WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer

Our plain-English summary of WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer, by L.M. Krug, T. Dao, A.B. Brown, et al (Cancer Immunology, Immunotherapy, 2010).

The study

• Authors: L.M. Krug, T. Dao, A.B. Brown, P. Maslak, W. Travis, S. Bekele, T. Korontsvit, V. Zakhaleva, J. Wolchok, J. Yuan, H. Li, L. Tyson, D.A. Scheinberg
• Journal: Cancer Immunology, Immunotherapy
• Published: 2010;59(10):1467-79
• Cited by: 104 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The transcription factor, WT1, is highly overexpressed in malignant pleural mesothelioma (MPM) and immunohistochemical stains for WT1 are used routinely to aid in its diagnosis. Using computer prediction analysis we designed analog peptides derived from WT1 sequences by substituting amino acids at key HLA-A0201 binding positions. We tested the safety and immunogenicity of a WT1 vaccine comprised of four class I and class II peptides in patients with thoracic neoplasms expressing WT1.

Methods: Therapy consisted of six subcutaneous vaccinations administered with Montanide adjuvant on weeks 0, 4, 6, 8, 10, and 12, with 6 additional monthly injections for responding patients. Injection sites were pre-stimulated with GM-CSF (70 mcg). Immune responses were evaluated by DTH, CD4 T-cell proliferation, CD8 T-cell interferon gamma release, intracellular cytokine staining, WT1 peptide MHC-tetramer staining, and cytotoxicity against WT1 positive tumor cells.

Results: Nine patients with MPM and 3 with NSCLC were vaccinated, with 8 patients receiving at least 6 vaccinations; in total, 10 patients were evaluable for immune response. Six out of nine patients tested demonstrated CD4 T-cell proliferation to WT1 specific peptides, and five of the six HLA-A0201 patients tested mounted a CD8 T-cell response. Stimulated T cells were capable of cytotoxicity against WT-1 positive cells. Vaccination also induced polyfunctional CD8 T cell responses.

Conclusions: This multivalent WT1 peptide analog vaccine induces immune responses in a high proportion of patients with thoracic malignancies with minimal toxicity. A randomized trial testing this vaccine as adjuvant therapy in MPM is planned.

In plain English

This small pilot trial at Memorial Sloan-Kettering Cancer Center tested the safety and immune effects of a vaccine of four peptides based on WT1, a protein strongly present in malignant pleural mesothelioma. Two were altered versions of WT1's natural sequence. It did not study asbestos exposure. Nine patients with malignant pleural mesothelioma and three with non-small cell lung cancer were vaccinated, and 10 could be evaluated for immune response. Seven of the 12 had mild (grade 1) injection-site reactions; no other side effects attributable to the vaccine were noted. Six of nine patients tested showed increased CD4 immune-cell responses to the vaccine peptides. Five of the six patients with tissue type HLA-A0201 who were tested mounted a CD8 immune-cell response. Among the nine mesothelioma patients, eight had disease progression within 1 to 6 months, and all eight later died. One remained without progression at 36 months. The authors concluded that the vaccine produced a high rate of immune responses. They cautioned that conclusions about treatment benefit were difficult because the group was small, highly selected and varied.

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: Pilot clinical trial (single group, no comparison group) testing the safety and immune effects of a WT1 peptide vaccine
• Who was studied: Patients at Memorial Sloan-Kettering Cancer Center, New York, whose tumors stained positive for WT1. Nine had malignant pleural mesothelioma, all of epithelioid histology, and 8 of these were evaluable for immune response. Three had stage III non-small cell lung cancer, and 2 of these were evaluable. Study dates are not given.
• Exposure: No asbestos exposure was studied. The exposure was a vaccine of four WT1-derived peptides. Two were native WT1 sequences (WT1-427 long and WT1-331 long), and two were altered ('heteroclitic') analog peptides (WT1-A1 and WT1-122A1 long). Each dose contained 200 micrograms of each peptide mixed with Montanide adjuvant, and injection sites were pre-stimulated with GM-CSF (70 mcg). Six injections were given at weeks 0, 4, 6, 8, 10 and 12, and responding patients could receive up to six more monthly.
• Main results:
  • Screening: 8 of 9 malignant pleural mesothelioma tumors screened stained positive for WT1, compared with 4 of 23 non-small cell lung cancer tumors.
  • Side effects: 7 of the 12 vaccinated patients had grade 1 injection-site reactions (swelling, redness or itching). No other toxicities attributable to the vaccine were noted.
  • CD4 immune response: 6 of the 9 patients tested (patients 4, 6, 8, 10, 11 and 12) showed significantly increased CD4 T-cell proliferation to the vaccine peptides after vaccination.
  • CD8 immune response: 5 of the 6 HLA-A0201 patients who were tested mounted a CD8 T-cell response. According to Table 1, a seventh HLA-A0201 patient (patient 7) received only one vaccination and was not evaluable.
  • Laboratory killing tests: T cells could be tested in patients 8, 3 and 4. In these patients, T cells taken after vaccination killed WT1-positive cells but not WT1-negative cells.
  • Disease progression: among the 9 mesothelioma patients, 8 had disease progression 1 to 6 months after starting vaccinations, and all of these subsequently died from disease.
  • One mesothelioma patient (patient 1) remained without progression 36 months after the start of the study.
  • Survival: median survival for the mesothelioma patients was 14 months, measured from the first vaccination.
• The authors' conclusion: The authors reported a high rate of both CD8 and CD4 immune responses to the vaccine. Toxicity was mostly grade one and limited to injection-site reactions. They planned a randomized trial in patients with resected malignant pleural mesothelioma to see whether clinical benefit can be measured.
• Limitations the authors state:
  • The authors stated that conclusions about the vaccine's therapeutic activity are difficult to draw, particularly in mesothelioma.
  • The mesothelioma patients were a mixed group. Some had relapsed after prior multimodality therapy and others had unresectable disease, which makes expected outcomes hard to predict.
  • The patients were highly selected and the sample was small.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Non-Small Cell Lung Cancer, Pleural Mesothelioma, Neoplasm, Cytokine, Wilms Tumor 1 (WT-1), Adjuvant Therapy.

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