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Mark R Albertini

Publications and source records attributed to Mark R Albertini.

9 recordsLinked to original sources
PubMed2025

SURROGATE SELECTION OVERSAMPLES EXPANDED T CELL CLONOTYPES.

Surrogate selection is an experimental design that without sequencing any DNA can restrict a sample of cells to those carrying certain genomic mutations. In immunological disease studies, this design may provide a relatively easy approach to enrich a lymphocyte sample with cells relevant to the disease response because the emergence of neutral mutations associates with the proliferation history of clonal subpopulations. A statistical analysis of clonotype sizes provides a structured, quantitative perspective on this useful property of surrogate selection. Our model specification couples within-clonotype birth-death processes with an exchangeable model across clonotypes. Beyond enrichment questions about the surrogate selection design, our framework enables a study of sampling properties of elementary sample diversity statistics; it also points to new statistics that may usefully measure the burden of somatic genomic alterations associated with clonal expansion. We examine statistical properties of immunological samples governed by the coupled model specification, and we illustrate calculations in surrogate selection studies of melanoma and in single-cell genomic studies of T cell repertoires.

Bayes’s rule↗
PubMed2006

A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children's Oncology Group.

PURPOSE: Evaluate the clinical safety, toxicity, immune activation/modulation, and maximal tolerated dose of hu14.18-IL2 (EMD 273063) in pediatric patients with recurrent/refractory neuroblastoma and other GD2-positive solid tumors. EXPERIMENTAL DESIGN: Twenty-seven pediatric patients with recurrent/refractory neuroblastoma and one with melanoma were treated with a humanized anti-GD2 monoclonal antibody linked to human interleukin 2 (IL-2). Cohorts of patients received hu14.18-IL2, administered i.v. over 4 hours for three consecutive days, at varying doses. Patients with stable disease, partial, or complete responses were eligible to receive up to three additional courses of therapy. RESULTS: Most of the clinical toxicities were anticipated and similar to those reported with IL-2 and anti-GD2 monoclonal antibody therapy and to those noted in the initial phase I study of hu14.18-IL2 in adults with metastatic melanoma. The maximal tolerated dose was determined to be 12 mg/m2/d, with agent-related dose-limiting toxicities of hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia. Three patients developed dose-limiting toxicity during course 1; seven patients in courses 2 to 4. Two patients required dopamine for hypotension. There were no treatment-related deaths, and all toxicity was reversible. Treatment with hu14.18-IL2 led to immune activation/modulation as evidenced by elevated serum levels of soluble IL-2 receptor alpha (sIL2Ralpha) and lymphocytosis. The median half-life of hu14.18-IL2 was 3.1 hours. There were no measurable complete or partial responses to hu14.18-IL2 in this study; however, three patients did show evidence of antitumor activity. CONCLUSION: Hu14.18-IL2 (EMD 273063) can be administered safely with reversible toxicities in pediatric patients at doses that induce immune activation. A phase II clinical trial of hu14.18-IL2, administered at a dose of 12 mg/m2/d x 3 days repeated every 28 days, will be done in pediatric patients with recurrent/refractory neuroblastoma.

Adolescent↗
PubMed2005

Phase I trial of combined treatment with ch14.18 and R24 monoclonal antibodies and interleukin-2 for patients with melanoma or sarcoma.

