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

Laheru, Dan; Lutz, Eric R.; Burke, James; Biedrzycki, Barbara; Solt, Sara; Onners, Beth; Tartakovsky, Irena; Nemunaitis, John; Le, Dung T.; Sugar, Elizabeth A.; Hege, Kristen; Jaffee, Elizabeth M.

doi:10.1158/1078-0432.ccr-07-0371

Cited by 314 publications

(231 citation statements)

References 36 publications

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“…The heightened vaccine-based antitumor immune response in irradiated hosts was associated with tumor regression and prolonged survival of mice. It had previously been thought that some cytotoxic agents, such as cyclophosphamide, might enhance the efficacy of adoptively transferred immunotherapy by augmenting the engraftment of adoptively transferred tumor-reactive effector T cells, [11][12][13] possibly by creating space. 1, 14 However, in our study, vaccination after irradiation without adoptive transfer yielded similar results, indicating that a self-reconstituted host immune system is reliable for antigen stimulation.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

et al. 2010

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Low-dose total body irradiation (LTBI) is used in the treatment of some cancers mainly for immune enhancement rather than cell killing. However, the mechanism underlying LTBI remains unknown. In this study, by analyzing the immune patterns of lymphocytes, we found that the percentage and absolute number of CD4 1 CD25 1 Foxp3 1 regulatory T cells are markedly decreased in naive mice following treatment with LTBI. On the contrary, the CD4 1 CD44 1 /CD8 1 CD44 1 effector-memory T cells are greatly increased. Importantly, naive mice treated with dendritic cell-gp100 tumor vaccines under LTBI induced an enhancement of antigen-specific proliferation and cytotoxicity as well as interferon-c (IFN-c) secretion against F10 melanoma tumor challenge, compared to treatment with either the tumor vaccine or LTBI alone. Consequently, the treatment resulted in a reduced tumor burden and prolonged mouse survival. Our data demonstrate that LTBI's enhancement of antitumor immunity was mainly associated with selectively decreasing the proportion and number of T regulatory cells, implying the potential application of the combination of LTBI and a tumor vaccine in antitumor therapy.

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Section: Discussionmentioning

confidence: 99%

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

et al. 2010

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“…47 In cancer patients, low doses of cyclophosphamide were shown to selectively deplete regulatory T cells 49 and enhance the induction of antigen-specific T-cells as well as increase survival when combined with immunotherapy. 50 We have now started a new clinical trial in which p53-SLP immunization is combined with cyclophosphamide to test whether this increases immunity and clinical activity. The percentage of IFN-g producing T-cells before immunization (pre-immun.)…”

Section: Discussionmentioning

confidence: 99%

Immunization with a P53 synthetic long peptide vaccine induces P53‐specific immune responses in ovarian cancer patients, a phase II trial

Leffers

Lambeck

Gooden

et al. 2009

Intl Journal of Cancer

129

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The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53‐SLP) vaccine, twenty patients with recurrent elevation of CA‐125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53‐SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no ≥ grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN‐γ producing p53‐specific T‐cell responses were induced in all patients who received all 4 immunizations as measured by IFN‐γ ELISPOT. An IFN‐γ secretion assay showed that vaccine‐induced p53‐specific T‐cells were CD4+, produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53‐specific response. P53‐specific T‐cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53‐specific T‐cells. As best clinical response, stable disease evaluated by CA‐125 levels and CT‐scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine‐induced immunity. This study shows that the p53‐SLP vaccine is safe, well tolerated and induces p53‐specific T‐cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper‐1 polarization and clinical efficacy. © 2009 UICC

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“…10 In this light, cancer vaccines could be employed in pancreatic cancer as adjuvants to conventional treatments and in the management of minimal residual disease after resection of the primary cancer.…”

Section: Uiccmentioning

confidence: 99%

“…[10][11][12][13] MUC-1 and K-ras also elicit a humoral response and have been used in phase I and I/II clinical trials. 11,14 Antimesothelin agents, namely recombinant immunotoxin, the chimeric antimesothelin mAb and the Listeria monocytogenesmesothelin vaccine are used in clinical practice or about to enter in clinical trials.…”

Section: Uiccmentioning

confidence: 99%

An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

Cappello¹,

Tomaino²,

Chiarle³

et al. 2009

Intl Journal of Cancer

107

125

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Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a very poor 5-year survival rate. a-Enolase is a glycolytic enzyme that also acts as a surface plasminogen receptor. We find that it is overexpressed in PDAC and present on the cell surface of PDAC cell lines. The clinical correlation of its expression with tumor status has been reported for lung and hepatocellular carcinoma. We have previously demonstrated that sera from PDAC patients contain IgG autoantibodies to a-enolase. The present work was intended to assess the ability of a-enolase to induce antigen-specific T cell responses. We show that a-enolase-pulsed dendritic cells (DC) specifically stimulate healthy autologous T cells to proliferate, secrete IFN-c and lyse PDAC cells but not normal cells. In vivo, a-enolase-specific T cells inhibited the growth of PDAC cells in immunodeficient mice. In 8 out of 12 PDAC patients with circulating IgG to a-enolase, the existence of a-enolase-specific T cells was also demonstrated. Taken as a whole, these results indicate that a-enolase elicits a PDAC-specific, integrated humoral and cellular response. It is thus a promising and clinically relevant molecular target candidate for immunotherapeutic approaches as new adjuvants to conventional treatments in pancreatic cancer. ' 2009 UICC

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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

Cited by 314 publications

References 36 publications

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

Immunization with a P53 synthetic long peptide vaccine induces P53‐specific immune responses in ovarian cancer patients, a phase II trial

An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

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