Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 3/2010

01-03-2010 | Melanomas

Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding GM-CSF in Patients with Stage IIIc and IV Melanoma

Authors: Howard L. Kaufman, MD, Dae Won Kim, MD, Gail DeRaffele, RN, Josephine Mitcham, BS, Rob S. Coffin, PhD, Seunghee Kim-Schulze, PhD

Published in: Annals of Surgical Oncology | Issue 3/2010

Login to get access

Abstract

Background

An oncolytic herpes simplex virus engineered to replicate selectively in tumor cells and to express granulocyte–macrophage colony-stimulating factor (GM-CSF) was tested as a direct intralesional vaccination in melanoma patients. The work reported herein was performed to better characterize the effect of vaccination on local and distant antitumor immunity.

Methods

Metastatic melanoma patients with accessible lesions were enrolled in a multicenter 50-patient phase II clinical trial of an oncolytic herpesvirus encoding GM-CSF (OncovexGM-CSF). An initial priming dose of 106 pfu vaccine was given by intratumoral injection, followed by 108 pfu every 2 weeks to 24 total doses. Peripheral blood and tumor tissue were collected for analysis of effector T cells, CD4+FoxP3+ regulatory T cells (Treg), CD8+FoxP3+ suppressor T cells (Ts), and myeloid-derived suppressive cells (MDSC).

Results

Phenotypic analysis of T cells derived from tumor samples suggested distinct differences from peripheral blood T cells. There was an increase in melanoma-associated antigen recognized by T cells (MART-1)-specific T cells in tumors undergoing regression after vaccination compared with T cells derived from melanoma patients not treated with vaccine. There was also a significant decrease in Treg and Ts cells in injected lesions compared with noninjected lesions in the same and different melanoma patients. Similarly MDSC were increased in melanoma lesions but underwent a significant decrease only in vaccinated lesions.

