055: A Study of Combination Immunotherapies in Patients Who Have Previously Received Treatment With Immune Checkpoint Inhibitors

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