Phase I adjuvant trial of multi-epitope p53 vaccine for patients with squamous cell carcinoma of the head and neck (SCCHN): A preliminary report

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
P. Andrade ◽  
A. Deleo ◽  
C. Visus ◽  
L. Butterfield ◽  
A. Argiris ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Antigen Processing ◽  
Vaccine Trial ◽  
Primary Lung Cancer ◽  
Delayed Type Hypersensitivity ◽  
Immune Recognition ◽  
Hla Antigen ◽  
Helper Peptide ◽  
P53 Peptides

3012 Background: Alteration in the tumor suppressor protein, p53, is one of the most common events in human cancers. Since most mutations of p53 are associated with accumulation of p53, the nonmutated portions of protein are readily accessible to degradation into wild type (wt) sequence peptides for immune recognition by T lymphocytes. Methods: A phase I trial was conducted in stage I-IVa patients (pts) with SCCHN with no active disease using autologous dendritic cells (DC) loaded with two HLA-A*0201-restricted T cell-defined p53 peptides alone (Arm 1, 5 pts), plus either a wt p53 helper peptide (Arm 2, 5 pts) or nonspecific helper peptide (dervied from tetanus toxoid, Arm 3, 6 pts). The accrual goal is 24 patients, divided into the 3 arms. Each pt received 3 intranodal vaccinations at 2-week intervals. The primary endpoint was immunological response using ELISPOT, tetramer or delayed type hypersensitivity (DTH)reactions to p53 peptides. Results: 16 pts have been vaccinated so far. Erythema or hematoma were observed at vaccine injection sites in two pts. At 15-mo median follow-up, 11/16 pts are alive without evidence of disease, 2 developed disease recurrence, and 1 pt developed a second primary lung cancer. Two have died of unrelated causes. Immunological analyses of the SCCHN patients’ responses to immunization indicate responses to both HLA-A2 binding peptides. Tetramer frequencies for p53-specific CTL or IFN-gamma ELISPOT assays indicated a 5/16 responders. Ongoing correlative analyses include characterization of human papillomavirus (HPV) infection, HLA, antigen processing machinery, and staining with soluble T cell receptor for HLA-A2-p53 peptide complexes on tumor cells. Conclusions: Adjuvant p53 peptide-loaded DC-based vaccination is feasible and safe in pts with SCCHN. A phase II wt p53-based vaccine trial will be proposed based on the most efficacious regimen used in this trial. No significant financial relationships to disclose.

scholarly journals Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India

PLoS ONE ◽  
2020 ◽  
Vol 15 (2) ◽  
pp. e0229461
Author(s):  
Sivasankaran Munusamy Ponnan ◽  
Peter Hayes ◽  
Natalia Fernandez ◽  
Kannan Thiruvengadam ◽  
Sathyamurthi Pattabiram ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Vaccine Trial ◽  
T Cell Responses ◽  
Prophylactic Vaccine ◽  
Subtype C ◽  
Cell Responses ◽  
Hiv 1

scholarly journals Helper T-Cell Responses and Clinical Activity of a Melanoma Vaccine With Multiple Peptides From MAGE and Melanocytic Differentiation Antigens

2008 ◽  
Vol 26 (30) ◽  
pp. 4973-4980 ◽  
Author(s):  
Craig L. Slingluff ◽  
Gina R. Petroni ◽  
Walter Olson ◽  
Andrea Czarkowski ◽  
William W. Grosh ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Peptide Vaccine ◽  
T Cell Responses ◽  
Delayed Type Hypersensitivity ◽  
Clinical Activity ◽  
Melanoma Vaccine ◽  
Cell Responses ◽  
Measurable Disease ◽  
Dose Levels

PurposeA phase I/II trial was performed to evaluate the safety and immunogenicity of a novel melanoma vaccine comprising six melanoma-associated peptides defined as antigenic targets for melanoma-reactive helper T cells. Source proteins for these peptides include MAGE proteins, MART-1/MelanA, gp100, and tyrosinase.Patients and MethodsThirty-nine patients with stage IIIB to IV melanoma were vaccinated with this six-peptide mixture weekly at three dose levels, with a preceding phase I dose escalation and subsequent random assignment among the dose levels. Helper T-lymphocyte responses were assessed by in vitro proliferation assay and delayed-type hypersensitivity skin testing. Patients with measurable disease were evaluated for objective clinical response by Response Evaluation Criteria in Solid Tumors.ResultsVaccination with the helper peptide vaccine was well tolerated. Proliferation assays revealed induction of T-cell responses to the melanoma helper peptides in 81% of patients. Among 17 patients with measurable disease, objective clinical responses were observed in two patients (12%), with response durations of 1 and 3.9+ years. Durable stable disease was observed in two additional patients for periods of 1.8 and 4.6+ years.ConclusionResults of this study support the safety and immunogenicity of a vaccine comprised of six melanoma helper peptides. There is also early evidence of clinical activity.

