A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy

Abstract Introduction: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH), colloquially referred to as double- or triple-hit lymphoma, is associated with poor outcomes prompting many centers to use dose-intensive immunochemotherapy. The benefit of treatment intensification in patients with HGBL-DH/TH with diffuse large B-cell lymphoma (DLBCL) morphology, who would otherwise receive standard-of-care rituximab, cyclophosphamide, vincristine and prednisone (R-CHOP), remains unclear because suitably powered randomized clinical trials have not been performed, and earlier studies included patients with high-grade morphology. Furthermore, selection bias due to the restriction of fluorescence in situ hybridization (FISH) testing to diagnose HGBL-DH/TH in patients with high-risk clinical presentation or aggressive tumor morphology confounds historical comparators. Since 2015, de novo DLBCL biopsies in British Columbia (BC) have undergone routine FISH testing in clinical practice. Concurrently, provincial guidelines were introduced recommending treatment with dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone and rituximab (DA-EPOCH-R) for appropriately fit patients aged 75 years (y) or younger with HGBL-DH/TH harboring BCL2 rearrangements with DLBCL morphology (HGBL-DH/TH-BCL2-DLBCL). A population-based analysis was conducted to assess the impact of the introduction of DA-EPOCH-R on outcomes in HGBL-DH/TH-BCL2-DLBCL. Methods: Outcomes of HGBL-DH/TH-BCL2-DLBCL patients diagnosed between 2015 to 2020 using clinical FISH performed on de novo DLBCL biopsies (DA-EPOCH-R era) were compared to patients with HGBL-DH/TH-BCL2-DLBCL identified from a historic province-wide cohort of de novo DLBCL diagnosed between 2005-2010 in BC that underwent universal FISH in a research setting (R-CHOP era). Patients with the rarer entity of HGBL-DH/TH harboring MYC and BCL6 rearrangements only (HGBL-DH-BCL6) were excluded and were not part of the original DA-EPOCH-R guideline. Multivariable Cox proportional hazards regression models were used to predict the independent effect of treatment era after controlling for the International Prognostic Index (IPI). Results: 99 patients with HGBL-DH/TH-BCL2-DLBCL were identified through routine clinical FISH in the DA-EPOCH-R era. Of 1172 de novo DLBCL patients in the historic R-CHOP era, 824 had adequate diagnostic material for evaluation by FISH, 52 of which were HGBL-DH/TH-BCL2-DLBCL. The analysis was restricted to patients aged 75y or younger, yielding 71 and 38 patients in the DA-EPOCH-R and R-CHOP eras, respectively. 7/38 (18%) biopsies in the R-CHOP era had undergone clinical FISH testing at diagnosis with results known to the treating physician. Median (interquartile range) follow-up in living patients was 2.8y (2.0-4.4y) in the DA-EPOCH-R era and 12.2y (11.2-13.4y) in the R-CHOP era. 49/71 (69%) patients received DA-EPOCH-R in the DA-EPOCH-R era, whereas 32/38 patients (84%) received R-CHOP in the R-CHOP era. Both eras had comparable baseline clinical characteristics with no significant difference in IPI risk groups (Table 1). The DA-EPOCH-R era was associated with superior 2-year time to progression (TTP, 73.9% vs 47.4%, p=0.016) and overall survival (OS, 77.7% vs 50.0%, p=0.022, Figure 1). After adjusting for IPI risk groups (low 0-2, high 3-5), the DA-EPOCH-R era was independently associated with superior TTP (hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.21-0.77, p=0.005) and OS (HR 0.39, 95% CI 0.21-0.76, p=0.005). After controlling for individual IPI factors, treatment era remained predictive of TTP (HR 0.38, 95% CI 0.19- 0.76, p=0.006) and OS (HR 0.39, 95% CI 0.19-0.79, p=0.008). Conclusions: Introduction of a provincial, population-based recommendation to use DA-EPOCH-R for appropriately fit patients aged 75y or younger is associated with improved real-world outcomes of HGBL-DH/TH-BCL2-DLBCL. The similarity between TTP and OS within each era suggests the high failure rate of conventional salvage therapy irrespective of frontline treatment, prompting further investigation of novel second-line therapies in this poor-prognosis population. Targeted capture sequencing to identify MYC translocation partners is underway, and the influence of the MYC partner on outcomes in both eras will be presented. Figure 1 Figure 1. Disclosures Sehn: Novartis: Consultancy; Genmab: Consultancy; Debiopharm: Consultancy. Slack: Seagen: Consultancy, Honoraria. Craig: Bayer: Consultancy. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Gerrie: Sandoz: Honoraria; Roche: Research Funding; Astrazeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Freeman: Teva: Research Funding; Roche: Research Funding; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Speakers Bureau; Incyte: Honoraria; Abbvie: Honoraria; Seattle Genetics: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau. Savage: Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Astra-Zeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Servier: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Steidl: Bayer: Consultancy; Trillium Therapeutics: Research Funding; Curis Inc.: Consultancy; AbbVie: Consultancy; Epizyme: Research Funding; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding. Scott: Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Rich/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Incyte: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy.