PURPOSE: We conducted a phase I trial of interleukin 2 (IL-2) in combination with chimeric 14.18 (ch14.18) and murine R24 antibodies to determine the maximal tolerated dose (MTD), immunological effects, and toxicity of this treatment combination. EXPERIMENTAL DESIGN: Twenty-seven patients with either melanoma (23 patients) or sarcoma (4 patients) were enrolled to receive a combination therapy with ch14.18 and R24 antibodies together with continuous infusion of Roche IL-2 (1.5 x 10(6) U/m(2)/day, 26 patients) or Chiron IL-2 (4.5 x 10(6) U/m(2)/day, 1 patient) given 4 days/week for 3 weeks. The antibodies ch14.18 (2-7.5 mg/m(2)/day) and R24 (1-10 mg/m(2)/day) were scheduled to be administered for 5 days during the second week of IL-2 therapy. RESULTS: When given in combination in this study, the MTD for ch14.18 was 5 mg/m(2)/day and the MTD for R24 was 5 mg/m(2)/day. Dose-limiting toxicities were severe allergic reactions to both ch14.18 and R24 as well as pain related to ch14.18. This ch14.18 MTD was lower than the 7.5 mg/m(2)/day MTD previously determined for ch14.18 given alone with the same dose and schedule of IL-2. Immunological effects included the induction of lymphokine-activated killer (LAK) activity and antibody-dependent cell-mediated cytoxicity (ADCC). Anti-idiotype response to ch14.18 was seen in six patients, including two melanoma patients who had a partial response to treatment. In addition to two partial responses, four patients had a stable disease and one patient remained without any evidence of disease. CONCLUSIONS: Immunotherapy with IL-2 in combination with ch14.18 and R24 antibodies augments LAK function and ADCC measured in vitro in all patients. While there exist theoretical advantages of combining these two antibodies, the MTD of ch14.18 and of R24 were lower than the MTD of each antibody in prior studies evaluating single antibody therapy with IL-2. As such, the combination of these two antibodies together with IL-2 therapy appeared to influence the MTD and toxicity of each of the administered antibodies.

Adult↗
PubMed2005

Phase II trial of weekly paclitaxel in patients with advanced melanoma.

New therapies are needed to improve the prognosis of patients with metastatic melanoma. This study evaluates the safety and efficacy of weekly paclitaxel in patients with metastatic melanoma. Patients received paclitaxel at 80 mg/m over 1 h, weekly for 3 weeks, followed by a 1-week rest period. Disease status was assessed every other cycle. Treatment was continued until patients experienced either disease progression or unacceptable toxicity. Twenty-seven patients were enrolled in this phase II clinical trial. Of these patients, two were subsequently determined to be ineligible. All patients, however, were considered to be evaluable for toxicity and all patients were included for response assessment in an intention-to-treat analysis. Patients received paclitaxel for a median of two cycles (range, <1-8). None of the 27 patients showed a response to treatment. Eight patients had stable disease. The median progression-free survival was 1.8 months (95% confidence interval, 1.7-2.5 months) and the median survival was 7.6 months (95% confidence interval, 4.7-9.7 months). The most common grade 3 toxicity was neutropenia (four patients) and one patient had grade 4 neutropenia. Other treatment-related grade 3 toxicities included hypersensitivity reaction (one patient) and diarrhoea (one patient). Of note, five patients had peripheral neuropathy; however, in each case, the neuropathy was only grade 1. Weekly paclitaxel is relatively well tolerated and can maintain disease stability for some metastatic melanoma patients. Unfortunately, the anti-tumour activity of this single-agent therapy is low and additional treatment innovations are needed.

Adult↗
PubMed2004

Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients.

PURPOSE: To evaluate the safety, toxicity, in vivo immunologic activation, and maximum-tolerated dose (MTD) of EMD 273063 (hu14.18-IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS: Thirty-three patients were treated with EMD 273063, a humanized anti-GD2 monoclonal antibody (mAb) linked to interleukin-2 (IL-2). EMD 273063 was given as a 4-hour intravenous infusion on days 1, 2, and 3 of week 1. Patients with stabilization or regression of disease could receive a second course of treatment at week 5. Dose levels evaluated were 0.8, 1.6, 3.2, 4.8, 6.0, and 7.5 mg/m2/d. RESULTS: Nineteen of 33 patients completed course 1 with stable disease and went on to receive course 2. Eight patients had stable disease on completion of course 2. Grade 3 adverse events included hypophosphatemia (11 patients), hyperglycemia (three patients), hypotension (two patients), thrombocytopenia (one patient), hypoxia (three patients), elevated hepatic transaminases (two patients), and hyperbilirubinemia (one patient). Opioids were required for treatment-associated arthralgias and/or myalgias during 17 of 52 treatment courses. No grade 4 adverse events were observed. Dose-limiting toxicities at the MTD included hypoxia, hypotension, and elevations in AST/ALT. Grade 3 toxicities were anticipated based on prior studies of IL-2 or anti-GD2 mAbs, and all resolved. Immune activation was induced, as measured by lymphocytosis, increased peripheral-blood natural killer activity, and cell numbers, and increased serum levels of the soluble alpha chain of the IL-2 receptor complex. CONCLUSION: Treatment with the immunocytokine EMD 273063 induced immune activation and was associated with reversible clinical toxicities at the MTD of 7.5 mg/m2/d in melanoma patients.

