Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment

Our plain-English summary of Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment, by Z. Tan, M.S. Chiu, C.W. Yan, et al (Molecular Therapy Oncolytics, 2021).

The study

• Authors: Z. Tan, M.S. Chiu, C.W. Yan, K. Man, Z. Chen
• Journal: Molecular Therapy Oncolytics
• Published: 2021;20:373-386
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The potency of cancer vaccines is often compromised by a variety of immunoinhibitory mechanisms, including stimulation of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pathway. Here, to overcome inhibition, we determined the potential of recombinant adeno-associated virus (rAAV)-vectored, PD1-based vaccination in the tumor microenvironment (TME) to activate antigen-specific T cell responses in the immune-competent murine mesothelioma model. We found that our rAAV-soluble PD1 (sPD1)-TWIST1 vaccine elicited and maintained TWIST1-specific cytotoxic T lymphocyte (CTL) responses and the PD-1 blocker systemically against lethal mesothelioma challenge after intramuscular injection, which was more effective than rAAV-TWIST1 or rAAV-sPD1 alone. More importantly, intratumoral injection of rAAV-sPD1-TWIST1 significantly enhanced immune surveillance by inducing TWIST1-specific CTL responses against vaccine-encoded TWIST1 and bystander gp70-AH1 epitopes, increasing CTL infiltration into the TME and decreasing tumor-associated immunosuppression, leading to complete elimination of established mesothelioma in 5 of 8 tumor-bearing mice. In addition, direct oncosuppression synergized with recruitment of T cells after localized rAAV-sPD1-TWIST1 treatment in a humanized mouse model to inhibit growth of REN human mesothelioma. Our results warrant clinical development of the rAAV-sPD1-TWIST1 vaccine to enhance immunotherapy against a wide range of TWIST1-expressing tumors.

© 2021 The Author(s).

In plain English

This was a laboratory study in mice testing an adeno-associated virus serotype DJ vector carrying a soluble PD-1 (sPD1) fused to a tumour antigen, as treatment for mesothelioma, described by the authors as an asbestos-associated cancer. In BALB/c mice, one intramuscular dose of rAAV-sPD1-p24 raised p24-specific T cells to 6.84% of splenic CD8+ T cells on day 21 versus 2% with rAAV-p24, and cleared implanted wild-type AB1 tumours in 2 of 4 mice. With the TWIST1 antigen, challenge six weeks after vaccination left 3 of 7 mice tumour-free (rAAV-sPD1-TWIST1) versus 2 of 7 (rAAV-TWIST1). Injected directly into established AB1 tumours, rAAV-sPD1-TWIST1 gave tumour-free survival in 5 of 8 mice, compared with 1 of 5 (rAAV-TWIST1) and 1 of 6 (rAAV-sPD1-p24); it raised CD3+ T cell infiltration and lowered immunosuppressive cells in the tumour. In NSG mice carrying REN human mesothelioma, tumour growth was significantly inhibited in all mice given live vector; in humanised NSG-huPBL mice, rAAV-hsPD1-TWIST1 had the most potent effect on tumour regression. The authors concluded local delivery of this vector has several advantages.

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 animal and cell-culture experiments in mouse mesothelioma models (immune-competent BALB/c and immunodeficient/humanised NSG mice)
• Who was studied: Laboratory mice at the University of Hong Kong: 6- to 8-week-old female BALB/c mice bearing murine AB1 or AB1-GAG mesothelioma, and NSG and humanised NSG-huPBL mice bearing REN human mesothelioma; group sizes of about 4 to 8 mice
• Exposure: Intramuscular or intratumoral injection of recombinant AAV-DJ vectors encoding sPD1-TWIST1, TWIST1, sPD1-p24, p24 or hsPD1-TWIST1 (2 x 10^10 to 5 x 10^11 genome copies)
• Main results:
  • In BALB/c mice, rAAV-sPD1-p24 gave a higher frequency of antigen-specific CD8+ T cells than rAAV-p24
  • After rAAV-sPD1-p24 vaccination, implanted wild-type AB1 tumours were eliminated in 2 of 4 mice; all rAAV-p24 mice died within 31 days
  • Prophylactic intramuscular TWIST1 vaccination with challenge at week 6: 3 of 7 tumour-free with rAAV-sPD1-TWIST1 versus 2 of 7 with rAAV-TWIST1
  • Peak peripheral TWIST1-specific CD8+ T cell frequencies were higher with rAAV-sPD1-TWIST1 but the difference was not statistically significant
  • Intratumoral treatment of 1-week-old AB1 tumours: tumour-free survival in 5 of 8 mice with rAAV-sPD1-TWIST1, 1 of 5 with rAAV-TWIST1 and 1 of 6 with rAAV-sPD1-p24
  • Intratumoral rAAV-sPD1-TWIST1 changed the tumour microenvironment of AB1 tumours
  • In (non-humanised) NSG mice bearing REN-Luc human mesothelioma, growth was significantly inhibited in all mice receiving live vector (rAAV-TWIST1 or rAAV-hsPD1-TWIST1)
  • In humanised NSG-huPBL mice with REN human mesothelioma, rAAV-hsPD1-TWIST1 produced the greatest tumour regression
• The authors' conclusion: The authors concluded that local AAV delivery of sPD1-TWIST1 improved antitumour efficacy and is a feasible cancer immunotherapy approach that may warrant clinical development
• Limitations the authors state:
  • The authors noted tumours may not be reachable for intratumoral injection in people
  • Existing human immunity to AAV may hinder translation
  • The cell types in the tumour expressing the vector-encoded antigens were not established

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Tumor Microenvironment, PD-L1, Immunotherapy.

Related studies

• Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination — Z. Tan, M.S. Chiu, et al. (2020)
• A Prime-Boost Vaccination Approach Induces Lung Resident Memory CD8+ T Cells Derived from Central Memory T Cells That Prevent Tumor Lung Metastasis — H. Xu, M. Yue, et al. (2024)
• Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells — Z. Yu, Z. Tan, et al. (2015)
• WT1-mRNA dendritic cell vaccination of patients with glioblastoma multiforme, malignant pleural mesothelioma, metastatic breast cancer, and other solid tumors: type 1 T-lymphocyte responses are associated with clinical outcome — Z.N. Berneman, M. De Laere, et al. (2025)
• Neoadjuvant anti-tumor vaccination prior to surgery enhances survival — S.A. Fisher, A. Cleaver, et al. (2014)
• Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types — T. van den Ende, H.G. van den Boorn, et al. (2020)

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