Vaccination with survivin and PSMA-derived peptides for controlling biochemical recurrence in prostate cancer: A pilot study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16042-e16042
Author(s):  
R. Valdagni ◽  
A. Marrari ◽  
P. Squarcina ◽  
S. Villa ◽  
P. Filipazzi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Pilot Study ◽  
Cd8 T Cells ◽  
Biochemical Recurrence ◽  
Tumor Vaccine ◽  
Low Frequency ◽  
Cross Reactivity ◽  
Treg Frequency ◽  
Priming Phase

e16042 Background: A significant percentage of patients (pts) progress after first line treatment of prostate cancer (PCa). We present preliminary results of pilot study using a multiple peptide-based anti-tumor vaccine. Methods: A phase I-II trial of vaccination (vax) with HLA-A*0201-restricted peptides from PSMA and Survivin was carried out in 20 pts with b-failure after surgery or radiotherapy (mean pre-vax PSA: 1.83 ng/ml). Vax consisted of two peptides from PSMA (PSMA4–12 and PSMA711–719) and one from Survivin (SVV96–104/97M) given by 4 fortnightly (priming) and 4 monthly administrations (boosting). To selectively eliminate regulatory T cells (Treg) and possibly enhance immunization, peptides were preceded by low dose cyclophosphamide (CTX, 300 mg/mq, i.v.). Antigen (Ag) and tumor-specific T cell responses were extensively monitored in peripheral blood together with CD4+CD25+Foxp3+ Treg frequency. PSA trend was also registered. Results: Vax was well tolerated. Most pts (19/20) showed a significant increase of SVV96–104/97M-specific T cells (mean 14 in pre-vax vs 170 in post-vax PBMC), while response to PSMA was achieved in about half of the pts and only to PSMA711–719 peptide (mean 12 in pre-vax vs 86 in post-vax PBMC). Increments of HLA-A*0201/SVV96–104/97M or PSMA711–719 multimer+ CD8+ T cells were induced in 50 and 35% pts, respectively. Vax-induced Ag-specific T cells displayed however limited cross-reactivity with HLA-A*0201+ PCa cells. No effect of CTX on Treg frequency was observed. 6 pts had no biochemical response to vax and switched to hormonal therapy, while 14/20 exhibited a significant although transient PSA decrease during vax (11 in the priming phase and 3 in boosting). Conclusions: Peptide vax could rapidly enhance Ag-specific immune responses in most treated pts. However, the reduced ability of vax-induced Ag-specific CD8+ T cells to cross-recognize PCa cells, together with their low frequency in PBMC, could explain why PSA control was achieved only transiently and in strict dependence with vax administration. Anti- tumor vax represent a useful tool for controlling PCa biochemical recurrence in the absence of major side effects, but immunization protocols inducing efficient tumor cell killing still need to be identified. No significant financial relationships to disclose.

148 Identification of prostate-restricted epithelial antigens for transgenic T cell adoptive therapy against prostate cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A161-A161
Author(s):  
Diana DeLucia ◽  
Tiffany Pariva ◽  
Roland Strong ◽  
Owen Witte ◽  
John Lee
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Adoptive Therapy ◽  
Mhc I ◽  
Epithelial Antigens ◽  
Ifn Γ ◽  
Stimulation Of

