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M A Morse,
A Hobeika,
D Serra,
K Aird,
M McKinney,
A Aldrich,
T Clay,
D Mourich,
H K Lyerly,
P L Iversen,
G R Devi
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ABSTRACT: CD4+CD25+regulatory T cells (T(reg)) impair anti-tumor and anti-viral immunity. As there are higher T(reg) levels in cancer patients compared with healthy individuals, there is considerable interest in eliminating them or altering their function as part of cancer or viral immunotherapy strategies. The scurfin transcriptional regulator encoded by the member of the forkhead winged helix protein family (FOXP3) is critical for maintaining the functions of T(reg). We hypothesized that targeting FOXP3 expression with a novel arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino (PPMO) based antisense would eliminate T(reg) and enhance the induction of effector T-cell responses. We observed that the PPMO was taken up by activated T cells in vitro and could downregulate FOXP3 expression, which otherwise increases during antigen-specific T-cell activation. Generation of antigen-specific T cells in response to peptide stimulation was enhanced by pre-treatment of peripheral blood mononuclear cells with the FOXP3-targeted PPMO. In summary, modulation of T(reg) levels using the FOXP3 PPMO antisense-based genomic strategy has the potential to optimize immunotherapy strategies in cancer and viral immunotherapy.
Cancer gene therapy 01/2012; 19(1):30-7. · 3.13 Impact Factor
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ABSTRACT: Selection of suitable antigens is critical for the development of cancer vaccines. Most desirable are over-expressed cell surface proteins that may serve as targets for both antibodies and T cells, thus maximizing a concerted immune response. Towards this goal, we characterized the relevance of tumour necrosis factor-α-converting enzyme (ADAM17) for such targeted therapeutics. ADAM17 is one of the several metalloproteinases that play a key role in epidermal growth factor receptor (EGFR) signalling and has recently emerged as a new therapeutic target in several tumour types. In the present study, we analysed the expression profile of ADAM17 in a variety of normal and cancer cells of human origin and found that this protein is over-expressed on the surface of several types of cancer cells compared to the normal counterparts. Furthermore, we analysed the presentation of a human leucocyte antigen (HLA)-A2-restricted epitope from ADAM17 protein to specific T cells established from normal donors as well as ovarian cancer patients. Our analysis revealed that the HLA-A2-restricted epitope is processed efficiently and presented by various cancer cells and not by normal cells. Tumour-specific T cell activation results in the secretion of both interferon-γ and granzyme B that can be blocked by HLA-A2 specific antibodies. Collectively, our data present evidence that ADAM17 can be a potential target antigen to devise novel immunotherapeutic strategies against ovarian, breast and prostate cancer.
Clinical & Experimental Immunology 03/2011; 163(3):324-32. · 3.36 Impact Factor
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ABSTRACT: Novel technologies to redirect T-cell killing against cancer cells are emerging. We hypothesised that metastatic human colorectal cancer (CRC) previously treated with conventional chemotherapy would be sensitive to T-cell killing mediated by carcinoembryonic antigen (CEA)/CD3-bispecific T-cell-engaging BiTE antibody (MEDI-565).
We analysed proliferation and lysis of CEA-positive (CEA+) CRC specimens that had survived previous systemic chemotherapy and biologic therapy to determine whether they could be killed by patient T cells engaged by MEDI-565 in vitro.
At low concentrations (0.1-1 ng ml(-1)), MEDI-565+ T cells caused reduced proliferation and enhanced apoptosis of CEA+ human CRC specimens. High levels of soluble CEA did not impair killing by redirected T cells and there was no increase in resistance to T-cell killing despite multiple rounds of exposure.
This study shows for the first time that metastatic CRC specimens derived from patients previously treated with conventional chemotherapy can be lysed by patient T cells. Clinical testing of cancer immunotherapies, such as MEDI-565 that result in exposure of tumours to large numbers of T cells, is warranted.
