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Avelumab induces superior Fc-Fc receptor-dependent natural killer cell stimulation and dendritic cell cross-talk compared to durvalumab

ABSTRACT: Natural killer cells and dendritic cells are instrumental in controlling cancer. However, the impact of PD-L1 blockade therapy on these immune cell types is not well understood. Furthermore, across many clinical trials, different anti-PD-L1 antibodies have produced varying levels of efficacy in patients, and the basis of these differences are obscure. Avelumab, a native Fc IgG1 antibody, and durvalumab, a mutant-Fc IgG1 antibody, are two of the most commonly used anti-PD-L1 agents for cancer immunotherapy. We compared the mechanistic effects of these agents. Our study shows the robust impact of Fc-signaling on NK cells by avelumab. In contrast, durvalumab failed to induce NK cell activation or promote NK-DC cross-talk.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273030 | GEO | 2025/05/14

REPOSITORIES: GEO

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Avelumab induces superior Fc-Fc receptor-dependent natural killer cell stimulation and dendritic cell cross-talk compared to durvalumab

Project description:Avelumab induces superior Fc-Fc receptor-dependent natural killer cell stimulation and dendritic cell cross-talk compared to durvalumab

| PRJNA1139817 | ENA

Immunotherapy Utilizing NK cells and ADCC Mediating Agents with Poly (ADP-ribose) polymerase (PARP) Inhibition

Project description:Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. Methods: We examined if olaparib, when combined with IgG1 antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab. Results: NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15RA further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2, and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma. Conclusions: These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.

2018-12-11 | GSE121682 | GEO

ALPN-202 induces a more potent anti-tumor T cell response in MC38/hPD-L1 tumors than PD-L1 blockade alone

Project description:Purpose: Use RNA-seq to characterize the anti-tumor immune response induced by ALPN-202 and compare to that of anti-PD-L1 treatment alone. Methods: mRNA was isolated from MC38/hPD-L1 tumors 72 hours after a single dose of ALPN-202 (n=4), anti-PD-L1 mAb (durvalumab) (n=4), or Fc control (n=4). Results: ALPN-202 treatment resulted in elevated expression of multiple T cell, NK cell, myeloid cell genes. Additionally, there was a strong increase in genes commonly associated with a proinflammatory response including cytokines, chemokines and surface markers. Conclusions: ALPN-202 treatment resulted in a strong anti-tumor immune response that was more potent than that generated by blockade of PD-L1 alone.

2022-02-10 | GSE161244 | GEO

Affect of Interferon Gamma on Chordoma Cells

Project description:IFN-g-induced gene expression profiles of UM-Chor1 cells were assessed by microarray analysis Chordoma is a rare bone tumor derived from notochord, which has shown to be resistant to conventional therapy, including chemotherapy and radiotherapy. Immunotherapy has the potential to be effective in cancers with resistance to conventional therapy. Checkpoint inhibition, including Programmed cell Death 1 (PD-1)/Programmed cell Death protein 1 (PD-L1) blockade has shown great promise in treating diverse cancers. The purpose of this study was to investigate the potential of anti-PD-L1 antibody therapy for chordoma. To this end, using 4 chordoma cell lines, we examined the expression of PD-L1 and performed in vitro NK cells killing assay for antibody-dependent cell-mediated cytotoxicity (ADCC) activity mediated by the anti-PD-L1 antibody, avelumab. Here, the expression of PD-L1 was markedly upregulated by IFN-g in all 4 chordoma cell lines, which resulted in increasing the sensitivity to ADCC. Next, to model a patient that received a tumor-antigen specific vaccine, chordoma cells were co-incubated with brachyury specific CD8+ T cells, culminating in significant upregulation of PD-L1 on the tumor cells mediated by CD8+ T cells IFN-g production. The functional consequence was the sensitivity of chordoma cells to ADCC mediated by avelumab. Finally, residential cancer stem cell subpopulations of chordoma cells were killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. Our findings show the potential of avelumab therapy in chordoma; a) alone, to enable endogenous NK cells to kill chordoma cells via ADCC, or b) in conjunction with T cells immunotherapy such a vaccine, to exploit enhanced NK cell killing of chordoma cells via ADCC.

