A phase I/II trial of oxidized autologous tumor vaccines during the “watch and wait” phase of chronic lymphocytic leukemia

2004 ◽  
Vol 54 (7) ◽  
pp. 635-646 ◽  
Author(s):  
David E. Spaner ◽  
Caitlin Hammond ◽  
Jenny Mena ◽  
Cindy Foden ◽  
Andrea Deabreu
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Lymphocytic Leukemia ◽  
Autologous Tumor ◽  
Watch And Wait ◽  
Tumor Vaccines

Immunotherapy of Chronic Lymphocytic Leukemia using CD40L and IL2 Expressing Autologous Tumor Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 768-768 ◽  
Author(s):  
Ettore Biagi ◽  
Uday Popat ◽  
Rousseau Raphael ◽  
Yvon Eric ◽  
Dotti Giampietro ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Cells ◽  
Tumor Antigens ◽  
Cd40 Ligand ◽  
Lymphocytic Leukemia ◽  
Autologous Tumor ◽  
Tumor Vaccines ◽  
Cd40 Stimulation ◽  
Pre Treatment

Abstract Transgenic human CD40 ligand (hCD40L) activates B-Chronic Lymphocytic Leukemia (B-CLL) cells by CD40 stimulation and may thereby enhance their capacity to present tumor antigens. Pre-clinical models show that co-expression of IL-2 further potentiates the immunogenicity of CD40L-expressing tumor cells. To discover whether these promising pre-clinical data could usefully be applied to patients with B-CLL, we used adenovectors to prepare hIL2- and hCD40L-expressing autologous tumor vaccines. Within these vaccines, a mean of 92% B-CLL cells were CD40L positive (versus <1% pre-treatment), and costimulatory molecules were also upregulated on the tumor cells (CD80 from 6% to 74% and CD86 from 16% to 73% positive cells). The mean secretion of IL-2 (measured by ELISA at 72 hours after transduction) was 1,780 pg/ml/10E6 cells (range = 175–400). To date, 8 patients have received between 5 and 8 subcutaneous injections in a modified Phase I design, in which the dose of IL-2 secreting cells was fixed at 2x10E7 per injection, while the dose of CD40L-expressing leukemia cells was escalated from 2x10E5 (level 1) to 2x10E7 (level 3) per injection. 12 additional patients will receive this final dose combination. Of those treated, two patients were in Rai stage 4; 2 in stage 3; 2 in stage 2; and 2 in stage 1. There were no adverse events from any injection in the patients. Injection-site biopsies revealed a modest infiltration of CD3+ cells, and the vaccine also had systemic immunomodulatory effects. Total T-cell numbers were significantly increased in only 2 patients, but an anti-B-CLL immune response was detected in 5/6 individuals currently analyzed. Using ELISPOT assays with autologous B-CLL cells as stimulators, and allogeneic B-CLL cells as controls, we found a rise in IFN-gamma spot-forming T-cells (<1/100,000 pre to >1/1500 post vaccination) and of Granzyme-B expressing T-cells (<1/100,000 pre to >1/2500 post). This reactivity is mediated at least in part by CD8-positive T cells with specificity to survivin, a known B-CLL associated tumor antigen. Although these immunologic effects have as yet been accompanied by only transient disease responses, our continuing accrual of additional patients who will receive immunomodulatory doses of vaccine should indicate whether the approach could contribute to the management of early or advanced B-CLL.

scholarly journals Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Daruka Mahadevan ◽  
Mark C. Lanasa ◽  
Charles Farber ◽  
Manjari Pandey ◽  
Maria Whelden ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Immune Checkpoint ◽  
Phase I Study ◽  
Lymphocytic Leukemia

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

scholarly journals Gene Immunotherapy of Chronic Lymphocytic Leukemia: A Phase I Study of Intranodally Injected Adenovirus Expressing a Chimeric CD154 Molecule

2012 ◽  
Vol 72 (12) ◽  
pp. 2937-2948 ◽  
Author(s):  
Januario E. Castro ◽  
Johanna Melo-Cardenas ◽  
Mauricio Urquiza ◽  
Juan S. Barajas-Gamboa ◽  
Ramin S. Pakbaz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase I Study ◽  
Lymphocytic Leukemia

A phase I/II study of ofatumumab (GSK1841157) in Japanese and Korean patients with relapsed or refractory B-cell chronic lymphocytic leukemia

2013 ◽  
Vol 98 (2) ◽  
pp. 164-170 ◽  
Author(s):  
Yoshiaki Ogawa ◽  
Michinori Ogura ◽  
Tatsuya Suzuki ◽  
Kiyoshi Ando ◽  
Toshiki Uchida ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Korean Patients ◽  
Cell Chronic Lymphocytic Leukemia

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients

2010 ◽  
Vol 68 (3) ◽  
pp. 643-651 ◽  
Author(s):  
Jonathan Hebb ◽  
Sarit Assouline ◽  
Caroline Rousseau ◽  
Pierre DesJardins ◽  
Stephen Caplan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Imatinib Mesylate ◽  
Phase I Study ◽  
Lymphocytic Leukemia ◽  
Previously Treated

scholarly journals Limited value of routine follow-up visits in chronic lymphocytic leukemia managed initially by watch and wait: A North Denmark population-based study

PLoS ONE ◽  
2018 ◽  
Vol 13 (12) ◽  
pp. e0208180 ◽  
Author(s):  
Caroline Holm Nørgaard ◽  
Nikoline Buus Søgaard ◽  
Jorne Lionel Biccler ◽  
Laura Pilgaard ◽  
Mathias Holmsgaard Eskesen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Population Based ◽  
Lymphocytic Leukemia ◽  
Watch And Wait ◽  
Population Based Study

scholarly journals Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia

2011 ◽  
Vol 53 (2) ◽  
pp. 211-217 ◽  
Author(s):  
Clive S. Zent ◽  
Brian J. Smith ◽  
Zuhair K. Ballas ◽  
James E. Wooldridge ◽  
Brian K. Link ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Lymphocytic Leukemia ◽  
Phase I Clinical Trial ◽  
Cpg Oligonucleotide ◽  
Previously Treated
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