Analysis of PSA-Specific T-Cell Responses of Prostate Cancer Patients Given a PSA-Based Vaccine on a Clinical Trial

2003 ◽  
Author(s):  
James Gulley ◽  
William Dahut ◽  
Philip M. Arlen ◽  
Kwong Tsang ◽  
Jeffrey Schlom
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cell ◽  
Cancer Patients ◽  
T Cell Responses ◽  
Cell Responses

Phase II Randomized Study of Vaccine Treatment of Advanced Prostate Cancer (E7897): A Trial of the Eastern Cooperative Oncology Group

2004 ◽  
Vol 22 (11) ◽  
pp. 2122-2132 ◽  
Author(s):  
Howard L. Kaufman ◽  
Wei Wang ◽  
Judith Manola ◽  
Robert S. DiPaola ◽  
Yoo-Joung Ko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cell ◽  
Phase Ii ◽  
Eastern Cooperative Oncology Group ◽  
T Cell Responses ◽  
Oncology Group ◽  
Clinical Progression ◽  
Cell Responses ◽  
Antibody Titers

Purpose A phase II clinical trial was conducted to evaluate the feasibility and tolerability of a prime/boost vaccine strategy using vaccinia virus and fowlpox virus expressing human prostate-specific antigen (PSA) in patients with biochemical progression after local therapy for prostate cancer. The induction of PSA-specific immunity was also evaluated. Patients and Methods A randomized clinical trial was conducted by the Eastern Cooperative Oncology group and 64 eligible patients were randomly assigned to receive four vaccinations with fowlpox-PSA (rF-PSA), three rF-PSA vaccines followed by one vaccinia-PSA (rV-PSA) vaccine, or one rV-PSA vaccine followed by three rF-PSA vaccines. The major end point was PSA response at 6 months, and immune monitoring included measurements of anti-PSA and anti-vaccinia antibody titers and PSA-specific T-cell responses. Results The prime/boost schedule was well tolerated with few adverse events. Of the eligible patients, 45.3% of men remained free of PSA progression at 19.1 months and 78.1% demonstrated clinical progression-free survival. There was a trend favoring the treatment group that received a priming dose of rV-PSA. Although no significant increases in anti-PSA antibody titers were detected, 46% of patients demonstrated an increase in PSA-reactive T-cells. Conclusion Therapy with poxviruses expressing PSA and delivered in a prime/boost regimen was feasible and associated with minimal toxicity in the cooperative group setting. A significant proportion of men remained free of PSA and clinical progression after 19 months follow-up, and nearly half demonstrated an increase in PSA-specific T-cell responses. Phase III studies are needed to define the role of vaccination in men with prostate cancer or those who are at risk for the disease.

scholarly journals Human kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients

2011 ◽  
Vol 61 (2) ◽  
pp. 169-179 ◽  
Author(s):  
Ray Wilkinson ◽  
Katherine Woods ◽  
Rachael D’Rozario ◽  
Rebecca Prue ◽  
Frank Vari ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Cancer Patients ◽  
Signal Peptide ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Healthy Donors ◽  
Kallikrein 4 ◽  
Cytotoxic T Cell Responses

RNA Based Cancer Vaccines - Clinical Trials in Patients with Prostate Cancer and Malignant Melanoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1805-1805
Author(s):  
Gunnar Kvalheim ◽  
Steinar Aamdal ◽  
Gustav Gaudernack
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Malignant Melanoma ◽  
Cancer Patients ◽  
Ex Vivo ◽  
T Cell Responses ◽  
T Cell Response ◽  
Patient Specific ◽  
Cell Responses ◽  
Melanoma Patients