BackgroundIn advanced prostate cancer (PCa), progression to castration-resistant PCa (CRPC) is inevitable and novel therapies for CRPC are needed. Adoptive transfer of T cells targeting tumor antigens is a promising approach in the cancer field. Unfortunately, identifying antigens expressed exclusively in prostate tumor cells has been challenging. Since the prostate is not an essential organ, we alternatively selected prostate-restricted epithelial antigens (PREAs) expressed in both malignant and normal prostate tissue for transgenic T cell studies.MethodsRNA-seq data sets identifying genes enriched in PCa were cross-referenced with the NIH Genotype-Expression database to identify PREAs. Using a novel molecular immunology approach, select PREAs and major histocompatibility complex class I (MHC-I) molecules were co-expressed in HEK293F cells, from which MHC–peptide complexes were efficiently isolated. Peptides were eluted and sequenced by mass spectrometry. Peptide–MHC binding was validated with a T2 stabilization assay and peptide immunodominance was determined using an interferon-γ (IFN-γ) ELISpot assay following stimulation of healthy HLA-A2+ peripheral blood mononuclear cells (PBMC) with peptide pools. Following peptide stimulation, CD8+ T cells with peptide-specific T cell receptors (TCR) were enriched by peptide–MHC-I dextramer labeling and fluorescence activated cell sorting for single cell TCR α/β chain sequencing.ResultsWe identified 11 A2+ peptides (8 previously unpublished) from prostatic acid phosphatase (ACPP), solute carrier family 45 member 3 (SLC45A3), and NK3 homeobox 1 (NKX3.1) that bound to HLA-A2 with varying affinities. Extended culture stimulation of PBMC with peptide pools from each PREA, compared to the standard overnight culture, revealed a greater number of IFN-γ producing cells overall and a greater breadth of response across all the peptides. Antigen specific CD8+ T cells were detectable at low frequencies in both male and female healthy PBMC for 7 of the 11 peptides. Dextramer-sorted antigen-specific cells were used for single-cell paired TCR αβ sequencing and transgenic T cell development.ConclusionsThrough this work we identified HLA-A2-presented antigenic peptides from the PREAs ACPP, SLC45A3, and NKX3.1 that can induce the expansion of IFN-γ producing CD8+ T cells. Through peptide–MHC-I dextramer labeling, we isolated PREA-specific CD8+ T cells and characterized TCR αβ sequences with potential anti-tumor functionality. Our results highlight a rapid and directed platform for the development of MHC-I-restricted transgenic CD8+ T cells targeting lineage-specific proteins expressed in prostate epithelia for adoptive therapy of advanced PCa.

scholarly journals TGF-[beta]-dependent Lymphoid Tissue Residency of Stem-like T cells Limits the Response to Tumor Vaccine

2021 ◽  
Author(s):  
Guo Li ◽  
Liwen Wang ◽  
Chaoyu Ma ◽  
Wei Liao ◽  
Yong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Tumor Vaccine ◽  
Tumor Control ◽  
Lymphoid Tissues ◽  
Dependent Manner ◽  
Multiple Tumor ◽  
Draining Lymph Node ◽  
Resident Memory T Cells

Stem-like CD8+ T cells represent the key subset responding to multiple tumor immunotherapies, including tumor vaccination. However, the signals that control the differentiation of stem-like T cells are not entirely known. Most previous investigations on stem-like T cells are focused on tumor infiltrating T cells (TIL). The behavior of stem-like T cells in other tissues remains to be elucidated. Tissue-resident memory T cells (TRM) are often defined as a non-circulating T cell population residing in non-lymphoid tissues. TILs carrying TRM features are associated with better tumor control. Here, we found that stem-like CD8+ T cells differentiated into TRMs in a TGF-β and tumor antigen dependent manner almost exclusively in tumor draining lymph node (TDLN). TDLN-resident stem-like T cells were negatively associated with the response to tumor vaccine. In other words, after tumor vaccine, TDLN stem-like T cells transiently lost TRM features, differentiated into migratory effectors and exerted tumor control.

scholarly journals Protective to a T: The Role of T Cells during Zika Virus Infection

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 820 ◽  
Author(s):  
Ryan D. Pardy ◽  
Martin J. Richer
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Zika Virus ◽  
Viral Infections ◽  
Cross Reactivity ◽  
Negative Effects ◽  
Cell Responses ◽  
Recent Emergence ◽  
Human Infections

CD4 and CD8 T cells are an important part of the host’s capacity to defend itself against viral infections. During flavivirus infections, T cells have been implicated in both protective and pathogenic responses. Given the recent emergence of Zika virus (ZIKV) as a prominent global health threat, the question remains as to how T cells contribute to anti-ZIKV immunity. Furthermore, high homology between ZIKV and other, co-circulating flaviviruses opens the possibility of positive or negative effects of cross-reactivity due to pre-existing immunity. In this review, we will discuss the CD4 and CD8 T cell responses to ZIKV, and the lessons we have learned from both mouse and human infections. In addition, we will consider the possibility of whether T cells, in the context of flavivirus-naïve and flavivirus-immune subjects, play a role in promoting ZIKV pathogenesis during infection.

scholarly journals Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer

2009 ◽  
Vol 27 (25) ◽  
pp. 4047-4054 ◽  
Author(s):  
Douglas G. McNeel ◽  
Edward J. Dunphy ◽  
James G. Davies ◽  
Thomas P. Frye ◽  
Laura E. Johnson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Acid Phosphatase ◽  
T Cell ◽  
Dna Vaccine ◽  
Cd8 T Cells ◽  
Doubling Time ◽  
Prostatic Acid Phosphatase ◽  
T Cell Response ◽  
Psa Doubling Time

Purpose Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer. Patients and Methods Twenty-two patients were treated in a dose-escalation trial with 100 μg, 500 μg, or 1,500 μg plasmid DNA, coadministered intradermally with 200 μg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment. Results No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFNγ-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054). Conclusion The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.

