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Biomedical subjects

John Nemunaitis

Publications and source records attributed to John Nemunaitis.

10 recordsLinked to original sources
PubMed2003

GVAX (GMCSF gene modified tumor vaccine) in advanced stage non small cell lung cancer.

Treatment for advanced stage non-small cell lung cancer is limited. In an attempt to determine whether immune stimulating activity can be induced with a GMCSF gene transduced autologous tumor vaccine (GVAX), 83 patients were entered into trial (20 with stage 1B/IIB disease and 63 with stage IIIB/IV disease). Patients fulfilling eligibility criteria underwent surgical harvest of autologous lung tumor tissue. The tissue was then processed, transfected with an E1 deleted, E3 deleted adenoviral GMCSF gene vector irradiated prior to injection. Patients received a series of six vaccinations (1 every two weeks). Forty-three of the 83 patients were eligible for treatment (10 in cohort A and 33 in cohort B). These results have previously been reported. GVAX was well tolerated. Three of 33 patients with advanced disease achieved complete response. Evidence of immunologic activity following vaccination in a subset of patients was suggested, based on antibody response to either autologous SV40 transformed tumor cells or allogeneic non-small cell lung cancer tumor cells. These results supported further clinical investigation with GVAX in non-small cell lung cancer.

Antineoplastic Agents↗
PubMed2003

Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients.

ONYX-015 is an adenovirus that selectively replicates in p53 dysfunctional or mutated malignant cells. We performed a pilot trial to determine the safety and feasibility of treatment with ONYX-015 delivered intravenously in patients with advanced malignancy. One cohort of five patients received ONYX-015 once a week for 6 weeks at a dose of 2 x 10(12) particles per infusion in combination with weekly infusions of irinotecan (CPT11, 125 mg per week) and 5-fluorouracil (5FU, 500 mg per week). A second cohort of five patients received the combination of ONYX-015 at a dose of 2 x 10(11) particles per week for 6 weeks in combination with interleukin 2 (IL 2, 1.1 x 10(6) units daily via subcutaneous injection for 5 days each week for 4 weeks). Toxicity attributable to ONYX-015 was limited to transient fever. All patients demonstrated elevations in neutralizing antibody titers within 4 weeks of the infusion of ONYX-015. Serum levels of IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma increased within 6 hours of viral infusion, suggesting immune activation. This response was more pronounced in the cohort of patients who received 2 x 10(12) particles per infusion. Two patients demonstrated uptake of viral particles in malignant tissue by quantitative PCR. Electron microscopy confirmed selective cytoplasmic viral particles within malignant cells but not within adjacent normal tissue in a third patient. In conclusion ONYX-015 can be administered safely in combination with CPT11, 5FU or low-dose IL 2 and is able to access malignant tissue following intravenous infusion. Further investigation of ONYX-015, possibly with agents that may modulate replication activity, or duration of virus survival, is indicated.

Adenoviridae↗
PubMed2003

Selective replicating viral vectors : potential for use in cancer gene therapy.

Treatment of cancer is limited by toxicity to normal tissue with standard approaches (chemotherapy, surgery and radiotherapy). The use of selective replicating viral vectors may enable the targeting of gene-modified viruses to malignant tissue without toxic effect. Studies of these vectors have demonstrated tumour-selective replication and minimal evidence of replication in normal tissue. The most advanced clinical results reported involve gene-modified adenoviral vectors. Several completed, histologically confirmed responses to local/regional injection have been induced, particularly in recurrent squamous cell carcinoma involving the head and neck region. Dose limiting toxicity above 10(13) viral particles per injection has been observed. Anti-tumour effect is demonstrable in animal models without evidence of significant toxicity when these vectors are used alone or in combination with chemotherapy, radiation therapy or as gene delivery vehicles. Preliminary clinical trials, particularly with E1B-deleted adenoviruses, report evidence of clinical activity in comparison with expected historical responses. Enhancement in replication selectivity to malignant tissue is also demonstrated preclinically and clinically with an E1B-deleted adenovirus utilising a prostate-specific antigen promoter. Other selective replicating viral vectors such as herpes simplex virus and vaccinia virus have also been explored clinically and suggest evidence of activity in patients with cancer. Modifications may one day enable more aggressive use of these new and exciting therapeutics as systemic gene delivery vehicles.

Animals↗
PubMed2002

Characterization of a novel prostate-specific antigen-activated peptide-doxorubicin conjugate in patients with prostate cancer.

