Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune cells within the prostate tumor microenvironment.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2564-2564 ◽  
Author(s):  
Lawrence Fong ◽  
Vivian K. Weinberg ◽  
Stephen E Chan ◽  
John M Corman ◽  
Christopher L Amling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Prostate Tumor ◽  
Localized Prostate Cancer ◽  
Cellular Immunotherapy ◽  
Cancer Tissue ◽  
Estimated Blood Loss ◽  
Pre Treatment

2564 Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with mCRPC have studied immune response in peripheral blood. The effects of sipuleucel-T on prostate tumors are unknown. Methods: NeoACT (P07-1; NCT00715104) is an open-label, phase 2 study of patients with localized prostate cancer who received sipuleucel-T prior to radical prostatectomy (RP) to examine the immunologic effects of treatment on prostate tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks prior to RP. The primary endpoint was the change in the frequency of lymphocytes between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP sipuleucel-T infusions. To date, tissue IHC analysis has been completed on 32 patients. Treatment-related AEs were manageable and transient. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant increases (≥3 fold) in CD3+ and CD4+ T cell populations were observed at the tumor interface (where benign and malignant glands interface), compared with the pre-treatment biopsy, benign RP tissue, and tumor RP tissue (ANOVA post hoc Newman-Keuls test: p<0.0001 for each comparison). FoxP3+ CD4+ T cells were also increased (p=0.0005) at the tumor interface, but represented a small fraction of the observed CD4+ T cells. Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased frequency of T cells in prostate cancer tissue at the interface of the benign and malignant glands. These data suggest that sipuleucel-T can modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response.

Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 181-181 ◽  
Author(s):  
Lawrence Fong ◽  
Vivian K. Weinberg ◽  
John M Corman ◽  
Christopher L Amling ◽  
Robert A Stephenson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Tumor Tissue ◽  
Cellular Therapy ◽  
Performance Status ◽  
Prostate Tumor ◽  
Localized Prostate Cancer ◽  
Cancer Tissue ◽  
Estimated Blood Loss ◽  
Pre Treatment

181 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To better understand the immunologic effects of sipuleucel-T, an open-label Phase 2 study (P07‐1; NCT00715104 ) of sipuleucel-T prior to radical prostatectomy (RP) was undertaken in patients with localized prostate cancer. Methods: Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to RP. Prostate biopsies (pre-treatment) and tissue from RP (post-treatment) were assessed for the presence of lymphocytes by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP infusions of sipuleucel-T. To date, tissue IHC analysis has been completed in 19 patients. Treatment-related AEs were manageable and reversible. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant increases (>2‐fold) in CD3+ and CD4+ T cells populations were observed at the tumor rim (where benign and malignant glands interface), compared with the pre-treatment biopsy (ANOVA post hoc Newman-Keuls test: p=0.0002, 0.0002, respectively). CD8+ T cells or CD56+ cells were not significantly increased at the tumor rim compared with benign biopsy regions. Conclusions: Neoadjuvant sipuleucel-T treatment appears to result in an increased frequency of T cells in prostate cancer tissue at the rim between the benign and malignant glands. These data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.

Antigen-specific immunity and tumor inflammation after vaccination with BPX-101, a drug-activated dendritic cell vaccine for metastatic castration-resistant prostate cancer (mCRPC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 176-176
Author(s):  
T. M. Wheeler ◽  
B. Zhao ◽  
G. Sonpavde ◽  
J. D. McMannis ◽  
Y. Bai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
T Cells ◽  
Injection Site ◽  
Specific Immune Response ◽  
Cell Vaccine ◽  
Cancer Tissue ◽  
Specific Immunity ◽  
Dc Vaccine ◽  
Prostate Cancer Tissue