Conclusions

Melanoma patients present with elevated levels of Tregs, Ts, and MDSC within established tumors. Direct injection of OncovexGM-CSF induces local and systemic antigen-specific T cell responses and decreases Treg, Ts, and MDSC in patients exhibiting therapeutic responses.
Literature
1.
Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10(4):292–303.
2.
Toda M, Martuza RL, Rabkin SD. Tumor growth inhibition by intratumoral inoculation of defective herpes simplex virus vectors expressing granulocyte-macrophage colony-stimulating factor. Mol Ther. 2000;2(4):324–9.CrossRefPubMed
3.
Hu JCC, Coffin RS, Davis CJ, et al. A Phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006;12(22):6737–47.CrossRefPubMed
4.
Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial with a second generation, GM-CSF encoding, oncolytic herpesvirus in unresectable metastatic melanoma. J Clin Oncol. 2008;26:(May 20 suppl; abstr 9008).
5.
Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.CrossRefPubMed
6.
Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.PubMed
7.
Whiteside TL. The role of immune cells in the tumor microenvironment. Cancer Treat Res. 2006;130:103–24.CrossRefPubMed
8.
Conejo-Garcia JR, Benencia F, Courreges M-C, et al. Tumor-infiltrating dendritic cell precursors recruited by a [beta]-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med. 2004;10(9):950–8.CrossRefPubMed
9.
Battaglia A, Buzzonetti A, Baranello C, et al. Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer. Cancer Immunol Immunother. 2009;58(9):1363–73.
10.
Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13.CrossRefPubMed
11.
Kaufman HL, DeRaffele G, Mitcham J, et al. Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. J Clin Invest. 2005;115(7):1903–12.CrossRefPubMed
12.
Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58(16):3491–4.PubMed
13.
Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001;61(13):5132–6.PubMed
14.
Chang CC, Ciubotariu R, Manavalan JS, et al. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol. 2002;3(3):237–43.CrossRefPubMed
15.
Najafian N, Chitnis T, Salama AD, et al. Regulatory functions of CD8+ CD28− T cells in an autoimmune disease model. J Clin Invest. 2003;112(7):1037–48.PubMed
16.
Rifa’i M, Kawamoto Y, Nakashima I, Suzuki H. Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J Exp Med. 2004;200(9):1123–34.CrossRefPubMed
17.
Xystrakis E, Dejean AS, Bernard I, et al. Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation. Blood. 2004;104(10):3294–301.CrossRefPubMed
18.
Cosmi L, Liotta F, Lazzeri E, et al. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood. 2003;102(12):4107–14.CrossRefPubMed
19.
Liu Z, Tugulea S, Cortesini R, Suciu-Foca N. Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8+CD28− T cells. Int Immunol. 1998;10(6):775–83.CrossRefPubMed
20.
Ciubotariu R, Colovai AI, Pennesi G, et al. Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+CD28− regulatory T cells. J Immunol. 1998;161(10):5193–202.PubMed
21.
Colovai AI, Liu Z, Ciubotariu R, et al. Induction of xenoreactive CD4+ T-cell anergy by suppressor CD8+ CD28− T cells. Transplantation. 2000;69(7):1304–10.CrossRefPubMed
22.
Chaput N, Louafi S, Bardier A, et al. Identification of CD8+CD25+FoxP3+ suppressive T cells in colorectal cancer tissue. Gut. 2008:gut.2008.158824.
23.
Kiniwa Y, Miyahara Y, Wang HY, et al. CD8+FoxP3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res. 2007;13(23):6947–58.CrossRefPubMed
24.
Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74 (advanced online publication).
25.
Rodriguez PC, Zea AH, Culotta KS, et al. Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem. 2002;277(24):21123–9.CrossRefPubMed
26.
Zea AH, Rodriguez PC, Atkins MB, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005;65(8):3044–8.PubMed
27.
Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92(11):4150–66.PubMed
28.
Cesana GC, DeRaffele G, Cohen S, et al. Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol. 2006;24(7):1169–77.CrossRefPubMed
29.
Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+CD25(hi) FoxP3+ regulatory T cells in cancer patients. Blood. 2006;107(6):2409–14.CrossRefPubMed
30.
Jandus C, Bioley G, Speiser DE, Romero P. Selective accumulation of differentiated FOXP3(+) CD4 (+) T cells in metastatic tumor lesions from melanoma patients compared to peripheral blood. Cancer Immunol Immunother. 2008;57(12):1795–805.CrossRefPubMed
31.
Filaci G, Fenoglio D, Fravega M, et al. CD8+CD28 T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol. 2007;179(7):4323–34.PubMed
32.
Maynard CL, Hatton RD, Helms WS, et al. Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of FoxP3 and Il10 genes in developing regulatory T cells. J Exp Med. 2009;206(2):343–57.CrossRefPubMed
33.
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63(19):6501–5.PubMed
34.
Shibakita M, Tachibana M, Dhar DK, et al. Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer. Clin Cancer Res. 1999;5(9):2464–9.PubMed
35.
Ohm JE, Gabrilovich DI, Sempowski GD, et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood. 2003;101(12):4878–86.CrossRefPubMed
36.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor FoxP3. Science. 2003;299(5609):1057–61.CrossRefPubMed
37.
Gavin MA, Rasmussen JP, Fontenot JD, et al. FoxP3-dependent programme of regulatory T-cell differentiation. Nature. 2007;445(7129):771–5.CrossRefPubMed
38.
Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al. A functionally specialized population of mucosal CD103+DCs induces FoxP3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204(8):1757–64.CrossRefPubMed
39.
Marigo I, Dolcetti L, Serafini P, et al. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008;222(1):162–79.CrossRefPubMed
40.
Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother. 2006;55(3):237–45.CrossRefPubMed
41.
Joetham A, Matsubara S, Okamoto M, et al. Plasticity of regulatory T cells: subversion of suppressive function and conversion to enhancement of lung allergic responses. J Immunol. 2008;180(11):7117–7124.PubMed
42.
Qin H, Vlad G, Cortesini R, et al. CD8+ suppressor and cytotoxic T cells recognize the same human leukocyte antigen-A2 restricted cytomegalovirus peptide. Hum Immunol. 2008;69(11):776–80.CrossRefPubMed
Metadata
Title
Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding GM-CSF in Patients with Stage IIIc and IV Melanoma
Authors
Howard L. Kaufman, MD
Dae Won Kim, MD
Gail DeRaffele, RN
Josephine Mitcham, BS
Rob S. Coffin, PhD
Seunghee Kim-Schulze, PhD
Publication date
01-03-2010
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 3/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0809-6

Other articles of this Issue 3/2010

Annals of Surgical Oncology 3/2010 Go to the issue

Breast Oncology

Ancient Greek and Greco–Roman Methods in Modern Surgical Treatment of Cancer

Gastrointestinal Oncology

Clinicopathological Features and Prognostic Factors of Proximal Gastric Carcinoma in a Population with High Helicobacter pylori Prevalence: A Single-Center, Large-Volume Study in Korea

Breast Oncology

Node Micrometastases Detection After Neoadjuvant Chemotherapy in Breast Cancer: Is It of Clinical Value?

Gynecologic Oncology

Role of Computed Tomography in the Surgical Management of Patients with Bowel Obstruction Secondary to Recurrent Ovarian Carcinoma

Colorectal Cancer

Clinically-Staged T3N0 Rectal Cancer: Is Preoperative Chemoradiotherapy the Optimal Treatment?

Letter to the Editor

Stage and Microscopic Positive Margins in the Treatment of Patients with Gastric Cancer