Inflammatory Adverse Events are Associated with Disease-Free Survival after Vaccine Therapy among Patients with Melanoma (original) (raw)
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Clinical Cancer Research, 2007
Purpose: Human melanoma cells express shared antigens recognized by CD8 + T lymphocytes, the most common of which are melanocytic differentiation proteins and cancer-testis antigens. However, peptide vaccines for melanoma usually target only one or two MHC class I^associated peptide antigens. Because melanomas commonly evade immune recognition by selective antigen loss, optimization of melanoma vaccines may require development of more complex multipeptide vaccines. Experimental Design: In a prospective randomized clinical trial, we have evaluated the safety and immunogenicity of a vaccine containing a mixture of 12 peptides from melanocytic differentiation proteins and cancer-testis antigens, designed for human leukocyte antigen types that represent 80% of the melanoma patient population. This was compared with a four-peptide vaccine with only melanocytic differentiation peptides. Immune responses were assessed in peripheral blood and in vaccine-draining lymph nodes. Results: These data show that (a) the 12-peptide mixture is immunogenic in all treated patients; (b) immunogenicity of individual peptides is maintained despite competition with additional peptides for binding to MHC molecules; (c) a broader and more robust immune response is induced by vaccination with the more complex 12-peptide mixture; and (d) clinical outcome in this peptide vaccine trial correlates with immune responses measured in the peripheral blood lymphocytes. Conclusions: These data support continued investigation of complex multipeptide vaccines for melanoma.
Cancer, 2010
The authors investigated whether there was a relationship between the induction of a delayed-type hypersensitivity (DTH) response to melanoma vaccine immunization and disease recurrence. They studied prospectively 94 evaluable patients with surgically resected Stage I1 malignant melanoma who were immunized to a partially purified, polyvalent, melanoma antigen vaccine. The DTH response to skin tests to the vaccine was measured before treatment and at the fourth vaccine immunization. Vaccine treatment induced a strong DTH response in 29 (31%) patients, an intermediate response in 24 (25%), and no response in 41 (44%). The median diseasefree survival (DFS) of patients with a strong, intermediate, and no DTH response to vaccine immunization was more than 72 months, 24 months, and 15 months, respectively. The relationship between an increase in the DTH response and a prolonged DFS was statistically significant (P = 0.02); clinically meaningful (the median DFS of patients with a strong DTH response was 4.7 years longer than that of nonresponders); and, by multivariate analysis, independent of disease severity or overall immune competence. These findings suggest, but do not prove, that vaccine treatment can slow the progression of melanoma in some patients.
Clinical Cancer Research, 2009
Purpose: Autologous melanoma cells display a broad variety of tumor antigens and were used for treatment of American Joint Committee on Cancer stages III and IV melanoma as an adjuvant or active therapy. Survival data and immune response were evaluated in vaccinated patients. Experimental Design: Forty-seven patients received 2,4-dinitrophenyl-conjugated autologous melanoma vaccine as an adjuvant (23 patients) or therapy (24 patients). CD4 and CD8 T-cell response in blood sampled before vaccination and after five or eight vaccine doses was evaluated against melanoma cells and autologous peripheral blood mononuclear cells using IFNγ enzyme-linked immunospot. Serum levels of antilivin, an inhibitor of apoptosis, and anti-gp100 IgG were determined. Results: The immunologic effect of the vaccine differed between the two groups of patients. In the adjuvant group, there was a significant increase in CD8 melanomareactive T cells (P = 0.035) after vaccination and an increase in antimelanoma CD4 T cells correlating with improved overall survival (P = 0.04). In the therapeutic group, there was no objective tumor regression; antimelanoma T-cell reactivity increased by a small amount, stayed the same, or in some cases decreased. In all patients, a significant increase was noted in CD4 T-cell reactivity against autologous peripheral blood mononuclear cells (P = 0.02), which did not affect survival. Increased antilivin IgG was associated with improved survival. Expression of MHC class II on melanoma cells was vital for the immunogenicity of the vaccine. Conclusion: Autologous melanoma cell vaccine is capable of inducing effective antimelanoma CD4 T-cell activity associated with improved survival. Patients with active metastatic disease generally displayed reduced immune response and gained little from active immunization.
International Journal of Cancer, 2001
Many peptide epitopes for cytotoxic T lymphocytes (CTLs) have been identified from melanocytic differentiation proteins. Vaccine trials with these peptides have been limited mostly to those associated with HLA-A2, and immune responses have been detected inconsistently. Cases of clinical regression have been observed after peptide vaccination in some trials, but melanoma regressions have not correlated well with T-cell responses measured in peripheral blood lymphocytes (PBLs). We vaccinated stage IV melanoma patients with a mixture of gp100 and tyrosinase peptides restricted by HLA-A1 (DAEKSDICTDEY), HLA-A2 (YLEPGPVTA and YMDGTMSQV) and HLA-A3 (ALLAVGATK) in an emulsion with GM-CSF and Montanide ISA-51 adjuvant. CTL responses were assessed in PBLs and in a lymph node draining a vaccine site (sentinel immunized node, SIN). We found CTL responses to vaccinating peptides in the SIN in 5/5 patients (100%). Equivalent assays detected peptide-reactive CTLs in PBLs of 2 of these 5 patients (40%). CTLs expanded from the SIN lysed melanoma cells naturally expressing tyrosinase or gp100. We demonstrated immunogenicity for peptides restricted by HLA-A1 and -A3 and for 1 HLA-A2 restricted peptide, YMDGTMSQV. Immune monitoring of clinical trials by evaluation of PBLs alone may under-estimate immunogenicity; evaluation of SIN provides a new and sensitive approach for defining responses to tumor vaccines and correlating these responses with clinical outcomes. This combination of an immunogenic vaccine strategy with a sensitive analysis of CTL responses demonstrates the potential for inducing and detecting anti-tumor immune responses in the majority of melanoma patients.