176 Background: We report evidence of antigen-specific immunity and severe prostate cancer inflammation and necrosis after vaccination in patients enrolled in a phase I-IIa clinical trial of BPX-101, a drug-activated DC vaccine for mCRPC. Methods: Twelve men with progressive, mCRPC were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and activating agent AP1903. BPX-101, which targets prostate-specific membrane antigen (PSMA), was administered intradermally every 2 weeks for 6 doses, followed 24 hours after each dose by infusion of AP1903 (0.4 mg/kg). Injection site skin biopsies were performed after the fourth vaccination. T cells cultured from the skin biopsy ex vivo were stimulated with PSMA protein or control antigens, and were analyzed using Luminex microspheres for 30 inflammatory cytokines/chemokines. One patient (#1007) with an intact prostate developed lower urinary tract bleeding after the fifth vaccination and underwent a transurethral resection of bleeding prostate cancer tissue. Paraffin-embedded blocks were stained for hematoxylin and eosin (H&E). Immunohistochemical stains for CD3, CD4, CD8 and CD34 were also performed. Results: Of 5 subjects with evaluable injection site biopsy results, all exhibited PSMA-specific immunity (3 TH1-biased and 2 TH2- biased). Subject 1007's injection site biopsy demonstrated a significant >10-fold increase in IFN-gamma and IL-2 after stimulation by PSMA, compared to stimulation by ovalbumin, consistent with induction of a strong PSMA-specific CTL or TH1-biased immune response. H&E stained resected prostate tissue demonstrated Gleason 8 (4+4) prostate adenocarcinoma exhibiting a severe inflammatory response, consisting of infiltrating plasma cells and CD4+ and CD8+ T cells. Large areas of necrosis were seen adjacent to inflamed prostate cancer tissue. Conclusions: Vaccination with BPX-101 followed by AP1903 can induce a strong, PSMA-specific immune response. Furthermore, evidence of severe prostate cancer-specific inflammation and necrosis, associated with a strong PSMA-specific immune response has been observed after multiple doses of BPX-101. [Table: see text]

Anti-Leukemia Immune Responses in CML Patients Treated with Imatinib Mesylate.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1108-1108
Author(s):  
Christiane I.-U. Chen ◽  
Holden T. Maecker ◽  
Wesley H. Neal ◽  
Rhoda Falkow ◽  
Peter P. Lee
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Post Treatment ◽  
Leukemia Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cytogenetic Remission ◽  
Pre Treatment

Abstract Imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, has revolutionized the treatment of patients with chronic myelogenous leukemia (CML). Most CML patients in chronic phase achieve hematologic remission with imatinib, while some achieve cytogenetic remission. As imatinib is an oral agent with few side effects, it has rapidly become the first-line therapy for most CML patients. However, this therapy does not represent a cure, as patients who discontinue the drug invariably relapse. Furthermore, imatinib resistance is beginning to emerge in some patients. Hence, the need to find alternate, potentially curative, therapies for CML remains. To date, the only curative treatment for CML is allogeneic bone marrow or stem cell transplantation (ABMT). A major mechanism of the curative potential of ABMT is immunological, as evidenced by the poor clinical outcome with T cell-depleted ABMT, and the efficacy of donor lymphocyte infusions (DLI) upon relapse. We hypothesized that an effective anti-leukemia immune response may emerge in patients entering remission on imatinib which may contribute to its clinical effectiveness. If so, strategies to further enhance this anti-leukemia immune response may lead to a potential cure. To determine if CML patients in remission on imatinib develop anti-leukemia immune responses, blood and bone marrow samples from patients before and after treatment were collected and analyzed. Pre-treatment samples were utilized as sources of autologous leukemic cells to detect anti-leukemia immune responses in post-treatment samples in IFN-g ELISPOT assays. Pre-treatment samples alone, post-treatment samples alone, and when available, serial post-treatment samples mixed together served as controls. In 9 of 14 patients investigated, IFN-g release was detected in pre- and post-treatment samples together with a median response of 22 spots above background (range 10 – 56 dots, p&lt;0.01), whereas serial post-treatment samples together in 8 patients yielded results similar to background (median 5, range 5 – 20). In 6 of these patients in hematologic (or cytogenetic) remission, sufficient cells were available to allow additional analyses via intracellular staining for IFN-g, TNF-a, and IL-2 in autologous leukemia stimulated T cells (CD4 and CD8) and NK cells. In 4 of 6 patients, leukemia-reactive T cells were detected, most prominently in CD4+ T cells expressing TNF-a (1.4 – 37%), followed by IL-2 (0.3 – 12%) and IFN-g (0.1 – 4.6%). NK cells did not show significant expression of these cytokines upon stimulation with autologous leukemia cells. In pre-treatment and post-treatment samples alone, IL-2, TNF-a, and IFN-g expression was not detectable (0 – 0.5%). These results suggest that a significant portion of CML patients in remission with imatinib develop an anti-leukemia immune response, most notably in CD4+ T cells. Mechanisms by which imatinib treatment leads to anti-leukemia immune responses, and the molecular targets to which these cells are directed, will be further investigated. This knowledge will be useful in the development of immunotherapy strategies against CML as well as other leukemias, and raises the hope that immunotherapy may be combined with imatinib to eradicate residual leukemia cells for a durable cure of the disease. intracellular cytokine staining CD4+ T Cells CD8+ T Cells IL-2 IFN- γ TNF- α IL-2 IFN- γ TNF- α pt 1 0.3 0 0.8 0.1 0.1 0.5 pt 1 0.3 0.1 1.4 0.1 0.1 0.4 pt 2 2.6 0.8 10.3 2.2 2.1 6.1 pt 3 21 2 37 2.3 0.7 1.7 pt 4 12 4.6 19 6.3 1.8 5.8

