Neoadjuvant anti-tumor vaccination prior to surgery enhances survival

Our plain-English summary of Neoadjuvant anti-tumor vaccination prior to surgery enhances survival, by S.A. Fisher, A. Cleaver, D.D. Lakhiani, et al (Journal of Translational Medicine, 2014).

The study

• Authors: S.A. Fisher, A. Cleaver, D.D. Lakhiani, A. Khong, T. Connor, B. Wylie, W.J. Lesterhuis, B.W. Robinson, R.A. Lake
• Journal: Journal of Translational Medicine
• Published: 2014;12:245
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: This study was conducted to determine if anti-tumor vaccination administered prior to partial debulking surgery could improve survival using a murine solid tumour model.

Methods: Tumor incidence and survival rates were compared in mice bearing subcutaneous AB1-HA mesothelioma tumors that received either sham surgery, debulking surgery or vaccination prior to debulking surgery. Additionally, mice were depleted of CD4 and/or CD8 T lymphocytes during vaccination to assess their involvement in vaccine induced anti-tumor immunity. Flow cytometry was performed to characterise changes in the proportion and activation status of immune cells associated with anti-tumor immunity.

Results: Neoadjuvant vaccination combined with debulking surgery resulted in decreased tumor burden, increased survival and generation of tumor-specific immunity compared to surgery alone. Depletion of CD8 T cells completely abrogated any vaccine induced anti-tumor immune response. Conversely, CD4 depletion enhanced CD8 T cell activation resulting in complete tumor regression in 70% of mice treated with combined surgery and vaccination therapy. Tumor free survival was associated with established immunological memory as defined by the induction of effector memory T cells and resistance to rechallenge with parental AB1 mesothelioma cells.

Conclusions: Neoadjuvant anti-cancer vaccination combined with partial debulking surgery induced CD8-dependent anti-tumor immunity that significantly delayed tumor outgrowth relative to surgery alone. Complete tumor eradication was observed when vaccination and surgery were performed in CD4 T cell depleted animals. This demonstrates that adjuvant immunotherapy can improve post-surgical survival following cancer debulking surgery and provides a scientific rational for clinical trials of such an approach.

In plain English

This was a laboratory experiment in mice. BALB/c mice carrying subcutaneous AB1-HA mesothelioma tumours (a cell line originally produced by injecting crocidolite asbestos into BALB/c mice and transfected with influenza haemagglutinin) were given sham surgery, 75% debulking surgery, vaccination, or vaccination before surgery; the first experiment used a PR8 prime with an rMVA-HA boost, while in the depletion experiments vaccinated mice received rMVA-HA twice, 7 days apart, together with antibodies depleting CD4 and/or CD8 T cells. The authors reported a significant delay in tumour growth (p less than 0.001) for the combined surgery plus vaccination group relative to the other treatment groups, and a survival benefit over surgery or vaccination alone. Depleting CD8 T cells, alone or with CD4 depletion, removed the vaccine-induced survival benefit. Complete tumour eradication occurred in 60% of CD4-depleted mice after debulking surgery in one experiment; in repeat experiments CD4 depletion given either prior to surgery or during vaccination eradicated tumour in 50% (5/10) of treated animals, rising to 70% (7/10) when vaccination was combined with surgery. Surviving mice resisted rechallenge with parental AB1 cells, and CD4 depletion was accompanied by increased CD8 proportion and activation (p less than 0.0001).

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) experiment using a murine mesothelioma tumour model, comparing vaccination, debulking surgery and their combination, with CD4 and/or CD8 T-cell depletion experiments
• Who was studied: Female BALB/c mice aged 6–8 weeks bearing subcutaneous AB1-HA mesothelioma tumours, randomised into groups of 5 (groups of n = 10 in the repeat survival experiments), at the University of Western Australia
• Exposure: Intervention studied: anti-HA vaccination (PR8 prime with rMVA-HA boost in the first experiment; rMVA-HA given twice 7 days apart in the depletion experiments) before 75% debulking surgery, with or without antibody depletion of CD4 and/or CD8 T cells; the AB1 line itself had been generated by intraperitoneal crocidolite asbestos in mice
• Main results:
  • Tumour growth was significantly delayed in the group given vaccination combined with surgery compared with the other treatment groups
  • Only the combination of neoadjuvant vaccination and 75% debulking surgery gave a significant survival benefit relative to surgery or vaccination alone
  • In CD8-depleted groups the vaccine-induced survival benefit was lost, with survival falling to that of the surgery-only group
  • Complete tumour eradication in 60% of CD4-depleted mice after debulking surgery in the first experiment
  • In repeat experiments, CD4 depletion given either before surgery or during vaccination eradicated tumour in 5/10 animals, rising to 7/10 when vaccination was combined with surgery
  • Tumour-free mice survived more than 60 days after surgery and resisted rechallenge with the parental AB1 line that does not express HA
  • CD4 depletion was followed by a significant rise in the proportion and ICOS activation status of CD8 T cells compared with non-depleted groups
  • More CD8+CD44+CD62L- effector memory T cells were found in lymph nodes and spleen of CD4-depleted groups than in controls
• The authors' conclusion: The authors concluded that transient CD4 T cell (or more specifically Treg) depletion combined with anti-tumour vaccination before debulking surgery was an effective strategy to enhance survival in this model, providing a basis for developing adjuvant immunotherapies
• Limitations the authors state:
  • The authors noted that, unlike an earlier melanoma study, combined vaccination and surgery could not prevent tumour outgrowth in their model
  • The authors stated that differences between models and vaccination protocols make direct comparison with other studies difficult
  • The authors noted that how CD4 depletion could be achieved clinically remains a consideration, and that CD4 depletion during adoptive cell therapy has been questioned

Topics

Medical terms in this study, explained in our Lexicon: Cytoreductive Surgery, Mesothelioma, Tumor Burden, Immunotherapy, Clinical Trial.

Related studies

• The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40 — A. Khong, A.L. Cleaver, et al. (2014)
• Fowlpox-based survivin vaccination for malignant mesothelioma therapy — P. Bertino, M. Panigada, et al. (2013)
• 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)
• Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity — W.J. Lesterhuis, J. Salmons, et al. (2013)
• Deliberately provoking local inflammation drives tumors to become their own protective vaccine site — C. Jackaman, A.M. Lew, et al. (2008)
• Types of surgery post-neoadjuvant chemotherapy for pleural mesothelioma — K. Kuribayashi, H. Doi, et al. (2019)

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