Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 386-386 ◽  
Author(s):  
Robin Kate Kelley ◽  
Emily Mitchell ◽  
Spencer Behr ◽  
Jimmy Hwang ◽  
Bridget Keenan ◽  
...  
Keyword(s):  
Immune Cell ◽  
Progression Free Survival ◽  
Immune Effector ◽  
Effector Cells ◽  
Gm Csf ◽  
Phase 2 Trial ◽  
Best Response ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stage 1

386 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1◦: Progression-free survival at 6 months (PFS6) with H0 25% vs. H1 50%. Key 2◦: Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.

Interleukin-2 and Granulocyte-Macrophage Colony Stimulating Factor Is an Alternative to Donor Lymphocyte Infusion for Relapse after Allogeneic Stem Cell Transplantation and Is Associated with Increase Immune Effector Cells and Polarization to Type 2 Dendritic Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1647-1647
Author(s):  
Carlos R. Bachier ◽  
Paul Shaughnessy ◽  
Brad Smith2 ◽  
Richard Salinas ◽  
Charles F. LeMaistre
Keyword(s):  
Stem Cell ◽  
Immune Activation ◽  
Interleukin 2 ◽  
Donor Lymphocyte Infusion ◽  
P Value ◽  
Immune Effector ◽  
Effector Cells ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Abstract Donor lymphocyte infusion (DLI) is use for relapse after allogeneic stem cell transplant (ASCT). Immune activation with cytokines maybe an alternative to DLI. We administered Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-2 (IL-2) at the time of relapse after ASCT in patients (pts) with hematologic malignancies. Pts. received subcutaneous GM-CSF at 500 mcg/day on days 1–14 and IL-2 at 1 × 106 units/m2/day on days 8–14. Pts. were off immunosuppressive therapy and had no prior history of graft versus host disease (GVHD) at the start of treatment. Twelve pts. received IL-2/GM-CSF for treatment of relapse AML (7), ALL (2), CML (1), MDS (2). Median age was 55 (range 8–66). Stem cell sources included: peripheral blood = 9, bone marrow = 2, umbilical cord blood (UCB) = 1. Donor sources were: match-related sibling = 4 and match-unrelated donor = 8 (UCB=1). Nine pts. had resistant relapse or primary resistant disease at time of ASCT. Median time from transplant to relapse was 4 months (range = 1–14). Two pts. had failed DLI and 5 pts. had received reinduction chemotherapy prior to IL-2/GM-CSF. Eight pts. responded to IL-2/GM-CSF (CR = 7, PR = 1). Two pts. remain disease free at 18 and 26 months post IL-2/ GM-CSF. Six pts. developed GVHD and of these 4 were responders. Two pts. had GM-CSF discontinued due to increase in peripheral blood blasts. No other toxicities related to IL-2/GM-CSF except for mild flu-like symptoms. The table below summarizes quantitative analysis of immune activation. Values represent means +/− standard error at day 0 (first day of GM-CSF), day 8 (prior to start of IL-2) and day 14 (last day of IL-2 and GM-CSF). P-values are based on paired t-test analysis of day 8 versus day 0 and day 14 versus day 0, respectively. Flow cytometric analysis showed an increase in the numbers of T-lymphocytes (CD3) and T-cell subsets (CD3/CD8 and CD3/CD4) as well as an increase in natural killer cells (CD16/56). Although no differences were seen in the number of dendritic cell subsets, DC1/DC2 ratios decreased with the administration of GM-CSF/IL-2. Limited (n= 4) CD4/FoxP3 analysis did not show change in absolute numbers with administration of GM-CSF/IL-2 (data not shown). In conclusion, cytokine therapy with IL-2/GM-CSF is well tolerated and is an alternative to DLI for relapse after ASCT. Flow cytometry analysis demonstrated a quantitative increase in immune effector cells and polarization to DC2. IMMUNE ACTIVATION FLOW CYTOMETRY ASSAYS D0 (Mean +/− SE) D8 (Mean +/− SE) D14 (Mean +/− SE) P-Value (Day7–0) P-Value (Day 14–0) SE=Standard Error; DC = dendritic cells CD3 (K/uL) 309 +/− 117 535 +/− 103 1306 +/− 403 0.034 0.027 CD3/CD8 (K/uL) 94 +/− 42 174 +/− 33 325 +/− 90 0.021 0.029 CD3/CD4 (K/uL) 309 +/− 117 404 +/− 102 977 +/− 310 0.249 0.045 CD16/CD56 (K/uL) 124 +/− 60 404 +/− 110 496 +/− 162 0.029 0.044 CD19 K/uL) 68 +/−39 89 +/− 36 116 +/− 31 0.183 0.044 Total Lymphs (K/uL 488 +/− 167 942 +/− 160 2353 +/− 532 0.016 0.013 CD11(DC1) (K/uL) 97.1 +/− 60.7 46.3 +/− 32.5 32.6 +/− 27.5 0.108 0.101 CD123(DC2) (K/uL) 32.1 +/− 7.3 39.7 +/− 15.9 45.4 +/− 35.8 0.694 0.628 DC1/DC2 2.77 +/− 1.26 0.68 +/− 0.35 0.61 +/− 0.07

scholarly journals Active Idiotypic Vaccination Versus Control Immunotherapy for Follicular Lymphoma