British Journal of Cancer 12/2009; 102(1):124-33. · 5.04 Impact Factor
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ABSTRACT: Recombinant serotype 5 adenovirus (Ad5) vectors lacking E1 expression induce robust immune responses against encoded transgenes in pre-clinical models, but have muted responses in human trials because of widespread pre-existing anti-adenovirus immunity. Attempts to circumvent Ad5-specific immunity by using alternative serotypes or modifying capsid components have not yielded profound clinical improvement. To address this issue, we explored a novel alternative strategy, specifically reducing the expression of structural Ad5 genes by creating E1 and E2b deleted recombinant Ad5 vectors. Our data show that [E1-, E2b-]vectors retaining the Ad5 serotype are potent immunogens in pre-clinical models despite the presence of significant Ad5-specific immunity, in contrast to [E1-] vectors. These pre-clinical studies with E1 and E2b-deleted recombinant Ad5 vectors suggest that anti-Ad immunity will no longer be a limiting factor, and that clinical trials to evaluate their performance are warranted.
Cancer gene therapy 03/2009; 16(9):673-82. · 3.13 Impact Factor
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H Gerke,
R White,
M F Byrne,
H Stiffier,
R M Mitchell,
H I Hurwitz, M A Morse,
M S Branch,
P S Jowell,
B Czito,
B Clary,
T N Pappas,
D S Tyler,
J Baillie
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ABSTRACT: It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy.
The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer.
One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002.
The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded.
Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage.
Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups.
Digestive and Liver Disease 07/2004; 36(6):412-8. · 3.05 Impact Factor
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M A Morse
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ABSTRACT: ISIS-2503, a 20-mer antisense oligonucleotide that inhibits Ha-Ras expression, is being developed by Isis Pharmaceuticals Inc as a potential treatmentfor cancer, particularly tumors that commonly have abnormalities of Ras function. It is in phase II trials. According to an April 2001 report by Bear Stearns & Co, Elan Corp plc had an unspecified collaboration with Isis for the development of ISIS-2503 [419357], but Isis later clarified that there was no agreement between the two companies and that ISIS-2503 had merely been used for the 'OraSense' joint venture that explores the use of antisense oligonucleotidesfor oral administration [419673].
Current opinion in molecular therapeutics 12/2001; 3(6):589-94. · 3.68 Impact Factor
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M A Morse
IDrugs: the investigational drugs journal 09/2001; 4(8):857-9. · 2.28 Impact Factor
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M A Morse
IDrugs: the investigational drugs journal 09/2001; 4(8):853-6. · 2.28 Impact Factor
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M A Morse
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ABSTRACT: Therion Biologics, the NCI and Aventis Pasteur are investigating CEA-TRICOM, a recombinant, pox virus-based vaccine that incorporates a triple dose of costimulatory molecules as well as the carcinoembryonic antigen (CEA) tumor antigen, for the potential treatment of colorectal cancer. CEA-TRICOM is designed to stimulate and strengthen the body's immune system to kill colorectal cancer cells. CEA-TRICOM is administered in a priming and boosting protocol using two unique pox virus vectors, rV-CEA-TRICOM (recombinant vaccinia vector) and rF-CEA-TRICOM (recombinant fowlpox vector). The TRICOM component of both rV-CEA-TRICOM and rF-CEA-TRICOM comprises three costimulatory molecule transgenes (B7-1, ICAM-1 and LFA-3) [414643], [414645], known to elicit strong cellular immune responses necessary for complete tumor destruction. In preclinical studies conducted by the NCI and Therion, researchers have demonstrated that this combination of three costimulatory molecules dramatically boosts the immune response to eradicate cancer in murine models [399610], [414631]. In February 2001, Therion Biologics and the NCI initiated a phase I trial of CEA-TRICOM [399610]. The phase I trial of CEA-TRICOM is designed to demonstrate proof-of-principle for using multiple costimulatory molecules in conjunction with a tumor antigen to improve the strength of cellular immune responses. It is a multistage, dose-escalation study that will assess the safety and immunologic effects of CEA-TRICOM in up to 42 patients who have advanced metastatic colorectal cancer. Subjects will receive rF-CEA-TRICOM alone, rV-CEA-TRICOM followed by booster vaccinations with rF-CEA-TRICOM or rV-CEA-TRICOM followed by rF-CEA-TRICOM and GM-CSF adjuvant. The primary measure of immune response will be the level of CEA-specific T-cells stimulated by vaccination, with levels of CEA-expressing tumor cells in the blood used as a potential secondary measure of treatment effect [399610].
