A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma

Object Early-phase clinical studies of glioma vaccines have shown feasibility and encouraging preliminary clinical activity. A vaccine that targets tumor angiogenesis factors in glioma microenvironment has not been reported. Therefore, we performed a pilot study to evaluate the safety and immunogenicity of a novel vaccination targeting tumor angiogenesis with synthetic peptides for vascular endothelial growth factor (VEGF) receptor epitopes in patients with recurrent/progressive high grade gliomas. Methods Eight patients received intranodal vaccinations weekly at a dose of 2mg/kg bodyweight 8 times. T-lymphocyte responses against VEGF receptor (VEGFR) epitopes were assessed by enzyme linked immunosorbent spot assays. Results This treatment was well-tolerated in patients. The first four vaccines induced positive immune responses against at least one of the targeted VEGFR epitopes in the peripheral blood mononuclear cells in 87.5% of patients. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months. Two patients with recurrent GBM demonstrated stable disease. Plasma IL-8 level was negatively correlated with overall survival. Conclusion These data demonstrate the safety and immunogenicity of VEGFR peptide vaccines targeting tumor vasculatures in high grade gliomas.

[1]  D. Reardon,et al.  An Update on the Role of Immunotherapy and Vaccine Strategies for Primary Brain Tumors , 2015, Current Treatment Options in Oncology.

[2]  J. Engh,et al.  Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  T. Kawase,et al.  Single-Copy Gain of Chromosome 1q Is a Negative Prognostic Marker in Pediatric Nonependymal, Nonpilocytic Gliomas , 2011, Neurosurgery.

[4]  Raymond Sawaya,et al.  Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[6]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[7]  K. Aldape,et al.  Tissue microdissection and degenerate oligonucleotide primed-polymerase chain reaction (DOP-PCR) is an effective method to analyze genetic aberrations in invasive tumors. , 2001, The Journal of molecular diagnostics : JMD.

[8]  K. Aldape,et al.  A randomized trial of bevacizumab for newly diagnosed glioblastoma. , 2014, The New England journal of medicine.

[9]  H. Zentgraf,et al.  Monoclonal antibody specific for IDH1 R132H mutation , 2009, Acta Neuropathologica.

[10]  M. Shibuya,et al.  Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. , 2005, Cancer research.

[11]  R. Mirimanoff,et al.  EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma. , 2010, European journal of cancer.

[12]  M. Shibuya,et al.  Inhibition of Tumor Growth with Antiangiogenic Cancer Vaccine Using Epitope Peptides Derived from Human Vascular Endothelial Growth Factor Receptor 1 , 2006, Clinical Cancer Research.

[13]  R. McLendon,et al.  EGFRvIII‐Targeted Vaccination Therapy of Malignant Glioma , 2009, Brain pathology.

[14]  K. Xie,et al.  Interleukin-8 and human cancer biology. , 2001, Cytokine & growth factor reviews.

[15]  Erwin G. Van Meir,et al.  The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. , 2005, Neuro-oncology.

[16]  S. Phuphanich,et al.  Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma , 2012, Cancer Immunology, Immunotherapy.

[17]  J. Kirkwood,et al.  Immunotherapy of cancer in 2012 , 2012, CA: a cancer journal for clinicians.

[18]  A. Friedman,et al.  Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas , 2008, Clinical Cancer Research.

[19]  M. Bredel,et al.  A phase 2 trial of single‐agent bevacizumab given in an every‐3‐week schedule for patients with recurrent high‐grade gliomas , 2010, Cancer.

[20]  T. Mikkelsen,et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  T. Chou,et al.  Immunotherapy of cancer. , 1970, British medical journal.

[22]  J. Becker,et al.  Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: Cessation of CTL responses is associated with disease progression , 2001, International journal of cancer.

[23]  A. Friedman,et al.  An epidermal growth factor receptor variant III–targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme , 2009, Molecular Cancer Therapeutics.

[24]  K. Hoang-Xuan,et al.  Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. , 2014, The New England journal of medicine.

[25]  P. Coulie,et al.  High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens , 2005, The Journal of experimental medicine.

[26]  C. Horak,et al.  Nivolumab plus ipilimumab in advanced melanoma. , 2013, The New England journal of medicine.

[27]  H. Uemura,et al.  Phase I clinical trial of human vascular endothelial growth factor receptor 1 peptide vaccines for patients with metastatic renal cell carcinoma , 2013, British Journal of Cancer.

[28]  D. Cheresh,et al.  VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. , 2012, Cancer cell.

[29]  J. Hatazawa,et al.  Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. , 2008, Journal of neurosurgery.

[30]  A. Ullrich,et al.  Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant , 1994, Nature.

[31]  L. Recht,et al.  A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. , 2015, Neuro-oncology.

[32]  M. Shigemori,et al.  Immunologic Evaluation of Personalized Peptide Vaccination for Patients with Advanced Malignant Glioma , 2005, Clinical Cancer Research.

[33]  K. Sugiyama,et al.  Phase II Study of Single-agent Bevacizumab in Japanese Patients with Recurrent Malignant Glioma† , 2012, Japanese journal of clinical oncology.

[34]  A. Dietz,et al.  Therapeutic vaccines for malignant brain tumors , 2008, Biologics : targets & therapy.

[35]  A. Mackensen,et al.  Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. , 2006, Journal of Clinical Oncology.

[36]  Tracy T Batchelor,et al.  AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. , 2007, Cancer cell.

[37]  K. Kurisu,et al.  Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen--A24 with recurrent or progressive glioblastoma multiforme. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  Laura A. Sullivan,et al.  The VEGF family in cancer and antibody-based strategies for their inhibition , 2010, mAbs.

[39]  Georg Breier,et al.  Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo , 1992, Nature.

[40]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[41]  R. McLendon,et al.  Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. , 2011, Neuro-oncology.

[42]  J. Becker,et al.  A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth , 2002, Nature Network Boston.

[43]  S. Stevanović,et al.  A vaccine targeting mutant IDH1 induces antitumour immunity , 2014, Nature.

[44]  Susan M. Chang,et al.  Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. , 2014, Neuro-oncology.

[45]  Naoya Hashimoto,et al.  Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. , 2015, The Lancet. Oncology.

[46]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[47]  P. Gutin,et al.  Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches , 2011, Radiation oncology.

[48]  S. Heiland,et al.  Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma , 2015, Oncotarget.

[49]  Yusuke Nakamura,et al.  Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer , 2010, Cancer science.

[50]  Yusuke Nakamura,et al.  Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer. , 2012, International journal of oncology.

[51]  A. Paetau,et al.  Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. , 1995, The American journal of pathology.

[52]  John Sampson,et al.  Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  J. Simes,et al.  Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma. , 2015, Neuro-oncology.