scholarly journals Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2400
Author(s):  
Justyna M. Przystal ◽  
Hannes Becker ◽  
Denis Canjuga ◽  
Foteini Tsiami ◽  
Nicole Anderle ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Host Cells ◽  
Autologous Tumor ◽  
Colony Stimulating Factor ◽  
Combination Treatments ◽  
Coculture Model ◽  
Antiglioma Activity ◽  
Stimulating Factor

Glioblastoma is an aggressive primary tumor of the central nervous system. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting therapeutic approach. Tumor-associated macrophages represent an abundant population of tumor-infiltrating host cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We investigated combination treatments of anti-CSF1R alone or in combination with anti-PD1 antibodies in an orthotopic syngeneic glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies led to longterm survivors in vivo. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Our results identify CSF1R as a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition.

TAMI-34. TARGETING CSF1R AND PD1 IN EXPERIMENTAL GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi205-vi205
Author(s):  
Hannes Becker ◽  
Justyna M Przystal ◽  
Denis Canjuga ◽  
Foteini Tsiami ◽  
Nicole Anderle ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Immunohistochemical Analysis ◽  
Post Treatment ◽  
Neurological Symptoms ◽  
Autologous Tumor ◽  
Colony Stimulating Factor ◽  
Tumor Associated Macrophages ◽  
Tissue Samples ◽  
Stimulating Factor

Abstract The treatment of glioblastoma remains a challenge. Novel therapeutic strategies are urgently needed. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting approach in this regard. Tumor-associated macrophages represent a distinct population of tumor-infiltrating immune cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival inside the tumor microenvironment. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We detected CSF1R expression in paired tissue samples of primary and corresponding progressive glioblastoma. We investigated anti-CSF1R treatment alone or in combination with anti-PD1 antibodies in the orthotopic syngeneic VM/Dk SMA560 glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies prolonged the latency until the onset of neurological symptoms and led to long-term survivors in vivo. Immunohistochemical analysis of post-treatment SMA-560 glioma revealed a modulation of the microenvironment, including increased T cell infiltration and reduced numbers of tumor-associated macrophages. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Taken together, our data indicates that CSF1R is a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition.

EXTH-48. NOVEL COMBINATION THERAPY IN PRECLINICAL GLIOMA MODELS USING THE CELL CYCLE STABILIZING COMPOUND ARGYRIN F AND CHECKPOINT INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi174-vi174
Author(s):  
Bianca Walter ◽  
Denis Canjuga ◽  
Simge G Yuez ◽  
Michael Ghosh ◽  
Przemyslaw Bozko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Clonogenic Survival ◽  
Autologous Tumor ◽  
Cycle Arrest ◽  
Resected Tissue ◽  
Infiltrating Lymphocytes

Abstract Glioblastoma are incurable aggressive tumors and remain a therapeutic challenge. Glioblastoma frequently harbor alterations in the retinoblastoma pathway with subsequent cell cycle abnormalities. Here, we aimed to investigate the anti-glioma activity of the cell cycle-stabilizing compound Argyrin F and its potential treatment-induced vulnerabilities to exploit possibilities for novel combination therapies. We investigated cell viability, clonogenic survival, cell cycle status and immunoblots of human and murine glioma cells treated with Argyrin F. Moreover, we established an ex vivo glioma model using residual freshly resected tissue from patients, i.e. patient-derived microtumors (PDMs). Additionally, we extracted autologous tumor infiltrating lymphocytes (TILs) to perform co-culturing experiments. We performed mass spectrometry-based immunopeptidomics and used the orthotopic syngeneic SMA560/VM/Dk glioma mouse model. Argyrin F displayed anti-glioma efficacy in glioma cell lines in vitro and in PDM models ex vivo. Moreover, Argyrin F treatment induced cell cycle arrest, reduced clonogenic survival in vitro and prolonged survival in vivo. Argyrin F-treated SMA560 glioma displayed 4.6-fold more glioma-infiltrating CD8+ T cells. We discovered a distinctive treatment-induced immunopeptidome. Combination of Argyrin F plus PD-1 antibody increased cellular toxicity in PDM/TILs co-cultures ex vivo and prolonged overall survival compared with monotherapies in vivo. We conclude that our experimental data suggest a novel combination of Argyrin F plus PD-1 blockade and its clinical translation.

scholarly journals Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer

Science ◽  
2020 ◽  
Vol 370 (6522) ◽  
pp. 1328-1334
Author(s):  
Sri Krishna ◽  
Frank J. Lowery ◽  
Amy R. Copeland ◽  
Erol Bahadiroglu ◽  
Ratnadeep Mukherjee ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Human Cancer ◽  
Clinical Success ◽  
Tumor Infiltrating Lymphocytes ◽  
Adoptive T Cell Therapy ◽  
Complete Regression ◽  
Autologous Tumor ◽  
T Cell Therapy ◽  
The Impact

Adoptive T cell therapy (ACT) using ex vivo–expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Using high-dimensional analysis of human ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39−CD69−) associated with complete cancer regression and TIL persistence and a terminally differentiated CD39-positive state (CD39+CD69+) associated with poor TIL persistence. Most antitumor neoantigen-reactive TILs were found in the differentiated CD39+ state. However, ACT responders retained a pool of CD39− stem-like neoantigen-specific TILs that was lacking in ACT nonresponders. Tumor-reactive stem-like TILs were capable of self-renewal, expansion, persistence, and superior antitumor response in vivo. These data suggest that TIL subsets mediating ACT response are distinct from TIL subsets enriched for antitumor reactivity.