scholarly journals Characterization of immunoactive and immunotolerant CD4+ T cells in breast cancer by measuring activity of signaling pathways that determine immune cell function

2020 ◽  
Author(s):  
Yvonne Wesseling-Rozendaal ◽  
Arie van Doorn ◽  
Karen Willard-Gallo ◽  
Anja van de Stolpe
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Treg Cells ◽  
Cd4 T Cell ◽  
Cancer Tissue ◽  
Pathway Activity

AbstractCancer immunotolerance can be reversed by checkpoint blockade immunotherapy in some patients, but response prediction remains a challenge. CD4+ T cells play an important role in activating adaptive immune responses against cancer. Conversion to an immune suppressive state impairs the anti-cancer immune response and is mainly effected by CD4+ Treg cells. A number of signal transduction pathways activate and control functions of CD4+ T cell subsets. As previously described, assays have been developed which enable quantitative measurement of the activity of signal transduction pathways (e.g. TGFβ, NFκB, PI3K-FOXO, JAK-STAT1/2, JAK-STAT3, Notch) in a cell or tissue sample. Using these assays, pathway activity profiles for various CD4+ T cell subsets were defined and cellular mechanisms underlying breast cancer-induced immunotolerance investigated in vitro. Results were used to measure the immune response state in a clinical breast cancer study.MethodsSignal transduction pathway activity scores were measured on Affymetrix expression microarray data of resting, immune-activated, and immune-activated CD4+ T cells incubated with breast cancer tissue supernatants, and of CD4+ Th1, Th2, and Treg cells, and in a clinical study in which CD4+ T cells were derived from blood, lymph node and cancer tissue from primary breast cancer patients (n=10).ResultsIn vitro CD4+ T cell activation induced PI3K, NFκB, JAK-STAT1/2, and JAK-STAT3 pathway activity. Simultaneous incubation with primary cancer supernatant reduced PI3K and NFκB, and partly reduced JAK-STAT3, pathway activity, while simultaneously increasing TGFβ pathway activity; characteristic of an immune tolerant state. CD4+ Th1, Th2, and Treg cells all had a specific pathway activity profile, with activated immune suppressive Treg cells characterized by NFκB, JAK-STAT3, TGFβ, and Notch pathway activity. An immune tolerant pathway profile was identified in CD4+ T cells from tumor infiltrate of a subset of primary breast cancer patients which could be contributed to activated Treg cells. A Treg pathway profile was also identified in blood samples.ConclusionSignaling pathway assays can be used to quantitatively measure the functional immune response state of lymphocyte subsets in vitro and in vivo. Clinical results suggest that in primary breast cancer the adaptive immune response of CD4+ T cells has frequently been replaced by immunosuppressive Treg cells, potentially causing resistance to checkpoint inhibition. In vitro study results suggest that this effect is mediated by soluble factors from cancer tissue (e.g. TGFβ). Signaling pathway activity analysis on TIL and/or blood samples is expected to improve predicting and monitoring response to checkpoint inhibitor immunotherapy.

