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Weixin Wang,
Meghan Corrigan-Cummins,
Justin Hudson,
Irina Maric,
Olga Simakova,
Sattva S Neelapu,
Larry W Kwak,
John E Janik, Barry Gause,
Elaine S Jaffe,
Katherine R Calvo
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ABSTRACT: MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma.
MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human microRNAs. Tandem gene expression profiles were obtained for predicting microRNA targets.
The expression of 133 microRNAs was significantly different (> 2-fold; P<0.05) between follicular lymphoma and follicular hyperplasia. Forty-four microRNAs in three groups generated a unique follicular lymphoma signature. Of these, ten microRNAs were increased (miR-193a-5p, -193b*, -345, -513b, -574-3p, -584, -663, -1287, -1295, and -1471), 11 microRNAs were decreased (miR-17*, -30a, -33a, -106a*, -141, -202, -205, -222, -301b, -431*, and -570), and 23 microRNAs formed a group that was increased in most cases of follicular lymphoma but showed lower expression in a subset of cases (let-7a, let-7f, miR-7-1*, -9, -9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -374b, -451, -454, -502-3p, -532-3p, -664*, -1274a, -1274b, and -1260). Higher expression of this last group was associated with improved response to chemotherapy. Gene expression analysis revealed increased expression of MAPK1, AKT1, PRKCE, IL4R and DROSHA and decreased expression of CDKN1A/p21, SOCS2, CHEK1, RAD51, KLF4, BLIMP1 and IRF4 in follicular lymphoma. Functional studies indicated that CDKN1A/p21 and SOCS2 expression is directly regulated by miR-20a/-20b and miR-194, respectively.
Follicular lymphoma is characterized by a unique microRNA signature, containing a subset of microRNAs whose expression correlate with response to chemotherapy. miR-20a/b and miR-194 target CDKN1A and SOCS2 in follicular lymphoma, potentially contributing to tumor cell proliferation and survival.
Haematologica 11/2011; 97(4):586-94. · 6.42 Impact Factor
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ABSTRACT: We report the case of a 65-year-old man who presented with epigastric pain and guaic-positive stool. Upper and lower endoscopy revealed abnormalities in the gastric antrum and terminal ileum. Biopsy of these sites revealed histologically and immunophenotypically distinct lymphomas: gastric extranodal marginal zone lymphoma in the background of Helicobacter pylori infection and follicular lymphoma of the terminal ileum. After treatment with an H. pylori eradication regimen, repeat endoscopy showed resolution of the gastric extranodal marginal zone lymphoma and persistence of the ileal follicular lymphoma. Interestingly, molecular studies performed on the biopsy specimens revealed a common IgH rearrangement, suggesting a common precursor cell responsible for these two malignant processes. We present this unique case with a review of the literature, highlighting treatment principles for these two subtypes of indolent gastrointestinal non-Hodgkin lymphoma.
American journal of therapeutics 10/2011;
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Osama Rahma,
Ed Ashtar,
Ramy Ibrahim,
Antoun Toubaji, Barry Gause,
Vincent Herrin,
Linehan W Marston,
Seth Steinberg,
Frank Grollman,
George Grimes,
Sarah Bernstein,
Jay Berzofsky,
Samir Khleif
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ABSTRACT: Abstract
Background
Due to the lack of specific tumor antigens, the majority of tested cancer vaccines for renal cell carcinoma (RCC) are based on tumor cell lysate. The identification of the von Hippel-Lindau ( VHL ) gene mutations in RCC patients provided the potential for developing a novel targeted vaccine for RCC. In this pilot study, we tested the feasibility of vaccinating advanced RCC patients with the corresponding mutant VHL peptides.
Methods
Six patients with advanced RCC and mutated VHL genes were vaccinated with the relevant VHL peptides. Patients were injected with the peptide mixed with Montanide subcutaneously (SQ) every 4 weeks until disease progression or until the utilization of all available peptide stock.
Results
Four out of five evaluable patients (80%) generated specific immune responses against the corresponding mutant VHL peptides. The vaccine was well tolerated. No grade III or IV toxicities occurred. The median overall survival (OS) and median progression-free survival (PFS) were 30.5 and 6.5 months, respectively.