Granulocyte-colony stimulating factor induces differentiation and apoptosis of CD2, CD7 positive hybrid leukemia cells in vivo and ex vivo

1997 ◽  
Vol 21 (8) ◽  
pp. 735-741 ◽  
Author(s):  
Hiroshi Fujiwara ◽  
Naomichi Arima ◽  
Kakushi Matsushita ◽  
Shiroh Hidaka ◽  
Hideo Ohtsubo ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Leukemia Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor

scholarly journals The role of interleukin-1 and granulocyte-macrophage colony-stimulating factor in the paracrine stimulation of an in vivo-derived murine myeloid leukemia

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1301-1310
Author(s):  
KB Leslie ◽  
HJ Ziltener ◽  
JW Schrader
Keyword(s):  
Cell Line ◽  
Host Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Stimulatory Activity ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

WEHI-274.3 is a cell line isolated from an in vivo-derived, murine myelomonocytic leukemia. Although the survival and growth of WEHI-274.3 cells in vitro is absolutely dependent on the addition of exogenous growth factors such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or colony-stimulating factor-1, when injected into syngeneic mice the cell line is tumorigenic. Sera from normal mice contain low levels of an activity that sustains survival of WEHI-274.3 but does not stimulate growth. In contrast, sera from mice bearing the WEHI-274.3 leukemia contained levels of CSF-1 and GM-CSF that stimulated the growth of WEHI-274.3 cells. Supernatants of cultures of WEHI-274.3 cells contained an activity that stimulated 3T3 fibroblasts to release an activity that stimulated the growth of the WEHI-274.3 cells. The 3T3-stimulatory activity released by the WEHI- 274.3 cells was neutralized completely with an antiserum specific for murine IL-1 alpha, but not with antiserum specific for IL-1 beta. Moreover, WEHI-274.3 cells both in vitro and in vivo contained high levels of IL-1 alpha and IL-1 beta mRNAs. The leukemia-stimulatory activity released by the 3T3 cells was neutralized by an antiserum specific for GM-CSF. We postulate that the IL-1 alpha constitutively released by the WEHI-274.3 cells stimulates the production of GM-CSF from host cells such as fibroblasts or endothelial cells. A similar paracrine mechanism of growth stimulation may occur in acute myeloid leukemias in humans.

scholarly journals Interactions of granulocyte-macrophage colony-stimulating factor (CSF), granulocyte CSF, and tumor necrosis factor alpha in the priming of the neutrophil respiratory burst

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 745-753 ◽  
Author(s):  
A Khwaja ◽  
JE Carver ◽  
DC Linch
Keyword(s):  
Respiratory Burst ◽  
Ex Vivo ◽  
Tnf Alpha ◽  
H2o2 Production ◽  
Colony Stimulating Factor ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Stimulating Factor

Abstract Exposure of neutrophils to a range of cytokines augments their response to subsequent agonist-induced activation of the respiratory burst. We have examined the effects of several of these factors, both singly and in combination, on the priming of f-met-leu-phe (FMLP) and complement C5a-stimulated neutrophil H2O2 production, using a whole blood flow cytometric assay designed to minimize artefactual activation. Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF alpha) produced a similar degree of priming of the FMLP-stimulated burst in vitro (558% +/- 86%, n = 41, and 581% +/- 95%, n = 21, of the response seen with FMLP alone, respectively), but with markedly different kinetics (half-maximal response 20 minutes and 7 minutes, respectively). Preincubation with granulocyte colony- stimulating factor (G-CSF) alone caused only modest priming (202% +/- 39%, n = 14). Priming with cytokine combinations of the FMLP-stimulated burst showed that the combinations of G-CSF and TNF alpha and GM-CSF and TNF alpha are highly synergistic, with recruitment of neutrophils unresponsive to priming by single agents. Priming with the combination of GM-CSF and G-CSF was not significantly different to priming with GM- CSF alone. Similar results were obtained using C5a as the respiratory burst stimulus. Significant priming of the FMLP-stimulated respiratory burst was seen in vivo in patients receiving an infusion of GM-CSF (332% +/- 50% of preinfusion response to FMLP, P less than .005, n = 8). Priming was also seen in patients receiving G-CSF (152% +/- 58%, n = 5), although this did not reach conventional significance levels (.05 less than P less than .1). Although GM-CSF infusion caused priming in vivo, this was 48% less than predicted by preinfusion in vitro responses. This result was not due to inadequate GM-CSF levels as addition of further GM-CSF ex vivo did not correct the response. However, these neutrophils were still able to respond appropriately to ex vivo priming with TNF alpha, with a doubling in H2O2 production.