PURPOSE: To evaluate safety and pharmacokinetics (PK), and determine the recommended dose for efficacy studies, of L-377202, a novel peptide conjugate of doxorubicin (Dox) that releases the active metabolites leucine-doxorubicin (Leu-Dox) and Dox on cleavage by membrane-bound prostate-specific antigen (PSA). PATIENTS AND METHODS: Nineteen patients with advanced hormone-refractory prostate cancer were treated intravenously with 71 cycles of L-377202 at escalating dose levels of 20 (n = 1), 40 (n = 3), 80 (n = 4), 160 (n = 3), 225 (n = 6), and 315 mg/m(2) (n = 2) once every 3 weeks. Toxicity, response, and PK of L-377202 were assessed. RESULTS: L-377202 was well tolerated. Dose-limiting grade 4 neutropenia was noted in two of two patients administered 315 mg/m(2) (both patients were able to resume therapy at 225 mg/m(2)). The recommended dose for efficacy studies was 225 mg/m(2), which induced grade 4 neutropenia in one of six patients. PK studies demonstrated that L-377202 was metabolized to Leu-Dox and Dox. PK were linear; after administration of single doses of 225 mg/m(2), the mean area under the concentration-time profiles of L-377202, Leu-Dox, and Dox were 6 micromol x L/h, 4 micromol x L/h, and 1 micromol x L/h, and peak concentrations were 14 micromol/L, 5 micromol/L, and 120 nmol/L, respectively. At 225 and 315 mg/m(2), five patients completed at least three cycles of therapy; two patients had a greater than 75% decrease in PSA, and one patient had a stabilized PSA. No response was noted at dose levels less than 225 mg/m(2). CONCLUSION: This is the first study of selective drug delivery in humans using a novel PSA-activated agent. L-377202 was cleaved to produce detectable levels of the active metabolites Leu-Dox and Dox. L-377202 was well tolerated and established a safe dose level for further study.

Aged↗
PubMed2002

Emerging new therapies for chemotherapy-resistant cancer using adenoviral vectors.

The treatment of cancer by genetic manipulation of either the tumor itself or the patient as a whole offers new avenues for the treatment of otherwise refractory cancers. Gene therapy seeks to correct underlying genetic defects in malignant tissue or to augment the host defense response or to promote selectivity of other therapies. Many innovative and exciting genetic targets have been recently identified. However, the field as a whole is still constrained by limitations of gene delivery. The most common vector for gene delivery is modified adenovirus. In this review, we survey a sampling of current therapeutic approaches that depend upon adenoviral delivery vehicles and outline the advantages and disadvantages of this vector system.

Adenoviridae↗
PubMed2002

Head and neck cancer: gene therapy approaches. Part 1: adenoviral vectors.

Treatment options for recurrent or refractory head and neck cancer are limited. The goal of gene therapy is to introduce new genetic material into cancer cells without affecting toxicity to surrounding malignant cells. The most common vehicles for delivery of genes are adenoviruses. Adenoviruses gain access to malignant and normal cell cytoplasm via viral ligand binding to a unique cell surface receptor (the coxsackie adenovirus receptor [CAR]). However, this receptor is not cancer specific. Genetic modification of adenoviral DNA can create cancer specific targeting. Adenoviruses can be modified to express cancer specific ligands thereby focusing binding to malignant tissue. Furthermore, adenoviral delivered genes can be put under cancer specific promoter control to further limit gene expression in malignant tissue. Increased antitumour activity from such modifications has been demonstrated preclinically and several clinical trials have been completed demonstrating safety and clinical activity of non-replicating and conditional replicating adenoviral vector thereby opening the door for gene delivery and cancer specific targeting.

Adenoviridae↗
PubMed2002

Head and neck cancer: gene therapy approaches. Part II: genes delivered.

In Part I, the review summarised the safety of adenoviral vectors and provided insight into approaches being undertaken to improve the specificity, durability and potency of adenoviral delivery vehicles. In Part II, brief discussions are held regarding results of preclinical and clinical trials with a variety of different genes, which have demonstrated antitumour activity in squamous cell carcinoma of the head and neck region (HNSCC). Studies have been performed with a variety of immune modulatory genes. Preliminary results demonstrate activity with several cytokine genes, tumour antigen genes and co-stimulatory molecule genes. Despite only preliminary results, thus far, a theoretical attractive feature for the use of gene therapy for the enhancement of immune modulation is that local injection of the gene product appears to be well tolerated. It is also successful in inducing systemic immune response, potentially providing effect to metastatic sites distal from the injected site. Animal studies have confirmed efficacy in the use of specific targeting of molecules regulating cancer growth (EGF receptor [EGFR], super oxide dismutase [SOD], cyclin D1, E1A and Bcl-2). These approaches are discussed. However, the most significant clinical advances for the use of gene therapy in advanced HNSCC involves two agents: Adp53 and ONYX-015. Preliminary Phase I and II results suggest evidence of efficacy and justify accrual Phase III trials, which are currently ongoing.

Adenoviridae↗
PubMed2002

Live viruses in cancer treatment.

Although antitumor activity and a low toxicity profile have been demonstrated for several oncolytic viruses, the development of viral therapy in cancer treatment has been limited by a lack of definitive phase III trials. The use of replicating viruses to potentiate the efficacy of standard cancer therapies also awaits conclusive clinical testing. Based on preliminary results with new generations of oncolytic viruses, ongoing research in this area appears encouraging. This article explores the principles of viral therapy for cancer and the past several decades of investigations with viruses such as Egypt 101, mumps, Newcastle disease, influenza, vaccinia, herpes simplex, and adenovirus serotype 5.

Biological Therapy↗