Search for effective treatments in patients with advanced refractory melanoma continues: can novel intratumoral therapies deliver?

Najjar, Yana G.

doi:10.1136/jitc-2021-002820

Cited by 4 publications

(4 citation statements)

References 21 publications

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“…Despite improved outcomes with first-line immune checkpoint inhibitors, a large proportion of patients with advanced melanoma ultimately do not benefit from this therapy due to primary or acquired resistance, and new treatment approaches are needed (27,28). In this pilot study, ONCOS-102 in combination with pembrolizumab was well tolerated across two dosing schedules [Part 1: ONCOS-102 priming (3 total doses) and sequential pembrolizumab; Part 2: ONCOS-102 priming and booster doses (12 total doses) in combination with pembrolizumab].…”

Section: Discussionmentioning

confidence: 99%

Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma

Shoushtari

Olszanski

Nyakas

et al. 2022

Clinical Cancer Research

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Purpose: Intratumoral oncolytic virotherapy may overcome anti–PD(L)-1 resistance by triggering pro-inflammatory remodeling of the tumor microenvironment. This pilot study investigated ONCOS-102 (oncolytic adenovirus expressing GM-CSF) plus anti–programmed cell death protein 1 (PD)-1 therapy in anti–PD-1–resistant melanoma. Experimental Design: Patients with advanced melanoma progressing after prior PD-1 blockade received intratumoral ONCOS-102 either as priming with 3 doses (3 × 1011 viral particles) during Week 1 [Part 1 (sequential treatment)] or as 4-dose priming and 8 booster doses every 3 weeks [Part 2 (combination treatment)]. From Week 3, all patients received pembrolizumab every 3 weeks (≤8 doses). The primary endpoint was safety. Objective response rate (ORR), progression-free survival, and immunologic activation in repeat biopsies were also investigated. Results: In 21 patients (Part 1, n = 9; Part 2, n = 12) ONCOS-102 plus pembrolizumab was well tolerated: most adverse events (AE) were mild/moderate in severity. Pyrexia (43%), chills (43%), and nausea (28%) were the most common ONCOS-102–related AEs. There were no dose-limiting toxicities. ORR was 35% [response evaluation in solid tumors (RECIST) 1.1, irRECIST]. Reduction in size of ≥1 non-injected lesions observed in 53% patients indicated a systemic effect. In injected tumors, persistent immune-related gene expression and T-cell infiltration were associated with clinical benefit. Viral persistence and efficacy in injected and non-injected lesions without additional toxicity supported Part 2 dosing regimen in future studies. Conclusions: ONCOS-102 plus pembrolizumab was well tolerated and led to objective responses in patients with anti–PD-1–resistant advanced melanoma. ONCOS-102 promoted T-cell infiltration, particularly cytotoxic CD8+ T cells, which persisted at Week 9, driving clinical benefit. Further investigation of ONCOS-102 plus PD-1 blockade is warranted.

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Section: Discussionmentioning

confidence: 99%

Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma

Shoushtari

Olszanski

Nyakas

et al. 2022

Clinical Cancer Research

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“…Therefore, stimulating and activating the T-cell response in tumor cells and having an immune-promoting TME are critical. Immune checkpoint blockade (ICB) is an initial form of TME immunotherapy based on antibodies ( 22 ). ICB prevents receptor ligands, such as CTLA4 and PD1 , from interacting with T-cell receptors, hence inhibiting T-cell activation and function.…”

Section: Discussionmentioning

confidence: 99%

“…However, these regimens are only effective for a subset of patients, with others showing only a limited response or response failure, especially in the advanced stages ( 23 , 24 ). Furthermore, most patients with advanced melanoma do not respond to ICI therapy due to primary or acquired drug tolerance ( 22 , 25 ). Combining anti- CTLA4 and anti- PD - 1 checkpoint inhibitors to enhance antitumor immune reactions, or ICIs combined with intratumoral oncolytic virotherapy, may trigger pro-inflammatory rebuilding of the TME to overcome anti- PD - L1 resistance.…”

Section: Discussionmentioning

confidence: 99%

“…It has been known that ICIs induce immunotoxicity while stimulating the body’s immune system, inevitably resulting in immune-related adverse events. The therapies mentioned above also cause different degrees of immune-related adverse events ( 22 , 26 ). Unfortunately, no highly sensitive and specific biomarker for ICIs has been reported.…”

Section: Discussionmentioning

confidence: 99%

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Bioinformatics analysis identifies PSMB8 as a key gene in the cutaneous malignant melanoma tumor microenvironment

Lin¹,

Yu²,

Wang³

et al. 2022

Ann Transl Med

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Background: Cutaneous tumors are commonly seen in clinical practice, and malignant melanoma (MM) is the leading cause of cutaneous tumor-induced death. The tumor microenvironment (TME), a critical part of tumorigenesis, has been a research hotspot in recent years. However, the effects of the MM microenvironment components remain elusive. This study aimed to analyze the various components in the TME of MM to identify factors affecting the tumorigenesis, progression, and metastasis of MM and the survival of MM patients. We also aimed to identify biomarkers related to TME rehabilitation to provide a new direction for MM treatment.Methods: We used bioinformatics to analyze the RNA-seq and somatic mutation data of 473 MM patients from The Cancer Genome Atlas database. Firstly, the patients' immunity and stroma were separately scored by the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) method. According to the median score, the participants were split into high-and low-score groups. Then, Gene Set Enrichment Analysis (GSEA) was performed, showing that high-expression genes were highly abundant in biological and metabolic activities associated with the immune system.Results: Differentially expressed genes (DEGs) and differentially mutated genes (DMGs) were identified and intersected to obtain the key immune-related genes PSMB8, FAM216B, DYSF, and FAM131C. PSMB8 was finally selected as the preferred immune-related prognostic marker; it was positively associated with overall survival and therefore considered a protective gene for MM patients. The GSEA analysis showed that PSMB8 with high expression had greater gene abundance in biological and metabolic processes related to immune system. In addition, CIBERSORT analysis showed an association between the proportion of tumorinfiltrating immune cells and PSMB8 expression.Conclusions: Our results suggest that PSMB8 might be associated with tumorigenesis and MM progression and could serve as a biomarker for the TME rehabilitation of MM. Our findings provide a new perspective and direction for the treatment of MM.

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Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity

Brown

2022

Cancer Treatment and Research

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Search for effective treatments in patients with advanced refractory melanoma continues: can novel intratumoral therapies deliver?

Cited by 4 publications

References 21 publications

Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma

Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma

Bioinformatics analysis identifies PSMB8 as a key gene in the cutaneous malignant melanoma tumor microenvironment

Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity

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