Allogeneic dendritic cell (DC) vaccination as an “off the shelf” treatment to prevent or delay relapse in elderly acute myeloid leukemia patients: Results of phase I study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3029-3029
Author(s):  
Arjan A van den Loosdrecht ◽  
Saskia Santegoets ◽  
Sandra van Wetering ◽  
Satwinder Kaugh Singh ◽  
Malika Koppes ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Cell Line ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Leukemia Cell Line ◽  
Delayed Type Hypersensitivity ◽  
Post Vaccination ◽  
Tumor Associated Antigens

3029 Background: Vaccines against tumor-associated antigens represent an appealing strategy for preventing tumor recurrence. A novel immunotherapy platform is represented by the DCOne cell line, which originates from a human myeloid leukemia cell line, endogenously expresses a range of tumor associated antigens and can be differentiated into mature dendritic cells. Methods: A phase I study enrolled 12 AML patients (age range 58-71) who were either in CR1/CR2 (n=5) or had smouldering disease (n=7), at high risk of relapse and ineligible for available post-remission therapies, in a 3+3 design, starting with 4 bi-weekly intradermal DCOne DC vaccinations of 10E6 cells (n=3), 25E6 (n=3) or 50E6 (n=6). Patients were monitored for clinical and immunological responses for 126 days and surviving patients were followed up after study completion. Results: Treatment was well tolerated in all patients, with expected toxicities of injection site reactions (< grade 2). During the study 3 patients died: 2 from infections and 1 from leukemia. Patients who survived more than 6 months post-vaccination showed remarkable survival (22 mo after the first patient was recruited, 3 patients have been alive for 22, 20 and 16 months respectively). One patient with smouldering AML at entry achieved CR2 after vaccination; one patient who was in CR2 at entry, relapsed 8 mo after vaccination and entered CR3 following a single low dose of 5-AZA. Remarkably, 1/5 patients that were evaluable by IFNg ELIPOTs showed vaccination-induced specific T cell responses to WT-1 and PRAME, antigens present in DCOne DC. In addition, increased post vaccination delayed type hypersensitivity reactions were observed in all cohorts. Furthermore, induction of systemic immune responses, with increases in CD4+ and CD8+ T cell proliferative responses and/or seroconversion to DCOne DC and/or AML blasts was seen in 5 out of 9 patients. Conclusions: Vaccination with DCOne derived DC is feasible in AML, generated cellular and humoral immune responses, and interesting clinical responses. The hypothesis that immune responses correlate with clinical benefit will be investigated in a randomised phase II trial. Clinical trial information: NCT01373515.

scholarly journals Immune regulation of in vitro murine megakaryocyte development. Role of T lymphocytes and Ia antigen expression.

1985 ◽  
Vol 162 (6) ◽  
pp. 2053-2067 ◽  
Author(s):  
M W Long ◽  
D N Shapiro
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
T Lymphocytes ◽  
Progenitor Cells ◽  
Immune Modulation ◽  
Immune Recognition ◽  
Activated T Cells ◽  
Ia Antigen ◽  
Cell Cycle Status

Mitogen-activated murine T lymphocytes or T cell hybridomas produce an activity (megakaryocyte [Mk] potentiator activity) that enhances the in vitro growth and development of Mk colonies. This activity was found in optimal concentrations (2.5%) in T cell hybridoma-conditioned medium, and was also produced by feeder layers of concanavalin A-activated T cells. A subpopulation of murine Mk progenitor cells (colony-forming units; CFU-Mk) bears the Ia antigen. Separate experiments indicated that T cell products stimulate CFU-Mk by increasing their basal levels of Ia expression as well as the frequency of cells actively synthesizing DNA. The hypothesis that the expression of this antigen was related to the cell cycle status of these progenitor cells was confirmed in studies that indicated that ablation of actively cycling cells in vivo abrogated the cytotoxic effects of anti-Ia monoclonal antibodies. The interdependence of T cell lymphokine regulation of both Ia expression and cell cycle status was also seen in in vitro experiments in which Ia+ progenitor cells were eliminated by complement-dependent cytotoxicity. The removal of Ia+ cells prevented 5-hydroxyurea-mediated inhibition of cells in S phase. We hypothesize that immune modulation of megakaryocytopoiesis occurs via soluble T cell products that augment Mk differentiation. Further, the mechanism of immune recognition/modulation may occur via Ia antigens present on the surface of these progenitor cells.

scholarly journals Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement

2021 ◽  
Author(s):  
Koen A. Marijt ◽  
Lisa Griffioen ◽  
Laura Blijleven ◽  
Sjoerd. H. van der Burg ◽  
Thorbald van Hall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Signal Sequence ◽  
Cell Repertoire ◽  
Cross Presentation ◽  
Normal Tissues ◽  
Cell Immunity

AbstractCancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.

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