Abstract Anti-tumour vaccines targeting the entire tumour antigen repertoire represent an attractive immunotherapeutic approach. This repertoire is present in the total mRNA isolated from the tumour. The mRNA from each cancer patient may be amplified and thus overcome the problem of limitation of material that has hampered the development of individualized vaccines. We have developed immuno-gene-therapy for malignant melanoma and prostate cancer. Monocyte-derived dendritic dells are transfected with autologous melanoma-mRNA or mRNA from three prostate cancer cell lines (DU-145, LN-CaP and PC-3). The vaccines may generate T cell responses against a broad repertoire of tumor-associated epitopes, and the melanoma approach moreover target patient-specific tumor antigens. Effective protocols were established for mRNA-transfection by square wave electroporation and for generation of clinical grade dendritic cells. A full scale preclinical evaluation demonstrated in vitro T cell responses in 6/6 advanced melanoma patients. The responses were specific to antigens encoded by the transfected tumor-mRNA. Recently, we have conducted two phase I/II trials, in advanced malignant melanoma and androgen-resistant prostate cancer. Successful vaccine preparations were obtained for all 41 patients elected. No serious adverse effects were observed. Specific T cell responses (T cell proliferation and/or IFNγ ELISPOT) were demonstrated in 9/19 evaluable melanoma patients and in 12/19 prostate cancer patients. The response rates were higher for patients receiving intradermal vaccination, compared to intranodal injection. Thirteen prostate cancer patients developed a decrease in log-slope PSA. The PSA-response was significantly related to the T cell response (p=0,002). We conclude that the tumour mRNA based DC-vaccine is feasible and safe, and that T cell responses are elicited in about 50% of patients. In the next generation clinical protocols, patients will undergo Treg depletion by chemotherapy (Temozolomide) prior to DC vaccination. Subsequently, T cells will be expanded ex vivo using the Dynabeads Clin Ex Vivo system before re-infusion into the patients.

Identification and characterisation of adenovirus specific T cell responses in prostate cancer patients receiving ADV5-RSV-TK gene therapy

2002 ◽  
Vol 1 (1) ◽  
pp. 8
Author(s):  
Richard van der Linden ◽  
Chris Bangma ◽  
Albert Osterhaus ◽  
Bart Haagmans
Keyword(s):  
Prostate Cancer ◽  
Gene Therapy ◽  
T Cell ◽  
Cancer Patients ◽  
T Cell Responses ◽  
Cell Responses

scholarly journals Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

2021 ◽  
Vol 9 (5) ◽  
pp. e002254
Author(s):  
Meenal Sinha ◽  
Li Zhang ◽  
Sumit Subudhi ◽  
Brandon Chen ◽  
Jaqueline Marquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
T Cell Responses ◽  
Castration Resistant Prostate Cancer ◽  
Cell Responses ◽  
Castration Resistant ◽  
Clinical Responses

BackgroundSipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.MethodsA total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.ResultsWe found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.ConclusionCombining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.

UP-02.085 Antigen-Specific T-Cell Responses Against Tumor-Antigens Are Controlled by Regulatory T-Cells in Prostate Cancer Patients

Urology ◽  
2011 ◽  
Vol 78 (3) ◽  
pp. S289
Author(s):  
B. Hadaschik ◽  
Y. Su ◽  
E. Hadaschik ◽  
M. Hohenfellner ◽  
P. Beckhove
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Tumor Antigens ◽  
T Cell Responses ◽  
Cell Responses

889 ANTIGEN-SPECIFIC T CELL RESPONSES AGAINST TUMOR-ANTIGENS ARE CONTROLLED BY REGULATORY T CELLS IN PROSTATE CANCER PATIENTS

2011 ◽  
Vol 185 (4S) ◽  
Author(s):  
Boris Hadaschik ◽  
Yun Su ◽  
Eva Hadaschik ◽  
Markus Hohenfellner ◽  
Philipp Beckhove
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Tumor Antigens ◽  
T Cell Responses ◽  
Cell Responses

scholarly journals 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A438-A438
Author(s):  
Mara Shainheit ◽  
Devin Champagne ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
Ece Bicak ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

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