Current opinion in molecular therapeutics 09/2001; 3(4):407-12. · 3.68 Impact Factor
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ABSTRACT: Laboratory isolates of human immunodeficiency virus type 1 (HIV-1) that utilize CXCR4 as a coreceptor infect primary human macrophages inefficiently even though these express a low but detectable level of cell surface CXCR4. In contrast, infection of primary macrophages by primary CXCR4-tropic HIV-1 isolates is readily detectable. Here, we provide evidence suggesting that this difference in cell tropism results from a higher requirement for cell surface CXCR4 for infection by laboratory HIV-1 isolates. Transfected COS7 cells that express a high level of CD4 but a low level of CXCR4 were infected significantly more efficiently by two primary CXCR4-tropic HIV-1 isolates compared to the prototypic laboratory HIV-1 isolate IIIB. More importantly, overexpression of either wild-type or signaling-defective CXCR4 on primary macrophages dramatically enhanced the efficiency of infection by the laboratory HIV-1 isolate yet only modestly enhanced infection by either primary CXCR4-tropic virus. Overexpression of CD4 had, in contrast, only a limited effect on macrophage infection by the laboratory HIV-1, although infection by the primary isolates was markedly enhanced. We therefore conclude that the laboratory CXCR4-tropic HIV-1 isolate exhibits a significantly higher CXCR4 requirement for efficient infection than do the primary CXCR4-tropic isolates and that this difference can explain the poor ability of the laboratory HIV-1 isolate to replicate in primary macrophages. More generally, we propose that the cell tropisms displayed by different strains of HIV-1 in culture can largely be explained on the basis of differential requirements for cell surface CD4 and/or coreceptor expression levels.
Journal of Virology 09/2001; 75(15):6776-85. · 5.40 Impact Factor
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ABSTRACT: Numerous cancer immunotherapy strategies are currently being tested in clinical trials. Although clinical efficacy will be the final test of these approaches, the long and complicated developmental pathway for these agents necessitates evaluating immunological responses as intermediate markers of the most likely candidates for success. This has emphasized the need for assays that accurately detect and quantitate T cell-mediated, antigen-specific immune responses. This review evaluates the currently used in vivo and in vitro methods of assessing T-cell number and function, including delayed-type hypersensitivity, tetramer analysis, ELISPOT, flow cytometry-based analysis of cytokine expression, and PCR-based detection of T-cell receptor gene usage or cytokine production. We provide examples of how each has been used to monitor recent clinical trials and a discussion of how well each correlates with clinical outcome.
Clinical Cancer Research 06/2001; 7(5):1127-35. · 7.74 Impact Factor
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Annals of Surgical Oncology 05/2001; 8(3):190-1. · 4.17 Impact Factor
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ABSTRACT: Clinically effective cancer immunotherapy has been sought for more than 100 years and has been recently applied most successfully in strategies that passively deliver immune effectors such as monoclonal antibodies (anti-CD20 for lymphoma and anti-HER2/neu for breast cancer), donor lymphocyte infusions in chronic myelongenous leukemia and non-myeloablative allogeneic peripheral blood progenitor transplants for renal cell carcinoma. There is mounting enthusiasm for strategies employing active stimulation of antitumour immune responses. These include vaccines based on tumour antigen proteins and peptides, autologous, allogeneic or gene-modified tumour cells, dendritic cells and antigen-encoding viral vector constructs. Indeed, randomised Phase III clinical trials of autologous tumour cell vaccines for colorectal cancer demonstrated an improvement in disease free survival and a trend toward improved overall survival [1]. Despite these preliminary successes, it is clear that the many strategies under development cannot all be evaluated for survival benefit in large clinical trials that require many years, patients and resources to complete. This highlights the need to develop intermediate markers to help prioritise which agents to test in prospective randomised Phase III trials.
Expert Opinion on Biological Therapy 04/2001; 1(2):153-8. · 3.51 Impact Factor
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ABSTRACT: The evaluation of cancer immunotherapy is predicated on the hypothesis that markers of tumor antigen-specific T-cell immunity will cone-late with clinical efficacy. Establishing which candidate vaccines should enter large-scale clinical trials will necessitate optimal application of immunologic monitoring assays. Evidence suggests that available techniques are adequate for the direct detection of clinically significant antigen-specific T-cell responses from tissue specimens. To achieve this goal, it is important to have an understanding of individual methods and their limitations, to include appropriate control antigens in the monitoring strategy, and to incorporate statistical considerations into the design and analysis of such studies.