T Cell Recognition of HCMV: Pan-Genome Analysis of Immunogenic Open-Reading Frames.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 606-606 ◽  
Author(s):  
Louis J. Picker ◽  
Andrew W. Sylwester ◽  
Bridget L. Mitchell ◽  
Cara Taormina ◽  
Christian Pelte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cross Reactivity ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses

Abstract Human Cytomegalovirus (HCMV) is among the largest and most complex of known viruses with 150–200nm virions enclosing a double stranded 230kb DNA genome capable of coding for >200 proteins. HCMV infection is life-long, and for the vast majority of immune competent individuals clinically benign. Disease occurs almost exclusively in the setting of immune deficiency, suggesting that the stable host-parasite relationship that characterizes these infections is the result of an evolutionarily “negotiated” balance between viral mechanisms of pathogenesis and the host immune response. In keeping with, and perhaps because of this balance, the human CD4+ T cell response to whole HCMV viral lysates is enormous, with median peripheral blood frequencies of HCMV-specific cells ~5–10 fold higher than for analogous preparations of other common viruses. Although certain HCMV ORFs have been identified as targets of either the CD4+ or CD8+ T cell response, the specificities comprising the CD4+ T cell response, and both the total frequencies and component parts of the CD8+ T cell response are unknown. Here, we used cytokine flow cytometry and ~14,000 overlapping 15mer peptides comprising all 213 HCMV ORFs encoding proteins >100 amino acids in length to precisely define the total CD4+ and CD8+ HCMV-specific T cell responses and the HCMV ORFs responsible for these responses in 33 HCMV-seropositive, HLA-disparate donors. An additional 9 HCMV seronegative donors were similarly examined to define the extent to which non-HCMV responses cross-react with HCMV-encoded epitopes. We found that when totaled, the median frequencies of HCMV-specific CD4+ and CD8+ T cells in the peripheral blood of the seropositive subjects were 4.0% and 4.5% for the total CD4+ or CD8+ T cell populations, respectively (which corresponds to 9.1% and 10.5% of the memory populations, respectively). The HCMV-specific CD4+ and CD8+ T cell responses included a median 12 and 7 different ORFs, respectively, and all told, 73 HCMV ORFs were identified as targets for both CD4+ and CD8+ T cells, 26 ORFs as targets for CD8+ T cells alone, and 43 ORFS as targets for CD4+ T cells alone. UL55, UL83, UL86, UL99, and UL122 were the HCMV ORFs most commonly recognized by CD4+ T cells; UL123, UL83, UL48, UL122 and UL28 were the HCMV ORFs most commonly recognized by CD8+ T cells. The relationship between immunogenicity and 1) HLA haplotype and 2) ORF expression and function will be discussed. HCMV-seronegative individuals were non-reactive with the vast majority of HCMV peptides. Only 7 potentially cross-reactive responses were identified (all by CD8+ T cells) to 3 ORFs (US32, US29 and UL116) out of a total of almost 4,000 potential responses, suggesting fortuitous cross-reactivity with HCMV epitopes is uncommon. These data provide the first glimpse of the total human T cell response to a complex infectious agent, and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.

scholarly journals Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects

2005 ◽  
Vol 202 (5) ◽  
pp. 673-685 ◽  
Author(s):  
Andrew W. Sylwester ◽  
Bridget L. Mitchell ◽  
John B. Edgar ◽  
Cara Taormina ◽  
Christian Pelte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Infectious Agent ◽  
Cross Reactivity ◽  
T Cell Response ◽  
Open Reading Frames ◽  
Human T Cell

Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4+ and/or CD8+ T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.

Mechanism of activation of natural killer and CD8 T cells by interleukin 15 in the prostate cancer microenvironment

The Lancet ◽  
2014 ◽  
Vol 383 ◽  
pp. S47
Author(s):  
Oussama Elhage ◽  
Christina Sakellariou ◽  
Osamu Ukimura ◽  
Inderbir Gill ◽  
Richard A Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Cancer Microenvironment ◽  
Interleukin 15
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