2014 ◽  
Vol 32 (17) ◽  
pp. 1797-1803 ◽  
Author(s):  
Ronald Levy ◽  
Kristen N. Ganjoo ◽  
John P. Leonard ◽  
Julie M. Vose ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Progression Free Survival ◽  
Keyhole Limpet Hemocyanin ◽  
Therapeutic Benefit ◽  
Gm Csf ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Significant Difference ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Purpose Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. Patients and Methods Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n = 287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. Results At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n = 195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. Conclusion This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.

scholarly journals Granulocyte Macrophage Colony-Stimulating Factor

2001 ◽  
Vol 194 (7) ◽  
pp. 873-882 ◽  
Author(s):  
Jonathan L. McQualter ◽  
Rima Darwiche ◽  
Christine Ewing ◽  
Manabu Onuki ◽  
Thomas W. Kay ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cell ◽  
Specific Antigen ◽  
Demyelinating Diseases ◽  
Colony Stimulating Factor ◽  
Cns Inflammation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, can be induced by immunization with a number of myelin antigens. In particular, myelin oligodendrocyte glycoprotein, a central nervous system (CNS)-specific antigen expressed on the myelin surface, is able to induce a paralytic MS-like disease with extensive CNS inflammation and demyelination in several strains of animals. Although not well understood, the egress of immune cells into the CNS in EAE is governed by a complex interplay between pro and antiinflammatory cytokines and chemokines. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is considered to play a central role in maintaining chronic inflammation. The present study was designed to investigate the previously unexplored role of GM-CSF in autoimmune-mediated demyelination. GM-CSF−/− mice are resistant to EAE, display decreased antigen-specific proliferation of splenocytes, and fail to sustain immune cell infiltrates in the CNS, thus revealing key activities for GM-CSF in the development of inflammatory demyelinating lesions and control of migration and/or proliferation of leukocytes within the CNS. These results hold implications for the pathogenesis of inflammatory and demyelinating diseases and may provide the basis for more effective therapies for inflammatory diseases, and more specifically for multiple sclerosis.

Granulocyte macrophage colony-stimulating factor and the intestinal innate immune cell homeostasis in Crohn's disease

2014 ◽  
Vol 306 (6) ◽  
pp. G455-G465 ◽  
Author(s):  
Jan Däbritz
Keyword(s):  
Crohn’S Disease ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Colony Stimulating Factor ◽  
Cell Homeostasis ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Current literature consolidates the view of Crohn's disease (CD) as a form of immunodeficiency highlighting dysregulation of intestinal innate immunity in the pathogenesis of CD. Intestinal macrophages derived from blood monocytes play a key role in sustaining the innate immune homeostasis in the intestine, suggesting that the monocyte/macrophage compartment might be an attractive therapeutic target for the management of CD. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that also promotes myeloid cell activation, proliferation, and differentiation. GM-CSF has a protective effect in human CD and mouse models of colitis. However, the role of GM-CSF in immune and inflammatory reactions in the intestine is not well defined. Beneficial effects exerted by GM-CSF during intestinal inflammation could relate to modulation of the mucosal barrier function in the intestine, including epithelial cell proliferation, survival, restitution, and immunomodulatory actions. The aim of this review is to summarize potential mechanistic roles of GM-CSF in intestinal innate immune cell homeostasis and to highlight its central role in maintenance of the intestinal immune barrier in the context of immunodeficiency in CD.

scholarly journals The diadenosine polyphosphates Ap3A and Ap4A and adenosine triphosphate interact with granulocyte-macrophage colony-stimulating factor to delay neutrophil apoptosis: implications for neutrophil: platelet interactions during inflammation

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3442-3449 ◽  
Author(s):  
L Gasmi ◽  
AG McLennan ◽  
SW Edwards
Keyword(s):  
Adenosine Triphosphate ◽  
Immune Cell ◽  
Cellular Morphology ◽  
Neutrophil Apoptosis ◽  
Colony Stimulating Factor ◽  
Diadenosine Polyphosphates ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Incubation of neutrophils with cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) delays their loss of function and changes in cellular morphology that are characteristic of apoptosis. Adenosine triphosphate (ATP) and the diadenosine polyphosphates Ap4A and AP3A were almost as effective as GM-CSF in delaying neutrophil apoptosis. The nucleotides could thus preserve cellular morphology, protect against chromatin fragmentation, and preserve functions such as NADPH oxidase activity and expression of CD16. Moreover, addition of ATP, AP3A and AP4A together with GM-CSF resulted in more pronounced protection from apoptosis than was observed during incubation with either the cytokine or the nucleotides alone. Because ATP, Ap3A, and AP4A may be secreted from activated platelets, these observations suggest that platelet-derived products, perhaps acting in combination with endothelial-derived or immune cell-derived cytokines, can regulate neutrophil function during certain types of inflammation.