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Gene Expression Profiling within the Context of JAK Inhibitor Therapy for Myelofibrosis: Correlation with Treatment Effect and Anemia Response

Blood ◽

10.1182/blood.v120.21.1751.1751 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1751-1751

Author(s):

Animesh Pardanani ◽

Rebecca R. Laborde ◽

Terra L Lasho ◽

Christy Finke ◽

Alexey A. Leontovich ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trial ◽

Immune Response ◽

Gene Expression Profiling ◽

Pathway Analysis ◽

Treatment Effect ◽

Expression Profiling ◽

Phase 1 ◽

Hemoglobin Level ◽

Jak Inhibitors

Abstract Abstract 1751 Background: JAK inhibitors have significant palliative benefit in myelofibrosis (MF), mainly in the form of improved constitutional symptoms and reduced splenomegaly. Preliminary data suggests that CYT387, a JAK-1/2 inhibitor, also has the ability to produce anemia responses (ASH Annual Meeting, 2011). In general, the mechanism(s) underlying treatment effects of JAK inhibitors remain unclear but likely represent a drug-specific balance between anti-clonal activity and modulation of immuno cellular-cytokine pathways. We conducted a gene expression profiling (GEP) study using primary cells from MF patients undergoing therapy with CYT387 followed by correlation with clinical data. Methods: Study subjects were enrolled in the Phase-1/2 study of CYT387 treatment in patients with primary (PMF), post-polycythemia vera (PPMF) or post-essential thrombocythemia (PTMF) myelofibrosis. Paired research samples were collected; the time points were pre-study and 12 weeks after commencing study treatment. PBMCs were purified from whole blood by Ficoll separation; RNA was isolated from this cell fraction for GEP analysis. Gene expression profiles were generated using Illumnia Human HT-12 v4 microarray. Pair wise analysis was conducted using the Wilcoxon signed-rank test with a p-value cutoff of 0.05 to generate lists of differentially expressed genes between assigned groups. Pathway analysis was conducted to identify relevant pathways enriched for differentially expressed genes. Comprehensive plasma cytokine profiling was performed using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results: Seventeen patients were studied based on sample availability; 11 (65%) mere male with median age of 66 years (range 53–85). Twelve (71%) were JAK2V617F mutation positive and the DIPSS-plus risk categorization was 10 (59%) high and 7 (41%) intermediate-2. All patients were evaluable for anemia response; 14 (82%) were red cell transfusion dependent at study start. Nine (53%) patients achieved anemia response by IWG-MRT criteria; of these, 8 patients achieved transfusion independence (minimum non-transfused hemoglobin level of 8 g/dL maintained for at least 12 weeks) and 1 had a sustained >2 g/dL increase in hemoglobin level above baseline. The initial pair wise analysis to identify differential patterns of gene expression compared pre- and post-treatment groups (Figure 1A). This revealed a cluster of significantly (p <0.05) down-regulated genes (minimum 2-fold; median 17-fold) following treatment (displayed in green; upper left quadrant). Pathway enrichment analysis revealed significant associations of these genes with cytokine regulation of immune response, cell proliferation, chemotaxis and cytoskeleton remodeling. We then conducted a pair wise analysis of anemia responders versus non-responders; this revealed a predominance of over expressed gene targets (median 35-fold) in the anemia responder group (Figure 1B) (displayed in red; upper right quadrant). Similar pathway analysis identified enrichment for genes involved in immune system function in this cluster. Conclusions: The current preliminary analysis suggests that genes relevant to immune response-cytokine pathways are significantly over expressed in patients who achieve anemia response following CYT387 therapy. This further suggests a dominant immune component that underpins ineffective hematopoiesis in responding patients. On the basis of broad treatment-related changes in gene expression we suggest that an important component of CYT387's treatment effect is down regulation of these dysregulated pathways. Ongoing studies include validation of select gene targets which will be tested prospectively in future treatment protocols, as well as correlation of gene expression with circulating cytokine-chemokine levels. Disclosures: Pardanani: Bristol-Myers Squibb: Clinical trial support, Clinical trial support Other; YM BioSciences: Clinical trial support, Clinical trial support Other; Sanofi-Aventis: Clinical trial support Other. Off Label Use: Data from Phase −1/2 study of CYT387 use in myelofibrosis is mentioned.