Surgery 04/2001; 129(3):248-54. · 3.10 Impact Factor
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ABSTRACT: Increased numbers of clinical trials, many of which are large, multicenter, and sometimes international, and the marked shift of funding for clinical trials to industry have made apparent the inadequacy of mechanisms for protecting human subjects that were developed when clinical research was generally carried out on a small scale at single institutions. To address concerns regarding the protection of human subjects, a group of professionals with expertise in various aspects of clinical trials was assembled in May 2000. Participants described and evaluated the mechanisms by which clinical trials are monitored, focusing on adverse event reporting and the processes by which various parties with oversight responsibilities interact in the course of these trials. In this article, we describe the manner in which adverse event reporting might function to enhance safety and the role of data monitoring committees in using aggregate data from these reports, outline the problems that now exist for institutional review boards as they are faced with multiple adverse event reports from clinical trials while conducting continuing review, and offer recommendations for improving the current approach.
JAMA The Journal of the American Medical Association 04/2001; 285(9):1201-5. · 30.03 Impact Factor
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ABSTRACT: Many clinical trials are testing the feasibility of stimulating the immune system to treat cancer. Although the efficacy of this approach will ultimately be determined by clinically relevant endpoints, detection of the magnitude and activity of the immune response is an important intermediate point in the development of these strategies. Assays that predict clinically relevant endpoints are particularly desirable for helping to determine which strategies should ultimately be tested in larger randomized clinical trials. In this review, we will discuss these cellular immunological assays and the current status of their role in clinical trials of immunotherapy.
Current opinion in molecular therapeutics 03/2001; 3(1):45-52. · 3.68 Impact Factor
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M A Morse
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ABSTRACT: Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137].
Current opinion in molecular therapeutics 03/2001; 3(1):97-101. · 3.68 Impact Factor
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M A Morse
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ABSTRACT: Biomira is developing the MUC-1 peptide-based vaccine BLP-25 for the potential treatment of cancer. It is in phase II trials for non-small cell lung cancer (NSCLC) [335997], [353448], [384703]. The MUC-1 mucin secreted by cancer cells has been shown to decrease the activity of certain immune response cells, including killer T-cells, and can inhibit the immune T-cell response by > 70%. BLP-25 is designed to target an immune response to the MUC-1 mucin that is shown by > 90% of common solid tumors. The introduction of IL-2 reverses the T-cell suppression caused by MUC-1 mucin, and enhances the cellular immune response > 100-fold. Biomira has been incorporating IL-2 into a liposomal delivery system for BLP-25 [274576]. In late 1998, Biomira entered into a research collaboration with Axis Genetics. The collaboration will assess the further potential of therapeutic cancer vaccines against MUC-1. Each company has developed a vaccine targeting the MUC-1 peptide and Biomira will be evaluating Axis's vaccine in preclinical trials [313395]. In December 1996, Biomira signed a licensing agreement whereby it was granted the rights to use Dana-Farber Cancer Institute's two US patents relating to MUC-1 (based on pioneering work at the Institute on the identification of cell-surface molecules that are characteristic of cancer cells) for peptide-based cancer vaccines [228101].
Current opinion in molecular therapeutics 03/2001; 3(1):102-5. · 3.68 Impact Factor
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ABSTRACT: Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a > 50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.
Cancer Research 03/2001; 61(3):1233-40. · 7.86 Impact Factor
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ABSTRACT: Successful application of active immunotherapy to the treatment of cancer will require stimulation of potent antigen-specific T-cell responses. It is not known how numerous or how potent these T cells must be in order to abrogate tumors, but the levels of immunity needed to control chronic viral infections may provide estimates for comparison. Evaluation of the efficacy of a vaccine strategy in attaining these levels of immunity will depend on the use of assays that create a picture of T-cell number and function that correlates with clinical outcomes. We discuss the currently available in vivo and in vitro T-cell assays and their relevance for detecting therapeutic levels of T-cell activity. We also propose a strategy for efficiently evaluating the immunologic efficacy of cancer vaccines so that the most promising candidates can be brought more rapidly into definitive clinical trials.
Critical Reviews in Immunology 02/2001; 21(1-3):287-97. · 3.32 Impact Factor
