Multi-antigen Vaccination With Simultaneous Engagement of the OX40 Receptor Delays Malignant Mesothelioma Growth and Increases Survival in Animal Models

Our plain-English summary of Multi-antigen Vaccination With Simultaneous Engagement of the OX40 Receptor Delays Malignant Mesothelioma Growth and Increases Survival in Animal Models, by P.R. Hoffmann, F.W. Hoffmann, T.A. Premeaux, et al (Frontiers in Oncology, 2019).

The study

• Authors: P.R. Hoffmann, F.W. Hoffmann, T.A. Premeaux, T. Fujita, E. Soprana, M. Panigada, G.M. Chew, G. Richard, P. Hindocha, M. Menor, V.S. Khadka, Y. Deng, L. Moise, L.C. Ndhlovu, A. Siccardi, A.D. Weinberg, A.S. De Groot, P. Bertino
• Journal: Frontiers in Oncology
• Published: 2019;9:720
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Mesothelioma (MM) is a rare and highly aggressive cancer that develops from mesothelial cells lining the pleura and other internal cavities, and is often associated with asbestos exposure. To date, no effective treatments have been made available for this pathology. Herein, we propose a novel immunotherapeutic approach based on a unique vaccine targeting a series of antigens that we found expressed in different MM tumors, but largely undetectable in normal tissues. This vaccine, that we term p-Tvax, is comprised of a series of immunogenic peptides presented by both MHC-I and -II to generate robust immune responses. The peptides were designed using in silico algorithms that discriminate between highly immunogenic T cell epitopes and other harmful epitopes, such as suppressive regulatory T cell epitopes and autoimmune epitopes. Vaccination of mice with p-Tvax led to antigen-specific immune responses that involved both CD8+ and CD4+ T cells, which exhibited cytolytic activity against MM cells in vitro. In mice carrying MM tumors, p-Tvax increased tumor infiltration of CD4+ T cells. Moreover, combining p-Tvax with an OX40 agonist led to decreased tumor growth and increased survival. Mice treated with this combination immunotherapy displayed higher numbers of tumor-infiltrating CD8+ and CD4+ T cells and reduced T regulatory cells in tumors. Collectively, these data suggest that the combination of p-Tvax with an OX40 agonist could be an effective strategy for MM treatment.

In plain English

This was a laboratory study in mice testing a multi-antigen peptide vaccine (p-Tvax) for malignant mesothelioma, alone and with an OX40 agonist antibody (OX86). Using mRNA microarrays of tumours grown from CRH5 and EOH6 mesothelioma cells (derived from asbestos- or erionite-injected mice) compared with normal mouse lung and kidney, the authors selected seven overexpressed antigens (KIF20A, KIF2C, MMP9, MNDA, OLFML2B, TROAP, ULBP1) and designed one peptide per antigen using in silico epitope algorithms. Vaccinated BALB/c mice produced IFN-gamma-secreting CD8+ and CD4+ T cells, and their T cells released granzyme B when cultured with three mesothelioma cell lines (AB12, CRH5, EOH6). In subcutaneous CRH5 tumours, p-Tvax alone or combined with OX86 reduced tumour growth; in the intraperitoneal EOH6 model, p-Tvax alone did not increase survival, while the combination prolonged survival over OX86 alone. In AB12-bearing mice, the combination improved survival, with 20% showing complete tumour regression. Combination-treated tumours contained more CD8+ and CD4+ T cells and fewer regulatory T cells. No adverse events were observed.

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: Animal (mouse) experimental study with in vitro immunology assays and tumour transcriptome analysis
• Who was studied: Female 6-8 week-old BALB/c mice (cohorts of five per treatment group) bearing tumours from three murine mesothelioma cell lines (CRH5, EOH6, AB12); laboratory study at the University of Hawaii and collaborating institutions
• Exposure: Intervention studied: two subcutaneous vaccinations with p-Tvax (10 µg each of seven peptides) with CpG ODN 1585 adjuvant, with or without two 200 µg injections of the OX40 agonist antibody OX86. The tumour cell lines came from asbestos- or erionite-induced mouse tumours.
• Main results:
  • Tumour cell origin: AB12 cells came from asbestos-induced mouse tumours, CRH5 and EOH6 from asbestos- or erionite-injected mice
  • T cells from vaccinated mice, after peptide stimulation, secreted granzyme B when co-cultured with all three mesothelioma cell lines (p less than 0.05, n = 3)
  • Subcutaneous CRH5 model: reduced tumour growth with p-Tvax alone or combined with OX86 versus unvaccinated controls or OX86 alone
  • Intraperitoneal EOH6 model: combination prolonged survival compared with OX86 alone, while p-Tvax alone did not increase survival
  • AB12 model: combination improved overall survival, with 20% of vaccinated mice showing complete tumour regression (authors' wording: 'dramatically improved')
  • Tumour-infiltrating cells in CRH5 tumours: the combination was associated with more CD8+ and CD4+ T cells and fewer Tregs; OX86 alone raised CD8+ T cells but lowered CD4+ T cells and Tregs
  • Safety observation: no adverse events were reported in any treatment group
• The authors' conclusion: The authors concluded that combining the p-Tvax vaccine with an OX40 agonist could be an attractive therapeutic strategy for mesothelioma patients.
• Limitations the authors state:
  • Only two normal mouse tissues (lung and kidney) were analysed for antigen expression, so the authors relied additionally on published transcriptome studies
  • Protein-level expression could not be confirmed for all seven antigens by western blot; the authors offered possible explanations
  • More quantitative confirmation of antigen-specific T cells with MHC tetramers was not possible because the reagents were unavailable

Topics

Medical terms in this study, explained in our Lexicon: OX40 receptor, Malignant Mesothelioma, Mesothelial Cells, Pleura, Asbestos Exposure, Pathology, Immunotherapy.

Related studies

• Fowlpox-based survivin vaccination for malignant mesothelioma therapy — P. Bertino, M. Panigada, et al. (2013)
• Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor — E. Nakataki, S. Yano, et al. (2006)
• Preclinical development of HIvax: Human survivin highly immunogenic vaccines — P.R. Hoffmann, M. Panigada, et al. (2015)
• Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody — H. Dazzi, P.S. Hasleton, et al. (1990)
• The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells — A. Catalano, R. Lazzarini, et al. (2009)
• High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma — H. Ollila, J. Paajanen, et al. (2021)

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