scholarly journals Interactions of granulocyte-macrophage colony-stimulating factor (CSF), granulocyte CSF, and tumor necrosis factor alpha in the priming of the neutrophil respiratory burst

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 745-753 ◽  
Author(s):  
A Khwaja ◽  
JE Carver ◽  
DC Linch
Keyword(s):  
Respiratory Burst ◽  
Ex Vivo ◽  
Tnf Alpha ◽  
H2o2 Production ◽  
Colony Stimulating Factor ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Stimulating Factor

Exposure of neutrophils to a range of cytokines augments their response to subsequent agonist-induced activation of the respiratory burst. We have examined the effects of several of these factors, both singly and in combination, on the priming of f-met-leu-phe (FMLP) and complement C5a-stimulated neutrophil H2O2 production, using a whole blood flow cytometric assay designed to minimize artefactual activation. Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF alpha) produced a similar degree of priming of the FMLP-stimulated burst in vitro (558% +/- 86%, n = 41, and 581% +/- 95%, n = 21, of the response seen with FMLP alone, respectively), but with markedly different kinetics (half-maximal response 20 minutes and 7 minutes, respectively). Preincubation with granulocyte colony- stimulating factor (G-CSF) alone caused only modest priming (202% +/- 39%, n = 14). Priming with cytokine combinations of the FMLP-stimulated burst showed that the combinations of G-CSF and TNF alpha and GM-CSF and TNF alpha are highly synergistic, with recruitment of neutrophils unresponsive to priming by single agents. Priming with the combination of GM-CSF and G-CSF was not significantly different to priming with GM- CSF alone. Similar results were obtained using C5a as the respiratory burst stimulus. Significant priming of the FMLP-stimulated respiratory burst was seen in vivo in patients receiving an infusion of GM-CSF (332% +/- 50% of preinfusion response to FMLP, P less than .005, n = 8). Priming was also seen in patients receiving G-CSF (152% +/- 58%, n = 5), although this did not reach conventional significance levels (.05 less than P less than .1). Although GM-CSF infusion caused priming in vivo, this was 48% less than predicted by preinfusion in vitro responses. This result was not due to inadequate GM-CSF levels as addition of further GM-CSF ex vivo did not correct the response. However, these neutrophils were still able to respond appropriately to ex vivo priming with TNF alpha, with a doubling in H2O2 production.

scholarly journals The role of interleukin-1 and granulocyte-macrophage colony-stimulating factor in the paracrine stimulation of an in vivo-derived murine myeloid leukemia

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1301-1310 ◽  
Author(s):  
KB Leslie ◽  
HJ Ziltener ◽  
JW Schrader
Keyword(s):  
Cell Line ◽  
Host Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Stimulatory Activity ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract WEHI-274.3 is a cell line isolated from an in vivo-derived, murine myelomonocytic leukemia. Although the survival and growth of WEHI-274.3 cells in vitro is absolutely dependent on the addition of exogenous growth factors such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or colony-stimulating factor-1, when injected into syngeneic mice the cell line is tumorigenic. Sera from normal mice contain low levels of an activity that sustains survival of WEHI-274.3 but does not stimulate growth. In contrast, sera from mice bearing the WEHI-274.3 leukemia contained levels of CSF-1 and GM-CSF that stimulated the growth of WEHI-274.3 cells. Supernatants of cultures of WEHI-274.3 cells contained an activity that stimulated 3T3 fibroblasts to release an activity that stimulated the growth of the WEHI-274.3 cells. The 3T3-stimulatory activity released by the WEHI- 274.3 cells was neutralized completely with an antiserum specific for murine IL-1 alpha, but not with antiserum specific for IL-1 beta. Moreover, WEHI-274.3 cells both in vitro and in vivo contained high levels of IL-1 alpha and IL-1 beta mRNAs. The leukemia-stimulatory activity released by the 3T3 cells was neutralized by an antiserum specific for GM-CSF. We postulate that the IL-1 alpha constitutively released by the WEHI-274.3 cells stimulates the production of GM-CSF from host cells such as fibroblasts or endothelial cells. A similar paracrine mechanism of growth stimulation may occur in acute myeloid leukemias in humans.

scholarly journals Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans

2020 ◽  
Vol 7 (11) ◽  
Author(s):  
Shichina Kannambath ◽  
Joseph N Jarvis ◽  
Rachel M Wake ◽  
Nicky Longley ◽  
Angela Loyse ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Association Study ◽  
Cryptococcal Meningitis ◽  
Genome Wide Association Study ◽  
Ex Vivo ◽  
Genome Wide Association ◽  
Colony Stimulating Factor ◽  
Genome Wide ◽  
Immunodeficiency Virus ◽  
Stimulating Factor

Abstract Background Cryptococcus is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%–10% of patients with HIV/acquired immune deficiency syndrome and profound CD4+ T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans. Methods We analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen). Results Six loci upstream of the colony-stimulating factor 1 (CSF1) gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at P < 10–6 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped CSF1 SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42–0.66; P = 5.96 × 10−8). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against Cryptococcus in HIV-infected patients and healthy, ethnically matched controls. Conclusions This first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis.

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