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Biomedical subjects

A A Melcher

Publications and source records attributed to A A Melcher.

11 recordsLinked to original sources
PubMed2004

Induction of cell stress through gene transfer of an engineered heat shock transcription factor enhances tumor immunogenicity.

Heat shock protein expression and release is closely associated with immunogenic forms of cell death. We show that activation of the stress response within tumor cells during cell death, using an engineered form of the heat shock transcription factor, leads to an immunogenic death. Cells dying through 'stressful death' show decreased phagocytosis by macrophages in vitro. Moreover, cells expressing heat shock proteins during cell death are significantly more protective against subsequent tumor challenge. These data demonstrate the utility of activating cellular stress programs over the course of cytotoxic therapies to enhance immune responses to dying cells.

Animals↗
PubMed2003

Concurrent chemoradiotherapy for squamous cell carcinoma of the anus using a shrinking field radiotherapy technique without a boost.

Chemoradiotherapy (CRT) is now widely accepted as the primary treatment modality for squamous cell cancer of the anus. While randomised trials have clearly shown CRT to be more effective than radiotherapy alone, there remains uncertainty over the optimal integration of chemotherapy and radiation. We describe a series of 50 patients treated by a site specialist gastrointestinal nonsurgical oncologist with CRT at a single UK centre. Chemotherapy comprised mitomycin C (MMC) (day 1) and 5-fluorouracil (5-FU) (days 1-4, and 29-32), concurrent with 50 Gy in 25 fractions radiation, using a two-phase shrinking field technique. A radiation boost was not planned. At a median follow-up of 48 months, 11 (22%) of the patients have failed locally, of which three have been surgically salvaged. Nine (18%) have died of anal cancer. These results are comparable with those from large randomised studies, and suggest that a two-phase shrinking field radiotherapy technique with no boost, concurrent with MMC/5-FU chemotherapy, is an effective regimen for this disease. The CRT regimen described here provides the basis for the 'control arm' of the current UK-randomised CRT trial in anal cancer (ACT2).

Adult↗
PubMed2001

Macrophages orchestrate the immune response to tumor cell death.

The mechanisms by which the immune system distinguishes normal developmental cell death from pathological immunogenic cell killing are central to effective cancer immunotherapy. Using HSVtk suicide gene therapy, we showed that macrophages can distinguish between tumor cells dying through classical apoptosis and tumor cells engineered to die through nonapoptotic mechanisms, resulting in secretion of either immunosuppressive cytokines (interleukin 10 and transforming growth factor beta) or inflammatory cytokines (tumor necrosis factor alpha or interleukin 1beta), respectively. Additionally heat shock protein 70 acts as one component of a bimodal alarm signal that activates macrophages in the presence of stressful, immunogenic tumor cell killing. These differential responses of macrophages can also be used to vaccinate mice against tumor challenge, using adoptive transfer, as well as to cure mice of established tumors.

Animals↗
PubMed2000

Cancer gene therapy: developments to 2000.

Cancer, at the molecular level, continues to be more thoroughly understood. With this understanding comes the opportunity for innovative therapeutic intervention. Gene therapy remains an attractive concept to treat cancer. However, a number of gene therapy clinical trials have now been reported and it is clear that barriers remain before gene therapy gains widespread clinical application. This article outlines current directions and novel developments in the field of cancer gene therapy, which attempt to overcome these obstacles.

Animals↗
PubMed1999

Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake.

Previously, we reported that killing tumor cells in vivo with the HSV thymidine kinase/ganciclovir system generates potent antitumor immunity, determined in part by the mechanism by which the cells die and by the levels of inducible heat shock protein (hsp) expression induced during the process of cell death. Here, we show that induction of hsp70 expression induces an infiltrate of T cells, macrophages, and predominantly dendritic cells (DCs) into the tumors as well as an intratumoral profile of Th1 cytokine expression (IFN-gamma, TNF-alpha, and IL-12) and enhances immunogenicity via a T cell-mediated mechanism. In addition, the protection conferred by hsp70 is both tumor and cell specific. We also demonstrate that hsp70 targets immature APC to make them significantly more able to capture Ags. This is likely to optimize cross-priming of the infiltrating APC with tumor Ags, which are simultaneously being released by the dying cells. In addition, using an Myc epitope-tagged hsp70 expression vector, we present evidence that hsp70 released from dying tumor cells is taken up directly into DCs and may, therefore, be involved in direct chaperoning of Ags into DCs. Taken together, our data suggest that hsp70 induction serves to signal the immune system of the presence of an immunologically relevant (dangerous) situation against which an immune reaction should be raised.

Animals↗
PubMed1998

A comparison of two planning techniques for radiotherapy of high grade astrocytomas.