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0474 Gene expression profiling from blood samples of MS patients receiving interferon-beta 1b therapy

Journal of the Neurological Sciences ◽

10.1016/s0022-510x(05)80842-1 ◽

2005 ◽

Vol 238 ◽

pp. S219

Keyword(s):

Gene Expression ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Interferon Beta ◽

Blood Samples

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Gene Expression Profiling of the Response to Interferon Beta in Epstein-Barr-Transformed and Primary B Cells of Patients with Multiple Sclerosis

PLoS ONE ◽

10.1371/journal.pone.0102331 ◽

2014 ◽

Vol 9 (7) ◽

pp. e102331 ◽

Cited By ~ 12

Author(s):

Rana Khsheibun ◽

Tamar Paperna ◽

Anat Volkowich ◽

Izabella Lejbkowicz ◽

Nili Avidan ◽

...

Keyword(s):

Gene Expression ◽

Multiple Sclerosis ◽

B Cells ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Interferon Beta ◽

Epstein Barr

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Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2010.12.053 ◽

2012 ◽

Vol 82 (2) ◽

pp. 739-742 ◽

Cited By ~ 13

Author(s):

Shilpen Patel ◽

Steven DiBiase ◽

Barry Meisenberg ◽

Todd Flannery ◽

Ashish Patel ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

High Grade Glioma ◽

Phase I Clinical Trial ◽

High Grade ◽

Concomitant Radiotherapy

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The basal subtype to predict clinical benefit from neoadjuvant chemotherapy: Final results from a phase II clinical trial of DDMVAC plus bevacizumab.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.291 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 291-291 ◽

Cited By ~ 1

Author(s):

Arlene O. Siefker-Radtke ◽

Woonyoung Choi ◽

Sima P. Porten ◽

Yu Shen ◽

Ashish M. Kamat ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trial ◽

Neoadjuvant Chemotherapy ◽

Bone Metastases ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Urothelial Cancer ◽

Basal Subtype ◽

Clinical Trial Results ◽

The Impact

291 Background: Gene expression profiling (GEP) suggests 3 main subtypes of urothelial cancer: basal, which historically has the worst prognosis with high proliferation and HIF-1 expression; p53-like, with decreased proliferation and increased markers of extracellular matrix (ECM); and luminal which has increased proliferation compared to p53-like tumors. We hypothesized that GEP of transurethral resections (TUR) and cystectomy specimens from patients on a neoadjuvant trial would predict benefit from chemotherapy. Methods: Sixty patients enrolled on a neoadjuvant trial of DDMVAC+B. TUR and cystectomy specimens were available for gene expression profiling in 39 and 33 patients, respectively, with matched specimens in 23 patients. The validation set consisted of 49 patients treated with perioperative MVAC on a previously published clinical trial. Results: Chemotherapy was quite active with pT0N0 and ≤ pT1N0 down-staging rates of 38% and 53%, respectively. Basal tumors had improved survival compared to luminal and p53-like (5-year OS 91%, 73% and 36%, p=0.015). A validation cohort of patients treated with perioperative MVAC confirmed this survival benefit (5-year OS basal, luminal, and p53-like 77%, 57%, and 57%, respectively, p =0.027). The use of bevacizumab in basal tumors did not confirm evidence of significant benefit in these small numbers of patients (5-year OS bevacizumab: 91% vs MVAC: 77%, p=0.68) Bone metastases within 2 years associated exclusively with the p53-like subtype (p53-like: 100%, luminal: 0%, basal 0%, p≤0.001). The p53-like subtype was enriched at cystectomy (basal to p53-like in 3/5 (60%), luminal to p53-like in 5/7 (71%), suggesting chemo-resistance in p53-like tumors. Conclusions: In contrast to historical expectations, the basal subtype was predictive of clinical outcomes from neoadjuvant chemotherapy, reflecting the impact of chemotherapy on highly proliferative tumors. Bone metastases were associated with the p53-like subtype which is enriched for ECM. We can no longer think of urothelial cancer as one disease; subtyping should be considered for all tumors, and may have implications on selecting therapy. Clinical trial information: NCT00506155.

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