Targeting the follicular lymphoma microenvironment through blockade of TNFα with etanercept

Friedberg, Jonathan W.; Jacobsen, Eric; Neuberg, Donna; Kutok, Jeffrey L.; Munoz, