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  • American Association for Cancer Research (AACR)  (17)
  • 1
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    K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 1 ( 2010-01-01), p. 338-347
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 1 ( 2010-01-01), p. 338-347
    Abstract: Purpose: Chronic myeloid leukemia (CML) can be responsive to T-cell–mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a GM-CSF producing vaccine derived from a CML cell line that expresses several CML-associated antigens. A pilot study was developed to determine if K562/GM-CSF immunotherapy could improve clinical responses to imatinib mesylate (IM) in patients with chronic myeloid leukemia. Experimental Design: Patients with chronic phase CML who achieved at least a major cytogeneic response but remained with persistent, measurable disease despite one or more years on imatinib mesylate were eligible. Each was given a series of four vaccines administered in three-week intervals, with or without topical imiquimod, while remaining on a stable dose of imatinib mesylate. CML disease burden was measured serially before and after vaccination. Results: Nineteen patients were vaccinated, with a median duration of previous imatinib mesylate therapy of 37 (13–53) months. Mean PCR measurements of BCR-ABL for the group declined significantly following the vaccines (P = 0.03). Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable. Conclusions: K562/GM-CSF vaccine appears to improve molecular responses in patients on imatinib mesylate, including achieving complete molecular remissions, despite long durations of previous imatinib mesylate therapy. Clin Cancer Res; 16(1); 338–47
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-2046
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 2
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    Abstract 5252: CC-223, a selective and potent mTOR kinase inhibitor, synergizes with 5-Aza and Erlotinib in eight NSCLC lines in vitro.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5252-5252
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5252-5252
    Abstract: CC-223 is a potent and selective mTOR kinase inhibitor currently undergoing Phase 1 clinical evaluation. We evaluated combinatorial effect of CC-223 with 5-Aza and erlotinib at three different ratios of the two combining agents in three different orders of addition in eight NSCLC lines. Combinational indices (CIs) were calculated based upon published method (Chou and Talalay, 1984). CC-223 synergized with azacitidine (CI & lt;0.7) in most of the lines at all ratios of combination when azacitidine was added first to the cells (SeqM2). Synergism (CI & lt;0.7) and moderate synergism (0.7 & lt;CI & lt;0.85) was also observed in some cell lines when CC-223 was added first (SeqM1) or simultaneously (Sim) with azacitidine; however, SeqM2 seems to generate better synergistic effect across all lines than SeqM1 and Sim. In SeqM2 addition, no significant difference was observed among different ratios of the two agents. CC-223 synergized with erlotinib (CI & lt;0.7) in most of the cell lines at a ratio of 1:30 (CC-223:erlotinib). Synergism and moderate synergism (0.7 & lt;CI & lt;0.85) were also observed at other ratios. Order of addition had no impact on the combinatorial effect for CC-223+erlotinib. Overall, the data demonstrated that CC-223 synergizes with azacitidine and erlotinib in multiple NSCLC cell lines in vitro. Order of addition has an impact for CC-223 combination with 5-Aza but not with Erlotinib. On the other hand, ratio of the two combinatorial agents is important for CC-223+erlotinib combination in vitro. Citation Format: Tam Tran, Kristen Hege, Deborah Mortensen, Heather Raymon, Shuichan Xu. CC-223, a selective and potent mTOR kinase inhibitor, synergizes with 5-Aza and Erlotinib in eight NSCLC lines in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5252. doi:10.1158/1538-7445.AM2013-5252
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-5252
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
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    detail.hit.zdb_id: 410466-3
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  • 3
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    Allogeneic Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Immunotherapy Alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation
    American Association for Cancer Research (AACR) ; 2008
    In:  Clinical Cancer Research Vol. 14, No. 5 ( 2008-03-01), p. 1455-1463
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 5 ( 2008-03-01), p. 1455-1463
    Abstract: Purpose: The combination of chemotherapy and immunotherapy has not been examined in patients with advanced pancreatic cancer. We conducted a study of two granulocyte macrophage colony-stimulating factor–secreting pancreatic cancer cell lines (CG8020/CG2505) as immunotherapy administered alone or in sequence with cyclophosphamide in patients with advanced pancreatic cancer. Experimental Design: This was an open-label study with two cohorts: cohort A, 30 patients administered a maximum of six doses of CG8020/CG2505 at 21-day intervals; and cohort B, 20 patients administered 250 mg/m2 of cyclophosphamide i.v. 1 day before the same immunotherapy given as in cohort A. The primary objective was to evaluate safety and duration of immunity. Secondary objectives included time to disease progression and median overall survival. Results: The administration of CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity. Median survival values in cohort A and cohort B were 2.3 and 4.3 months, respectively. CD8+ T-cell responses to HLA class I–restricted mesothelin epitopes were identified predominantly in patients treated with cyclophosphamide + CG8020/CG2505 immunotherapy. Conclusion: Granulocyte macrophage colony-stimulating factor–secreting pancreatic cancer cell lines CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity in patients with advanced pancreatic cancer. Also, mesothelin-specific T-cell responses were detected/enhanced in some patients treated with CG8020/CG2505 immunotherapy. In addition, cyclophosphamide-modulated immunotherapy resulted in median survival in a gemcitabine-resistant population similar to chemotherapy alone. These findings support additional investigation of cyclophosphamide with CG8020/CG2505 immunotherapy in patients with advanced pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-07-0371
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 4
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    Abstract 5588: T cell activation in relation to clinical responsiveness in patients with metastatic hormone-refractory prostate cancer receiving combined Prostate GVAX and anti-CTLA4 immunotherapy
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5588-5588
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5588-5588
    Abstract: The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). Patients received a 500 million cell GVAX priming dose on day 1 followed by 12 bi-weekly intradermal administrations of 300 million cells, while Ipilimumab was administered every 4 wks from day 1 for a total of 6 times. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was clinically active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3-5 mg/kg Ipilimumab doses and PSA stabilizations (Stable Disease, SD) were observed in 1/3 pts in lower (0.3 and 1 mg/kg), and in 7/22 in the higher (3-5 mg/kg) dose levels. Phenotypic and functional (anti-tumor) effector T cell activation was monitored to identify changes that might predict or correlate with clinical efficacy. Most notably, pronounced and significant increases in frequencies of activated and effector CD4+ and CD8+ T cells were observed by HLA-DR and ICOS expression upon administration of high (3 and 5 mg/kg) but not of low (0.3 and 1 mg/kg) Ipilimumab doses. We also observed a significant increase of CTLA4 and PD-1 expression on CD4+ T cells compared to pre-treatment values in the 3 mg/kg Ipilimumab-administered patients. The latter might be indicative of the induction of concomitant negative feedback signaling. As an indiciation of Tumor-Associated Antigen (TAA) specific responsiveness we tested HLA-Tetramer (Tm) reactivity to NY-ESO and PSMA in HLA-A2 or -A3 positive patients. For NY-ESO, GVAX/Ipi-induced increased seroreactivity (by Western Blot or ELISA) was observed in 6/28 patients. Of these 6 patients, three could be tested for Tm reactivity and in two (1SD, 1 Progressive Disease, PD) increased NY-ESO157 rates were found concomitant with increasing serum Ab levels, whereas no Tm reactivity was detected in 8 patients without seroconversions. Whereas PSMA seroconversions were observed in a total of 12/28 patients (and of note, in 4/5 PR), no Tm positivity at any time was found in a total of 15 patients tested. Further functional Treg and CTL analyses are ongoing. So far, only early HLA-DR upregulation on CD4+ or CD8+ T cells (visit 1 versus visit 3) showed any value for response prediction, since it was observed to significant levels in patients with PR or SD, but not in patients with PD. Citation Format: {Authors}. {Abstract title} [abstract] . In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5588.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-5588
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 5
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    Abstract 2934: Increased type-2 T cell rates and coincidence of Th17 spikes with autoimmune events and PSA declines upon combined prostate GVAX and anti-CTLA4 immunotherapy
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2934-2934
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2934-2934
    Abstract: The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). All patients received a 500 million cell priming dose of GVAX on day 1 followed by bi-weekly intradermal treatments of 300 million cells over a 24-week period. Ipilimumab was administered every 4 wks from day 1 during the same period. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3-5 mg/kg Ipilimumab doses, and were associated with Autoimmune Breakthrough Events (ABE), including Grade 2 or 3 hypophysitis and Grade 3 alveolitis. PSA stabilizations (Stable Disease, SD) were observed in 1/3 pts in lower (0.3 and 1 mg/kg), and in 7 of 22 in the higher (3-5 mg/kg) dose levels. In this study, cytokine profiles of peripheral blood-derived T cells were determined ex vivo and after in vitro stimulation with PMA and ionomycin by intracellular staining for IL-2, −4, −5, −10, TNF-α, IFN-γ and IL-17A. Of these cytokines, only IL-4 was detectable ex vivo in CD4+ and CD8+ T cells; post-treatment increases were detectable in the higher (3-5 mg/kg) but not in the lower (0.3-1 mg/kg) Ipilimumab dose levels. After PMA/ionomycin stimulation, no consistent changes were observed in the frequencies of IFN-γ, IL-2 and TNF-α-producing type-1 T cells compared to pre-treatment values. In contrast, significantly increased rates of IL-4 and IL-5 producing CD4+ and CD8+ T cells were found upon treatment (visit 1 versus visit 5) at higher (3-5 mg/kg) Ipilimumab dose levels. Overall these data clearly demonstrate a shift in favor of a Type-2 cytokine profile due to the GVAX/Ipilimumab administration. The frequencies of IL-17A producing CD4+ T (Th17) cells increased over the course of treatment in 5 of 18 patients. Of note, in 3 (PR) out of 5 of these patients this increase of the Th17 subset coincided with onset of hypophysitis and/or adrenal insufficiencies, as well as the onset of PSA decline. The two patients with increased Th17 rates without these pituitary or adrenal-related ABE showed SD. In summary, our results show that combined GVAX/Ipilimumab administration gives rise to Type-2/Th17 cytokine profiles in mHRPC patients, but that only increases in Th17 show a relation to ABE and PSA responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2934.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-2934
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 6
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    Abstract 5512: Immune correlates of clinical response and survival in castration-resistant prostate cancer patients treated with prostate GVAX and anti-CTLA4 immunotherapy
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5512-5512
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5512-5512
    Abstract: The effects of Prostate GVAX and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with castration resistant prostate cancer. Results showed that the GVAX/Ipilimumab combination was clinically active with PSA declines of more than 50% (Partial Response, PR) in 6 and PSA stabilizations (Stable Disease, SD) in 11 of 28 patients. Immune response monitoring was performed to identify changes that might predict or correlate with clinical efficacy. Upon administration of high Ipilimumab dosages (3 or 5 mg/kg), significant increases in frequencies of activated CD4+ and/or CD8+ T cells were observed by HLA-DR, PD-1, FoxP3 and ICOS expression. Monitoring over the course of treatment, revealed these markers to be differentially associatied with survival, as were levels of effector/memory T cells or Tregs. Early HLA-DR upregulation appeared useful as a marker for response prediction, since it was observed to significant levels in PR or SD, but not in PD patients. In addition, GVAX/Ipilimumab administration was found to induce Th2/Th17 cytokine profiles, as determined ex vivo by intracellular staining of peripheral T cells. Significantly increased levels of IL-4 in both CD4+ and CD8+ T cells were observed in patients with PR or SD, but not in patients with PD and, importantly, profound up-regulation of CD4+IL-5+ T cell frequencies was associated with improved overall survival (p=0.03). Similarly, significantly increased Th17 rates were only observed in patients with PR and SD (p & lt;0.05). Of particular interest, the increased Th17 frequencies coincided with onset of hypophysitis and/or adrenal insufficiencies, as well as of PSA declines in PR patients. As an indication of tumor-specific responsiveness, IgG antibody responses against 11 (prostate) tumor-associated antigens were determined by western blot and ELISA. Increased seroreactivity to prostate-specific membrane antigen (PSMA), pyridoxamine 5′-phosphate oxidase (PNPO) and/or Neuropilin-2 (NRP2) was significantly correlated with improved overall survival (p & lt;0.03). Our data indicate that changes in frequencies of activated memory/effector T cells and Tregs, Th2 and Th17 rates and seroconversion to multiple tumor antigens may define a predictive immune profile for patients with potential benefit from Prostate GVAX and/or anti-CTLA4 immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5512. doi:10.1158/1538-7445.AM2011-5512
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5512
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 20 ( 2013-10-15), p. 5722-5732
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 20 ( 2013-10-15), p. 5722-5732
    Abstract: Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it. Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance. Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death. Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0527
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 1225457-5
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  • 8
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    Abstract 1229: Pre-existing NY-ESO-1-specific T cell reactivity is associated with improved clinical outcome in castration resistant prostate cancer patients treated with Prostate GVAX and ipilimumab.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1229-1229
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1229-1229
    Abstract: The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic castration resistant prostate cancer (van den Eertwegh et al, Lancet Oncology, 13: 509-17 2012). The GVAX and ipilimumab combination treatment led to PSA declines of more than 50% (Partial Response, PR) in 5 of 28 patients, PSA stabilizations (Stable Disease, SD) in 12 of 28 patients and disease progression (PD) in 11 of 28 patients. Regressing bone and lymph node metastases were observed in 2/5 PR patients. As an indication of tumor antigen-specific responsiveness we analyzed serologic and T cell responses against NY-ESO-1 before, during and after treatment. NY-ESO-1 seroreactivity (determined by ELISA) was observed in seven of 28 patients (25%). Five patients were seropositive at baseline and 2 became seropositive following treatment; no significant correlations were found with clinical benefit or survival. NY-ESO-1 T cell reactivity was determined in 19 patients by IFNγ ELISPOT after stimulation with a peptide pool of overlapping 20-mer peptides covering the immunodominant region aa121-180. NY-ESO-1-specific T cell responses were detected in 13 of 19 patients (68%) at any time before or during treatment. Increases in the frequency of NY-ESO-1 