Lymphoid and myeloid biomarkers for clinical outcome of combined immunotherapy with granulocyte-macrophage colony-stimulating factor-tranduced allogeneic prostate cancer cells (GVAX) and ipilimumab in castration-resistant prostate cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2562-2562
Author(s):  
Alfons JM van den Eertwegh ◽  
Tanja de Gruijl ◽  
Saskia Santegoets ◽  
Anita Stam ◽  
Mary E von Blomberg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Clinical Outcome ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Pre Treatment

2562 Background: In a phase-I dose escalation trial in patients with castration-resistant prostate cancer we showed that GVAX and ipilimumab had an acceptable safety profile. Moreover, we observed tumor responses and prolonged survival as compared to the Halabi predicted overall survival (OS). However, ipilimumab can also lead to severe immune-related adverse events. To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity. Methods: Patients had castration-resistant prostate cancer and were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period combined with monthly intravenous administrations of ipilimumab. Each cohort of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets in blood were performed. Results: We observed a significantly prolonged OS for patients with high pre-treatment frequencies of CD4+CTLA-4+, CD4+PD-1+, or differentiated CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or CD4+CD25hiFoxP3+ regulatory T cells. In contrast, increased frequencies of granulocytic Myeloid-Derived Suppressor Cells (MDSC) and high pre-treatment frequencies of monocytic CD14+HLA-DRlo/- MDSC were associated with reduced OS. Treatment-induced CD4+ T cell differentiation and CD4+ and CD8+ T cell activation was associated with clinical benefit. Moreover, treatment-induced activation of CD1c+ conventional Dendritic Cells (cDC) and 6-sulfo LacNAc+ inflammatory DC were associated with significantly prolonged OS. Conclusions: Together these data provide an immune profile to predict clinical outcome. Importantly, cluster analysis revealed pre-treatment, CRPC-associated expression of CTLA-4+ by CD4+ T cells to be a dominant predictor for OS after GVAX/ipilimumab. This potentially biomarker for patient selection should be validated in patients treated with ipilimumab.

scholarly journals OP0033 REGULATORY T CELL CD39 EXPRESSION AS A PREDICTOR OF EARLY REMISSION-INDUCTION WITH METHOTREXATE IN NEW-ONSET RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 18.2-18
Author(s):  
P. Brown ◽  
A. Anderson ◽  
B. Hargreaves ◽  
A. Morgan ◽  
J. D. Isaacs ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Disease Modifying Therapy ◽  
Blood Mononuclear Cells ◽  
Treatment Naïve ◽  
Disease Modifying ◽  
Pre Treatment