Melanoma vaccines: The problems of local immunosuppression
Human Immunology, 2009
The incidence of cutaneous melanoma in Europe is rising, and the disease is incurable once metastases occur. Because melanoma expresses antigens that can be specifically recognized by the immune system, and because this disease occasionally undergoes spontaneous regression mediated by anti-tumor immunity, a number of different melanoma vaccines have been developed and tested clinically. Although most such vaccines show efficacy in vitro and an ability to stimulate anti-melanoma immune responses in blood, they have proved disappointing in clinical practice. It has become increasingly clear that the interaction between melanoma and the immune system is determined locally, within the tumor or draining lymph nodes. It is now clear that melanoma cells have the ability to anergize the immune system by inducing an immunosuppressive microenvironment that may explain the inability of systemic vaccines to alter patient outcomes. This subversion of the immune system involves alteration of dendritic cell (DC) function by tumor-derived cytokines, leading to the generation of suppressive and regulatory T lymphocytes. Successful melanoma vaccination probably requires therapeutic neutralization of the immunosuppressive microenvironment, which will require greater understanding of the molecular mechanisms used by the tumor to promote immunosuppression. Nevertheless, if these problems can be overcome, it seems likely that the efficacy of melanoma vaccines could be greatly enhanced. ᭧ Cutaneous melanoma affects approximately 60,000 patients each year in Europe, resulting in approximately 14,400 deaths, and the incidence is still rising. The prognosis for the patient with a melanoma depends upon its extent: although the 5-year survival is close to 90% for localized malignancies, it is less than 20% once the patient has distant metastases [1].
Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma
2011
Douglas J. Schwartzentruber, M.D., David H. Lawson, M.D., Jon M. Richards, M.D., Ph.D., Robert M. Conry, M.D., Donald M. Miller, M.D., Ph.D., Jonathan Treisman, M.D., Fawaz Gailani, M.D., Lee Riley, M.D., Ph.D., Kevin Conlon, M.D., Barbara Pockaj, M.D., Kari L. Kendra, M.D., Ph.D., Richard L. White, M.D., Rene Gonzalez, M.D., Timothy M. Kuzel, M.D., Brendan Curti, M.D., Phillip D. Leming, M.D., Eric D. Whitman, M.D., Jai Balkissoon, M.D., Douglas S. Reintgen, M.D., Howard Kaufman, M.D., Francesco M. Marincola, M.D., Maria J. Merino, M.D., Steven A. Rosenberg, M.D., Ph.D., Peter Choyke, M.D., Don Vena, B.S., and Patrick Hwu, M.D.
2012
ECOG 1696 was a Phase II multi-center trial testing vaccination with melanoma peptides, gp100, MART-1 and tyrosinase delivered alone, with GM-CSF, IFN-a2b or both cytokines to HLA-A2 1 patients with metastatic melanoma. Here, the frequency of circulating CD8 1 tetramer 1 (tet 1 ) T cells and maturation stages of responding T cells were serially monitored and compared with baseline values in a subset of patients (n 5 37) from this trial. Multiparameter flow cytometry was used to measure the frequency of CD8 1 T cells specific for gp100, MART-1, tyrosinase and influenza (FLU) peptides. Expression of CD45RA/CCR7 on CD8 1 tet 1 T cells and CD25, CD27, CD28 on all circulating T cells was determined. Vaccine-induced changes in the CD8 1 tet 1 T cell frequency and phenotype were compared with results of IFN-c ELISPOT assays and with clinical responses. The frequency of CD8 1 tet 1 T cells in the circulation was increased for the melanoma peptides (p < 0.03-0.0001) but not for FLU (p < 0.9). Only gp100-and MART-1-specific T cells differentiated to CD45RA 1 CCR7effector/memory T cells. In contrast to the IFN-c ELISPOT frequency, previously correlated with overall survival (Kirkwood et al., Clin Cancer Res 2009;15:1443-51), neither the frequency nor differentiation stage of CD8 1 tet 1 T cells correlated with clinical responses. Delivery of GM-CSF and/or IFN-a2b had no effects on the frequency or differentiation of CD8 1 tet 1 , CD81 or CD41 T cells. Phenotypic analyses of CD8 1 tet 1 T cells did not correlate with clinical responses to the vaccine, indicating that functional assessments of peptide-specific T cells are preferable for monitoring of anti-tumor vaccines.
Clinical Cancer Research, 2013
Purpose: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. Experimental Design: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CTL (12MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6MHP) alone (group D), in incomplete Freund's adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro-stimulated IFN-γ ELIspot assay, and HTL responses were assessed using a proliferation assay. Results: In groups A to D, respectively, CTL response rates to 12 melanoma peptides were 43%, 47%, 28%, and 5%, and HT...