Adult↗
PubMed2004

Dendritic cell-based immunotherapy for cancer and relevant challenges for transfusion medicine.

The encouraging results from dendritic cell-related cancer immunotherapy have created tremendous interest for its broad clinical application. Dendritic cells are the most potent antigen-presenting cells. In cancer patients, dendritic cell production and function along with other antitumor immune defenses are compromised. Autologous dendritic cells enriched and sensitized in vitro with tumor-associated antigens can effectively elicit host cellular immunity against cancer and result in clinical antitumor responses through either direct injection or ex vivo generation of antitumor T lymphocytes. In small group studies, clinical response rates have reached 50% in patients with advanced stage of cancer. These cellular products caused minimal side effects and were well tolerated. The isolation and preparation of clinical grade dendritic cells have been driven by transfusion medicine specialists who are well versed in similar processes for hematopoietic stem-cell preparation. The purpose of this article is to review the mechanisms of tumor immune surveillance and the biology of dendritic cells relevant to tumor antigen presentation, sensitization, and T-lymphocyte stimulation. Information on tumor-associated antigens and clinical trial results with dendritic cell-based cancer immunotherapy are summarized. The potential challenges for blood banking/transfusion medicine involving both technical and regulatory issues are discussed.

Antigen Presentation↗
PubMed2003

Localization of transfected B7-1 (CD80) DNA in human melanoma cells after particle-mediated gene transfer.

The purpose of this study was to evaluate stable DNA transfection of M-21 human melanoma cells with particle-mediated gene transfer (PMGT) with B7-1 cDNA and to identify sites of gene integration. Stable B7-1 transfectants (M-21-B7) were obtained with PMGT using a plasmid vector containing cDNA for both B7-1 and neomycin phosphotransferase, with subsequent selection with G418. The transfected cells were flow sorted by B7-1 expression into two populations, bright and dim. The bright population had 85%-90% of cells expressing B7-1; the dim population had less than 50% of cells with B7-1 expression. Chromosome analysis with fluorescence in situ hybridization (FISH) and G-banding showed that 70% of bright cells had two main integration sites, with extensive amplification of the transgene. The dim population had random signal distribution, with little or no amplification, despite G418 selection. Because B7-1 has been mapped to 3q21, FISH was performed using a chromosome 3 painting probe (WCP) together with a probe for B7-1. In transfected bright M-21 cells, amplified genes that hybridized with the B7-1 construct were localized to chromosome 3 material inserted into marker chromosomes. These data suggest that B7-1 insertion may involve homologous recombination, but maintenance of integration and amplification required selection.

B7-1 Antigen↗
PubMed2003

Preclinical and clinical development of immunocytokines.

Advances in preclinical and clinical development have demonstrated that monoclonal antibodies and immuno-activating cytokines have a beneficial role in certain clinical oncology settings. Genetic engineering has now been used to create 'immunocytokines (ICs)'. These are fusion proteins that consist of an immune-activating cytokine linked to a tumor-reactive monoclonal antibody. Preclinical data demonstrate that ICs are far more effective in murine tumor models than the separate molecules from which they are derived. Clinical testing of ICs has recently begun using an anti-GD2 monoclonal antibody linked to interleukin-2 (IL-2) (hu14.18-IL-2), and using an antibody directed against the human epithelial cell adhesion molecule linked to IL-2 (KS-IL-2).

Animals↗