specific T cells following treatment were only observed in five of these (26%). A remarkably high number of nine out of 19 patients (47%) already exhibited NY-ESO-1-specific T cell reactivity before treatment. Interestingly, three of four (75%) PR patients displayed pre-existing frequencies of NY-ESO-1 T cells, whereas these cells were only detected in six of 15 SD/PD (40%) patients. Moreover, patients with pre-existing NY-ESO-1 T cell reactivity demonstrated a significantly prolonged overall survival (p=0.044, log-rank test). These data suggest that baseline NY-ESO-1 T cell reactivity may have predictive value for the clinical outcome of prostate GVAX and/or ipilimumab treatment. Citation Format: Anita GM Stam, Saskia JAM Santegoets, Alfons JM van den Eertwegh, Rik J. Scheper, Sinéad M. Lougheed, Helen Gall, Karin Jooss, Natalie Sacks, Thomas Harding, Kristen Hege, Israel Lowy, Sacha Gnjatic, Jedd D. Wolchok, Winald R. Gerritsen, Tanja D. de Gruijl. Pre-existing NY-ESO-1-specific T cell reactivity is associated with improved clinical outcome in castration resistant prostate cancer patients treated with Prostate GVAX and ipilimumab. [abstract] . In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2013-1229
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1229
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
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    Abstract 2538: Dendritic and T cell functions in patients with metastatic hormone-refractory prostate cancer treated with GVAX immunotherapy for prostate cancer and ipilimumab
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 9_Supplement ( 2008-05-15), p. 2538-2538
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 9_Supplement ( 2008-05-15), p. 2538-2538
    Abstract: The effects of a combination of two allogeneic, GM-CSF-secreting prostate cancer cell lines (GVAX Immunotherapy for Prostate Cancer, Cell Genesys, Inc.) and escalating doses of the anti-CTLA4 antibody ipilimumab (MDX-010, Medarex, Inc.) are currently being evaluated in a Phase I trial of patients with metastatic, hormone-refractory prostate cancer (HRPC). The anticipated synergy of these two novel therapies may potentially lead to augmented T cell-mediated anti-tumor immunity via improved dendritic cell (DC) functions and blockade of inhibitory feedback loops in activated tumor-specific T cells. All patients received a 500 million cell prime dose of the cellular immunotherapy on day 1 followed by bi-weekly intradermal administrations of 300 million cells for a 24-week period. Ipilimumab was administered every 4 wks from day 1 during the same period. Patients were enrolled in cohorts of 3; each cohort was assigned an escalating dose of ipilimumab at 0.3, 1, 3 or 5 mg/kg. Results showed PSA declines of & gt;50% in 5/6 patients at the two highest dose levels of anti-CTLA-4, as well as resolution of multiple lesions on bone scan in two patients, and resolution of abdominal lymph node disease by CT scan and improvement in bone pain in one patient each. T cell activation was monitored to identify changes that correlate with clinical efficacy. Preliminary DC and T cell data are encouraging. Pre-treatment frequencies of circulating myeloid DC (MDC) subsets were significantly reduced in the enrolled HRPC patients, as compared to age- and sex-matched healthy controls. A transient increase in MDC frequencies was observed at the lowest ipilimumab dose level (0.3 mg/kg), but not at the two highest dose levels. The latter may be explained by an observed massive recruitment of MDC to the immunotherapy injection sites. Evidence of transient activation of circulating MDC, concomitant increases of the activation marker HLA-DR on circulating T cells and increased frequencies of circulating memory/effector T cells was found during treatment at the higher ipilimumab dose levels. The transient activation of circulating MDC and T cells showed a reverse kinetics with serum PSA levels. Furthermore, intense skin reactions were observed in response to administration of the cellular immunotherapy, which is consistent with the observed increases in T cell infiltration and Granzyme B expression in injection site biopsies taken during the treatment course and is suggestive of early immune activation. To increase the chances of detecting tumor-specific T cells, both blood and injection sites are monitored for T cell reactivity. Functional regulatory T cell activity is tested in parallel. These on-going analyses are expected to yield valuable data concerning immune effects achieved by the GVAX/ipilimumab combination.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2008-2538
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 10
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    Phase I/II Trial of an Allogeneic Cellular Immunotherapy in Hormone-Naïve Prostate Cancer
    American Association for Cancer Research (AACR) ; 2006
    In:  Clinical Cancer Research Vol. 12, No. 11 ( 2006-06-01), p. 3394-3401
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 11 ( 2006-06-01), p. 3394-3401
    Abstract: Purpose: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. Patients and Methods: A single-institution phase I/II trial was done in hormone therapy–naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 × 108 GM-CSF gene–transduced, irradiated, cancer cells (6 × 107 LNCaP cells and 6 × 107 PC-3 cells) for 8 weeks. Results: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P & lt; 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. Conclusions: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-0145
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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