Background:The long term outcomes for patients with rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate remains the key first line disease modifying therapy for the majority of patients, with 40% achieving an ACR50 on monotherapy(1). There are at present no effective biomarkers to predict treatment response, preventing effective personalisation of therapy. A putative mechanism of action of methotrexate, the potentiation of anti-inflammatory adenosine signalling, may inform biomarker discovery. By antagonism of the ATIC enzyme in the purine synthesis pathway, methotrexate has been proposed to increase the release of adenosine moieties from cells, which exert an anti-inflammatory effect through interaction with ADORA2 receptors(2). Lower expression of CD39 (a cell surface 5-’ectonucleotidase required for the first step in the conversion of ATP to adenosine) on circulating regulatory T-Lymphocytes (Tregs) was previously identified in patients already established on methotrexate who were not responding (DAS28 >4.0 vs <3.0)(3). We therefore hypothesised that pre-treatment CD39 expression on these cells may have clinical utility as a predictor of early methotrexate efficacy.Objectives:To characterise CD39 expression in peripheral blood mononuclear cells in RA patients naïve to disease modifying therapy commencing methotrexate, and relate this expression to 4 variable DAS28CRP remission (<2.6) at 6 months.Methods:68 treatment naïve early RA patients starting methotrexate were recruited from the Newcastle Early Arthritis Clinic and followed up for 6 months. Serial blood samples were taken before and during methotrexate therapy with peripheral blood mononuclear cells isolated by density centrifugation. Expression of CD39 by major immune subsets (CD4+ and CD8+ T-cells, B-lymphocytes, natural killer cells and monocytes) was determined by flow cytometry. The statistical analysis used was binomial logistic regression with baseline DAS28CRP used as a covariate due to the significant association of baseline disease activity with treatment response.Results:Higher pre-treatment CD39 expression was observed in circulating CD4+ T-cells of patients who subsequently achieved clinical remission at 6 months versus those who did not (median fluorescence 4854.0 vs 3324.2; p = 0.0108; Figure 1-A). This CD39 expression pattern was primarily accounted for by the CD4+CD25 high sub-population (median fluorescence 9804.7 vs 6455.5; p = 0.0065; Figure 1-B). These CD25 high cells were observed to have higher FoxP3 and lower CD127 expression than their CD39 negative counterparts, indicating a Treg phenotype. No significant associations were observed with any other circulating subset. A ROC curve demonstrates the discriminative utility of differential CD39 expression in the CD4+CD25 high population for the prediction of DAS28CRP remission in this cohort, showing greater specificity than sensitivity for remission prediction(AUC: 0.725; 95% CI: 0.53 - 0.92; Figure 1-C). Longitudinally, no significant induction or suppression of the CD39 marker was observed amongst patients who did or did not achieve remission over the 6 months follow-up period.Figure 1.Six month DAS28CRP remission versus pre-treatment median fluorescence of CD39 expression on CD4+ T-cells (A); CD25 High expressing CD4+ T-cells (B); and ROC curve of predictive utility of pre-treatment CD39 expression on CD25 High CD4+ T-cells (C).Conclusion:These findings support the potential role of CD39 in the mechanism of methotrexate response. Expression of CD39 on circulating Tregs in treatment-naïve RA patients may have particular value in identifying early RA patients likely to respond to methotrexate, and hence add value to evolving multi-parameter discriminatory algorithms.References:[1]Hazlewood GS, et al. BMJ. 2016 21;353:i1777[2]Brown PM, et al. Nat Rev Rheumatol. 2016;12(12):731-742[3]Peres RS, et al. Proc Natl Acad Sci U S A. 2015;112(8):2509-2514Disclosure of Interests:None declared

Function and dysfunction of CD4 + T cells in the immune response to melanoma

1999 ◽  
Vol 48 (7) ◽  
pp. 363-370 ◽  
Author(s):  
Wolfgang H. Fischer ◽  
Per thor Straten ◽  
Patrick Terheyden ◽  
J&#x000FC;rgen C. Becker
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells

scholarly journals IMMU-15. PD-1 BLOCKADE ACTIVATES CD4 T CELLS AND THE INNATE IMMUNE RESPONSE FOR GLIOBLASTOMA ERADICATION

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi115-vi116 ◽  
Author(s):  
Sarah R Klein ◽  
Maria Carmela Speranza ◽  
Prafulla C Gokhale ◽  
Margaret K Wilkens ◽  
Kristen L Jones ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Innate Immune Response ◽  
Cd4 T Cells ◽  
Innate Immune
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