Phase II Trial of the Anti-GD2 Monoclonal Antibody 3F8 and Granulocyte-Macrophage Colony-Stimulating Factor for Neuroblastoma

2001 ◽  
Vol 19 (22) ◽  
pp. 4189-4194 ◽  
Author(s):  
Brian H. Kushner ◽  
Kim Kramer ◽  
Nai-Kong V. Cheung
Keyword(s):  
Monoclonal Antibody ◽  
Intensive Therapy ◽  
Progression Free Survival ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Antibody Titers ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Human Antimouse Antibody ◽  
Stimulating Factor

PURPOSE: To describe oncolytic effects of treatment with anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with neuroblastoma (NB). PATIENTS AND METHODS: Patients were eligible for 3F8/GM-CSF if intensive therapy had not eradicated potentially lethal NB. One cycle consisted of GM-CSF (subcutaneous bolus) on days 1 through 5, 11, and 12, and GM-CSF (2-hour intravenous [IV] infusion) followed after a 1-hour interval by 3F8 (1.5-hour IV infusion) on days 6 through 10 and 13 through 17. GM-CSF was dosed at 250 μg/m2/d on days 1 through 7 and at 500 μg/m2/d on days 8 through 17. 3F8 was dosed at 10 mg/m2/d (100 mg/m2/cycle). 3F8 was given with an opiate and an antihistamine. Patients without progressive disease (PD) or elevated human antimouse antibody titers could be treated again beginning 3 weeks after completion of a cycle. RESULTS: Among 19 patients treated for NB resistant to induction therapy, 12 of 15 had complete remission (CR) of bone marrow (BM) disease, and three others who had less than partial responses achieved prolonged progression-free survival (one remains on study at 21+ months, two had PD at 12 and 17 months). Among patients treated for recurrent NB resistant to retrieval therapy, five of 10 had CR in BM. The 15 patients treated for PD fared poorly, although two had scintigraphic findings suggestive of a short-term response. Side effects were limited to readily manageable pain and, less commonly, rash of short duration; hence, patients were treated as outpatients. CONCLUSION: 3F8/GM-CSF is well tolerated and shows promise for treatment of minimal residual NB in BM.

scholarly journals Inflammation and the pathophysiology of Alzheimer's disease

2000 ◽  
Vol 2 (3) ◽  
pp. 233-239
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Inflammatory Response ◽  
Immune Effector ◽  
Effector Cells ◽  
Ongoing Work ◽  
Immune Effector Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Brain

There is increasing evidence that a chronic inflammatory response in the brain in Alzheimer's disease (AD) ultimately leads to neuronal injury and cognitive decline. Microglia, the primary immune effector cells of the brain, are thought to be key to this process. This paper discusses the evidence for inflammation in AD, and describes the mechanism whereby microglia generate neurotoxic cytokines, reactive oxygen species, and nitric oxide. Evidence that the cytokine macrophage colony-stimulating factor (M-CSF) is an important cofactor in microglial activation in AD is presented. Ongoing work using organotypic hippocampal expiant cultures to model the inflammatory process in the AD brain is also discussed. Potential avenues for therapeutic intervention are outlined.

FCGR2A Polymorphism Is Correlated With Clinical Outcome After Immunotherapy of Neuroblastoma With Anti-GD2 Antibody and Granulocyte Macrophage Colony-Stimulating Factor

2006 ◽  
Vol 24 (18) ◽  
pp. 2885-2890 ◽  
Author(s):  
Nai-Kong V. Cheung ◽  
Rebecca Sowers ◽  
Andrew J. Vickers ◽  
Irene Y. Cheung ◽  
Brian H. Kushner ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Progression Free Survival ◽  
Colony Stimulating Factor ◽  
Molecular Monitoring ◽  
Entire Cohort ◽  
Gm Csf ◽  
Qrt Pcr ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Purpose Anti-GD2 murine IgG3 antibody 3F8 kills neuroblastoma cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Granulocyte macrophage colony-stimulating factor (GM-CSF) enhances phagocyte-mediated ADCC. The differential affinity of the human FCGR polymorphic alleles for 3F8 may influence the effectiveness of antibody immunotherapy. Patients and Methods The entire cohort of high risk neuroblastoma patients (N = 136) treated on protocol using 3F8 and GM-CSF were the subjects of this analysis. Tumor response was measured by standard clinical tools plus sensitive molecular monitoring using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Polymorphic alleles of FCGR2A and FCGR3A were determined by PCR plus direct sequencing using genomic DNA samples obtained from marrow or blood of patients. Results FCGR2A (R/R) genotype correlated with progression-free survival for the entire cohort (P = .049) and for the subset of patients with no history of prior relapse (P = .023). FCGR2A (R/R) also correlated with marrow remission 2.5 months after treatment initiation: by histology (P = .021 and P = .036, for the entire cohort and the subset, respectively) and by qRT-PCR (P = .052 and P = .033, respectively). Conclusion The favorable outcome associated with FCGR2A (R/R) genotype is consistent with the proposed role of FCGR2A and phagocyte-mediated ADCC in 3F8 plus GM-CSF immunotherapy.

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