Conclusions
The vaccine demonstrated safety and proved efficacy in generating specific immune response to the mutant VHL peptide. Despite the fact that the preparation of these custom-made vaccines is time consuming, the utilization of VHL as a vaccine target presents a promising approach because of the lack of other specific targets for RCC. Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials. Trial registration: 98C0139
Journal of Translational Medicine. 01/2010;
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Osama E Rahma,
Ed Ashtar,
Ramy Ibrahim,
Antoun Toubaji, Barry Gause,
Vincent E Herrin,
W Marston Linehan,
Seth M Steinberg,
Frank Grollman,
George Grimes,
Sarah A Bernstein,
Jay A Berzofsky,
Samir N Khleif
[show abstract]
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ABSTRACT: Due to the lack of specific tumor antigens, the majority of tested cancer vaccines for renal cell carcinoma (RCC) are based on tumor cell lysate. The identification of the von Hippel-Lindau (VHL) gene mutations in RCC patients provided the potential for developing a novel targeted vaccine for RCC. In this pilot study, we tested the feasibility of vaccinating advanced RCC patients with the corresponding mutant VHL peptides.
Six patients with advanced RCC and mutated VHL genes were vaccinated with the relevant VHL peptides. Patients were injected with the peptide mixed with Montanide subcutaneously (SQ) every 4 weeks until disease progression or until the utilization of all available peptide stock.
Four out of five evaluable patients (80%) generated specific immune responses against the corresponding mutant VHL peptides. The vaccine was well tolerated. No grade III or IV toxicities occurred. The median overall survival (OS) and median progression-free survival (PFS) were 30.5 and 6.5 months, respectively.
The vaccine demonstrated safety and proved efficacy in generating specific immune response to the mutant VHL peptide. Despite the fact that the preparation of these custom-made vaccines is time consuming, the utilization of VHL as a vaccine target presents a promising approach because of the lack of other specific targets for RCC. Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials. Trial registration: 98C0139.
Journal of Translational Medicine 01/2010; 8:8. · 3.41 Impact Factor
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Antoun Toubaji,
Moujahed Achtar,
Maurizio Provenzano,
Vincent E Herrin,
Robert Behrens,
Michael Hamilton,
Sarah Bernstein,
David Venzon, Barry Gause,
Francesco Marincola,
Samir N Khleif
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ABSTRACT: There is mounting evidence describing the immunosuppressive role of bulky metastatic disease, thus countering the therapeutic effects of tumor vaccine. Therefore, adjuvant immunotherapy may have a better impact on clinical outcome. In this phase II clinical trial, we aimed to test the feasibility of using a specific mutant ras peptide vaccine as an adjuvant immunotherapy in pancreatic and colorectal cancer patients.
Twelve patients with no evidence of disease (NED), five pancreatic and seven colorectal cancer patients were vaccinated subcutaneously with 13-mer mutant ras peptide, corresponding to their tumor's ras mutation. Vaccinations were given every 4 weeks, up to a total of six vaccines.
No serious acute or delayed systemic side effects were seen. We detected specific immune responses to the relevant mutant ras peptide by measuring IFN-gamma mRNA expression by quantitative real-time PCR. Five out of eleven patients showed a positive immune response. Furthermore, the five pancreatic cancer patients have shown a mean disease-free survival (DFS) of 35.2+ months and a mean overall survival (OS) of 44.4+ months. The seven colorectal cancer patients have shown a mean disease-free survival (DFS) of 27.2+ months and a mean overall survival (OS) of 41.5+ months.
In this study, we found that it is feasible to use mutant ras vaccine in the adjuvant setting. This vaccine is safe, can induce specific immune responses, and it appears to have a positive outcome in overall survival. Therefore, we believe that such an approach warrants further investigation in combination with other therapies.
Cancer Immunology and Immunotherapy 10/2008; 57(9):1413-20. · 3.70 Impact Factor
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Deirdre O'Mahony,
John C Morris,
Cate Quinn,
Wendy Gao,
Wyndham H Wilson, Barry Gause,
Stefania Pittaluga,
Sattva Neelapu,
Margaret Brown,
Thomas A Fleisher,
James L Gulley,
Jeffrey Schlom,
Robert Nussenblatt,
Paul Albert,
Thomas A Davis,
Israel Lowy,
Mike Petrus,
Thomas A Waldmann,
John E Janik
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ABSTRACT: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.
Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles.
Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.
Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.
Clinical Cancer Research 03/2007; 13(3):958-64. · 7.74 Impact Factor