2017-01-01 | GSE77732 | GEO

Interferon Gamma mRNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non–Small-Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab

Project description:An unmet need in cancer treatment is identification of biomarkers of response to PD-1 or PD-L1 immune checkpoint inhibitors that predict therapeutic outcomes in patients with non–small-cell lung carcinoma (NSCLC) and urothelial cancer (UC). Expression of PD-L1 measured by immunohistochemistry has limited capacity for predicting outcomes of immune checkpoint therapy because expression of this biomarker does not correlate highly with treatment response. In addition, PD-L1 as measured on tumor cells, which has been approved by the FDA for both companion and complementary diagnostic utility, does not necessarily reflect anti-tumor activity of tumor-infiltrating lymphocytes. Results presented in this report demonstrate that gene expression levels of four interferon gamma (IFNγ)-inducible mRNAs correlate with improved clinical outcomes in patients with NSCLC or UC treated with the PD-L1 inhibitor durvalumab. This IFNγ gene signature may augment the predictive value of PD-L1 and other biomarkers in identifying cancer patients most likely to respond to therapy with durvalumab or other immune checkpoint inhibitors.

2018-02-14 | GSE110390 | GEO

Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial

Project description:Randomized phase II trial patients with early-stage non-small cell lung cancer were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation. We report, based on transcriptome analyses of resected tumors, a correlation between an increase of immune pathway genes and freedom from recurrence.

2023-11-26 | GSE248378 | GEO

Phase 1 trial of durvalumab (anti-PD-L1) in combination with lenalidomide in relapsed/refractory cutaneous T cell lymphoma

Project description:T cells in cutaneous T-cell lymphoma (CTCL) are functionally exhausted, expressing immune inhibitory molecules such as PD1 and PD-L1. Durvalumab selectively targets PD-L1 on exhausted T cells and distinct cells within the CTCL tumor microenvironment (TME) and may restore an anti-tumor immune response. The oral immunomodulator lenalidomide, which has shown activity in CTCL, may enhance immune checkpoint blockade by durvalumab. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab in patients with refractory/advanced CTCL (NCT03011814). Primary objectives were to assess safety and tolerability and identify the maximum tolerated dose/recommended phase 2 dose. Secondary and tertiary objectives were to investigate efficacy and the effects on the TME. Thirteen patients enrolled in sequential cohorts received fixed dose durvalumab and dose escalation of lenalidomide. Thirteen patients were evaluable for toxicities and 12 for response in phase 1. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1-3 (DLT evaluation period). The most frequent AEs were tumor flare, fatigue, neutropenia and leukopenia. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Median cycles of treatment were 11 (range, 3-42+). Median duration of response was 25.5 (range 8-36.5) months. Anti-PD-L1/lenalidomide showed clinical activity; there were 7 partial responses, 4 stable disease and 1 progressive disease. Adaptive and innate immune signatures potentially predictive of response seen in gene expression profiling of serial skin samples were downregulation of TNF-alpha signaling via NFκB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders vs up-regulation of MYC targets and pro-inflammatory pathways in non-responders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment status and response.

2024-07-11 | GSE271668 | GEO

Expression data from durvalumab, oleclumab and combo-treated xenograft NSCLC tumors

Project description:Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations do not respond to anti-PD-1 (L1) as well as tumors without an EGFR mutation. We showed in a xenograft mouse model of EGFR-mutated NSCLC that, neither durvalumab nor oleclumab alone inhibited tumor growth compared to the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth and increased gene expressions that corresponded to inflammation and T cell function in tumors treated. We used microarrays to study gene expressions that corresponded to enhanced immune response in antibody-treated mice.

2022-02-23 | GSE190731 | GEO

PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma

Project description:Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n=26), or durvalumab and trametinib given concomitantly (cohort B, n=20) or sequentially (cohort C, n=22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma.

2020-09-24 | GSE158403 | GEO

Effects of durvalumab alone or combined with tremelimumab on preexisting cells in the tumor microenvironment

Project description:Immune checkpoint blockade with anti–PD-1/L1 or anti–CTLA-4 therapies has shown promising results across multiple cancer types, but the mechanisms within the tumor microenvironment (TME) have not been fully characterized. We used single-cell RNA sequencing to investigate the effects of anti–PD-L1 monoclonal antibody (mAb) durvalumab (D) alone and combined with an anti–CTLA-4 mAb, tremelimumab (T), on distinct subsets of immune cells. Upon treatment with D or D+T, two NSCLC tumors showed elevated IFNγ responses, although they differed in magnitude of response but differed in other areas. Our results highlight that D and D+T in the TME have some consistent effects across tumors but also exhibit tumor-specific effects depending on composition and functional state of immune cells in the TME at time of treatment. This complex tumor-specific interplay of diverse immune subtypes in the TME is critical to better understand patient response to immunotherapy.

2021-09-01 | GSE131933 | GEO

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