The purpose of this study was to compare two planning techniques for the delivery of radical localized postoperative radiotherapy in the treatment of high grade astrocytomas. Conventional orthogonal plain film planning (CONP) was compared with CT planning (CTP) in terms of the size of the target volumes treated, the amount of normal brain irradiated and the accuracy of localization. Twenty consecutive adults with high grade astrocytomas, who were treated with radiotherapy between March and October 1996, were planned with CONP and CTP, using postoperative, contrast-enhanced CT scans to define the tumour volume. The planning target areas, volumes and the 100%, 80% and 50% isodose areas produced using the two planning methods were measured and compared using Student's paired t-test. The target volume length was also measured and compared as an independent factor. The difference between entry points of the central axis of the lateral fields was noted. Nineteen of 20 patients had a reduction in planning target volumes using CTP compared with CONP. The difference between the mean volumes was clinically relevant, with 288 cm3 representing a 25% reduction, and statistically significant at the P<0.001 level. The planning target volumes were reduced in 18/20 patients (mean 24 cm2, 23%, P<0.001). Similarly, there were highly significant reductions in the 100%, 80% and 50% isodose areas. The target volume lengths were not found to be significantly different. When considering the accuracy of localization, the entry point of the CONP lateral field deviated by a mean distance of 1.6 cm relative to CTP (superiorinferior 1.3 cm; anteriorposterior 0.8 cm; range 04.1 cm). In two patients, this would have led to a geographical miss of macroscopic disease. In patients with high grade astrocytomas, CTP is preferred to conventional planning. It leads to appreciable reductions in the size of the planning target areas and volumes receiving radical doses of radiation, it significantly reduces the amount of normal brain tissue being irradiated and is more accurate in terms of tumour localization. These differences are likely to lead to a reduction in treatment morbidity. We recommend CTP for all patients receiving radical radiotherapy.

Adult↗
PubMed1997

A family of bicistronic vectors to enhance both local and systemic antitumor effects of HSVtk or cytokine expression in a murine melanoma model.

The herpes simplex virus-thymidine kinase/ganciclovir (HSVtk/GCV) system produces both direct and immune-mediated tumor cell killing. Here, we compare the efficacy of HSVtk/GCV with cytokines, alone and in combination, on the tumorigenicity and immunogenicity of B16 cells. With respect to single gene modifications, only HSVtk/GCV, or high-level interleukin-2 (IL-2) secretion, completely prevented tumor growth, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) generated the best levels of long-term systemic protection. To augment both local killing and immune activation, we constructed bicistronic constructs that express HSVtk and a cytokine within the same cell. Co-expression of HSVtk with IL-2 or GM-CSF enhanced the local antitumor activity of any gene alone. In a tumor-prevention model, HSVtk killing, in an environment preprimed with GM-CSF, generated the best long-term immune protection. However, in a short-term therapy model, continued IL-2 expression was most effective against 3-day established tumors. This probably reflects differences in the activities of IL-2 and GM-CSF in generating short-term, nonspecific immune stimulation compared to long-term immunological memory, respectively. As a prelude to in vivo delivery experiments, we also demonstrated that these bicistronic cassettes can be packaged normally into retroviral (5 x 10(5) virus/ml from pooled populations) and adenoviral vectors (5 x 10(9) virus/ml) and function as predicted within virally infected cells. This family of bicistronic vectors can be used to stimulate synergy between suicide and cytokine genes, overcomes the problems of delivering two genes on separate vectors, and should allow easier preparation of vectors for the delivery of multiple genes to patients' tumor cells.

Adenoviridae↗
PubMed1996

Epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastro-oesophageal cancer.

High response rates have been reported in the treatment of advanced gastric cancer with epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF), including instances of unresectable disease being rendered operable by chemotherapy. We report our experience with ECF as neoadjuvant treatment in gastric and lower oesophageal carcinoma. Twenty-seven patients were treated, of whom ten (37%) had carcinoma of the stomach and 17 (63%) tumours of the lower oesophagus. Histology in the majority of cases, 21 (78%), was adenocarcinoma. Before chemotherapy ten patients (37%) had evidence of initially unresectable locally advanced disease, 16 (59%) had localised disease only and one patient (4%) had a localised primary with a single liver metastasis. Epirubicin (50 mg m(-2) i.v.) and cisplatin (60 mg m(-2) i.v.) were administered every 3 weeks for four cycles together with a continuous 12 week infusion of 5-fluorouracil (200 mg m(-2) day(-1)). Fifteen of 24 assessable patients (62%) had symptomatic improvement on chemotherapy. On combined surgical and/or radiological assessment, 15 of the 27 patients (56%) had objective evidence of tumour response. In all patients assessment for radical surgery was made following chemotherapy. Eighteen patients (67%) proceeded to operation: of these, 11 had complete resection of their disease, one had a histologically incomplete resection and six were found to have unresectable disease. No pathological complete responses were observed. Only one of the ten patients with locally advanced disease achieved complete surgical resection after chemotherapy. At a median follow-up of 36 months from date of diagnosis (range 30-47 months), 19 of the 27 patients (70%) have died. Of 11 patients who had a complete surgical resection, one died post-operatively, three have subsequently relapsed (of whom two have died) and seven remain disease free. Toxicity from treatment was mild and included emesis, myelosuppression, stomatitis and exfoliation. Myelosuppression caused modification of treatment in 14 of 108 chemotherapy cycles (13%). There was one surgical death but no chemotherapy-related deaths. These early results show encouraging symptomatic and objective responses of gastro-oesophageal carcinoma to ECF, but provide no instances of ECF achieving complete pathological response. Only randomised trials can establish the role of neoadjuvant ECF chemotherapy in both initially resectable and unresectable carcinoma of the stomach and lower oesophagus.

Adult↗
PubMed1994

Malignant change in a mediastinal dermoid cyst.

Mature benign cystic teratomas, or dermoid cysts, usually arise in the ovary. They can, however, occur at other sites, including the mediastinum. Malignant change within dermoid cysts is a rare but recognized complication, occurring in 1%-2% of cases. A case of malignant change within a mediastinal dermoid cyst occurring 19 years after initial presentation is described.

Cell Transformation, Neoplastic↗