scholarly journals Effects of combination treatment with durvalumab plus tremelimumab on the tumor microenvironment in non-small-cell lung carcinoma

Author(s):  
Li Cheng ◽  
Todd Creasy ◽  
Fernanda Pilataxi ◽  
Lydia Greenlees ◽  
Luis Vence ◽  
...  

AbstractThe rapid development of immune checkpoint blockade (ICB) therapies has revolutionized the cancer treatment landscape and brightened the long-term forecast for many cancer patients. However, the specific genomic and proteomic changes in tumors treated with different ICB treatments have yet to be fully characterized. We treated four non-small-cell lung carcinoma (NSCLC) tumor digests ex vivo with the anti-PD-L1 antibody durvalumab (D) alone or in combination with the anti-CTLA-4 antibody tremelimumab (T) to explore changes in gene and protein expression associated with these ICB therapies. All four tumors showed a robust increase in interferon gamma (IFN-γ) production (100–300% higher than isotype control) in both D- and D + T-treated tumors. Three of the four tumors showed additional increases in IFN-γ production with D + T compared with D (40–70%). A substantial reduction in interleukin 10 (IL-10) was also found in three of the four tumors (reduced to 4–8%) in response to D and D + T. Conventional CD4 + /CD8 + populations and T cell activation markers increased after D and D + T treatment. D and D + T upregulated multiple IPA pathways involving T cell activation. D + T resulted in additional upregulation of Th1/Th2 pathways through a different set of genes, as well as greater reduction in genes involved in epithelial-mesenchymal transition (EMT), angiogenesis, and cancer stemness. Our results demonstrated that D + T augmented the effects of D in the microenvironment of this set of NSCLC tumors. The specific impact of D + T on the regulation of EMT, angiogenesis, and cancer stemness warrants further evaluation in a larger set of tumors.

2003 ◽  
Vol 10 (11) ◽  
pp. 850-858 ◽  
Author(s):  
Luis E Raez ◽  
Peter A Cassileth ◽  
James J Schlesselman ◽  
Swaminathan Padmanabhan ◽  
Eva Z Fisher ◽  
...  

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9046-9046
Author(s):  
Timothy Dudley Clay ◽  
Margarita Majem ◽  
Enriqueta Felip ◽  
Bernard Doger ◽  
Enric Carcereny Costa ◽  
...  

9046 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 1st line non-small cell lung carcinoma (NSCLC) part of the phase II trial (NCT03625323). Methods: Patients (pts) with untreated, immunotherapy naïve, advanced NSCLC unselected for PD-L1 expression were recruited into part A. The study used a Simon's 2-stage design (17 pts planned for stage 1 and 19 pts for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks locally and with blinded independent central review (BICR) retrospectively. The study was approved by ethic committees and institutional review boards. Results: In total 36 pts were enrolled. At data cut-off (Jan 2021; median FU of 14 months), the median age was 69 yrs (range 53-84) and 69 % were male. The ECOG PS 0 and 1 was 42% and 58% respectively. Patients had squamous (42%) and non-squamous (58%) NSCLC and 95% presented with metastatic disease. All PD-L1 subgroups (TPS < 1 %, ≥ 1 % to ≤49 %; ≥50 %) were represented with 36% pts having ≥50% TPS. Pts received a median of 7.0 (range 1 – 31) pembrolizumab and 11.5 (range 1-22) efti administrations. Responses as per BICR and local read are shown in the table. ORR (local, iRECIST) by different PD-L1 subgroups was 27% for pts with TPS<1%, 39 % for TPS ≥1 %and 54% for ≥50 % TPS. Median PFS (n=36) was 8.2 months while median OS was not yet reached. The most common (> 20 %) treatment emergent adverse events (AEs) were asthenia (47 %), cough (36 %), decreased appetite (36 %), dyspnea (32 %), pruritus (31 %), fatigue (28 %), diarrhea (25 %), anemia (25 %), constipation (25 %) and back pain (22%). Two patients discontinued treatment due to adverse reactions (Grade 4 immune-mediated hepatitis, Grade 3 AST+ALT increase). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in 1st line advanced NSCLC patients across all PD-L1 (TPS) levels. Clinical trial information: NCT03625323. [Table: see text]


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3116-TPS3116 ◽  
Author(s):  
Aung Naing ◽  
Siwen Hu-Lieskovan ◽  
Ramaswamy Govindan ◽  
Kim Allyson Margolin ◽  
Melissa Ann Moles ◽  
...  

TPS3116 Background: Cancer cells contain unique DNA mutations that result in altered amino acid sequences known as neoantigens. Growing evidence supports a central role for neoantigens as targets for tumor directed immune responses. Tumor mutational burden as well as neoantigen load have been associated with anti-tumor activity of checkpoint inhibitors. Vaccines targeting neoantigens offer a highly specific way to induce de novo T cell reactivity and to expand existing T cell responses against neoantigens. Here, we describe NEO-PV-01, a personalized, neoantigen vaccine designed specifically for the molecular profile of each individual’s tumor. Methods: NT-001 is a single-arm, phase IB study designed to evaluate the safety of administering NEO-PV-01 + adjuvant (Poly-ICLC) with nivolumab in patients with advanced melanoma, smoking-associated non-small cell lung carcinoma, or transitional cell carcinoma of the bladder who have received no more than one prior systemic treatment. Patients undergo a baseline tumor biopsy and HLA typing. DNA and RNA sequencing is performed on the tumors as well as peripheral blood to serve as normal DNA controls. On Day 1, patients begin treatment with nivolumab at a dose of 240 mg IV while their customized vaccine is being generated. Each vaccine is custom designed for the individual patient and contains up to 20 peptides 14-35 amino acids in length. The peptides are pooled into four groups and mixed with Poly-ICLC at the time of administration. Beginning at Week 12, patients receive five priming immunizations over a three-week period followed by booster vaccinations at Weeks 19 and 23. The primary endpoint is safety. Secondary endpoints are ORR, CBR, PFS, and assessment of response conversion between Week 12 and Week 24. Exploratory endpoints include extensive immune monitoring. Clinical trial information: NCT02897765.


2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e21239-e21239
Author(s):  
Andre Kunert ◽  
Edwin A. Basak ◽  
Daan Hurkmans ◽  
Yarne Klaver ◽  
Mandy van Brakel ◽  
...  

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