Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model

Our plain-English summary of Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model, by M. Garofalo, M. Wieczorek, I. Anders, et al (Frontiers in Oncology, 2023).

The study

• Authors: M. Garofalo, M. Wieczorek, I. Anders, M. Staniszewska, M. Lazniewski, M. Prygiel, A.A. Zasada, T. Szczepińska, D. Plewczynski, S. Salmaso, P. Caliceti, V. Cerullo, R. Alemany, B. Rinner, K. Pancer, L. Kuryk
• Journal: Frontiers in Oncology
• Published: 2023;13:1259314
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant mesothelioma is a rare and aggressive form of cancer. Despite improvements in cancer treatment, there are still no curative treatment modalities for advanced stage of the malignancy. The aim of this study was to evaluate the anti-tumor efficacy of a novel combinatorial therapy combining AdV5/3-D24-ICOSL-CD40L, an oncolytic vector, with an anti-PD-1 monoclonal antibody.

Methods: The efficacy of the vector was confirmed in vitro in three mesothelioma cell lines - H226, Mero-82, and MSTO-211H, and subsequently the antineoplastic properties in combination with anti-PD-1 was evaluated in xenograft H226 mesothelioma BALB/c and humanized NSG mouse models.

Results And Discussion: Anticancer efficacy was attributed to reduced tumour volume and increased infiltration of tumour infiltrating lymphocytes, including activated cytotoxic T-cells (GrB+CD8+). Additionally, a correlation between tumour volume and activated CD8+ tumour infiltrating lymphocytes was observed. These findings were confirmed by transcriptomic analysis carried out on resected human tumour tissue, which also revealed upregulation of CD83 and CRTAM, as well as several chemokines (CXCL3, CXCL9, CXCL11) in the tumour microenvironment. Furthermore, according to observations, the combinatorial therapy had the strongest effect on reducing mesothelin and MUC16 levels. Gene set enrichment analysis suggested that the combinatorial therapy induced changes to the expression of genes belonging to the "adaptive immune response" gene ontology category. Combinatorial therapy with oncolytic adenovirus with checkpoint inhibitors may improve anticancer efficacy and survival by targeted cancer cell destruction and triggering of immunogenic cell death. Obtained results support further assessment of the AdV5/3-D24-ICOSL-CD40L in combination with checkpoint inhibitors as a novel therapeutic perspective for mesothelioma treatment.

Copyright © 2023 Garofalo, Wieczorek, Anders, Staniszewska, Lazniewski, Prygiel, Zasada, Szczepińska, Plewczynski, Salmaso, Caliceti, Cerullo, Alemany, Rinner, Pancer and Kuryk.

In plain English

This preclinical study tested an oncolytic adenovirus, AdV5/3-D24-ICOSL-CD40L, alone and combined with an anti-PD-1 antibody (pembrolizumab), against human mesothelioma. In vitro, three human mesothelioma cell lines (H226, Mero-82, MSTO-211H) were treated; the armed virus showed enhanced killing compared with AdV5/3-D24, which the authors stated was not statistically significant, and markers of immunogenic cell death were observed. H226 cells were then grown as subcutaneous xenografts in immunodeficient BALB/c nude mice (5 mice per group) and in humanized CD34+ NSG mice (4 mice, 8 tumours per group), with virus given intratumorally and anti-PD-1 intravenously on days 0, 3, 6, 9, 12 and 15. In the humanized model, mean tumour volume at day 35 was 93 mm3 for the combination versus 164 mm3 (virus alone), 216 mm3 (anti-PD-1) and 241 mm3 (control); combination versus mock p less than or equal to 0.01. Combination treatment was accompanied by more activated GrB+CD8+ tumour-infiltrating T cells and lowered MUC16 and mesothelin expression. The authors concluded that the combination could enhance anti-cancer performance and survival, and that further studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: in vitro experiments in human mesothelioma cell lines followed by xenograft mouse experiments (immunodeficient and humanized models)
• Who was studied: Human mesothelioma cell lines H226, Mero-82 and MSTO-211H in vitro; H226 subcutaneous xenografts in BALB/c nude mice (5 mice, 5 tumours per group) and in human CD34+ stem-cell-engrafted NSG mice (4 mice, 8 tumours per group)
• Exposure: Treatments compared: oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L, AdV5/3-D24, anti-PD-1 (pembrolizumab), their combinations, and PBS control; in vitro 0.1 to 100 viral particles per cell with or without anti-PD-1 100 µg/mL; in vivo 1x10^8 VP (immunodeficient model) or 2x10^9 VP (humanized model) intratumorally plus anti-PD-1 intravenously on days 0, 3, 6, 9, 12 and 15
• Main results:
  • In vitro, the armed virus killed cells more than AdV5/3-D24 in all three mesothelioma cell lines, but the authors reported this difference as not statistically significant
  • In the immunodeficient BALB/c nude H226 model, end-of-study mean tumour volumes were lower in virus-treated and combination groups than in anti-PD-1 and control groups (numbers as printed)
  • In the humanized H226 NSG model, mean tumour volume at day 35 was 93 mm3 for the combination, 164 mm3 virus alone, 216 mm3 anti-PD-1 and 241 mm3 control
  • Activated cytotoxic GrB+CD8+ tumour-infiltrating T cells were increased in mice given the combination compared with control (p less than or equal to 0.01)
  • A statistically significant correlation between tumour volume and GrB+CD8+ tumour-infiltrating lymphocytes was reported (p printed as 0,022)
  • RNA sequencing of explanted humanized-mouse tumours found 3,190 (virus), 1,158 (anti-PD-1) and 825 (combination) differentially expressed genes versus control
  • MUC16 expression fell most with combination therapy (fold change decreased by 2.33, adjusted p-value less than 0.01); MSLN (mesothelin) fell by 1.35 (adjusted p-value 0.01) with the combination
  • Deconvolution of the bulk RNA-seq data indicated increased CD8+ T-cell levels in the tumour microenvironment only after combination therapy
• The authors' conclusion: The authors concluded that their preclinical observations support the idea that this combination could enhance anti-cancer performance and overall survival, with further studies needed to confirm the findings
• Limitations the authors state:
  • The authors noted the BALB/c nude model is immunodeficient, so immunological properties of the vector and anti-PD-1 could not be properly assessed there
  • The authors stated the anti-tumour effects in the nude mouse model included no contribution from host adaptive immunity
  • The authors described the link between the co-stimulatory transgenes and increased GrB+CD8+ infiltration as speculation
  • The authors stated that further studies are required to confirm the reported findings

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Monoclonal Antibody, Mesothelin, checkpoint inhibitors.

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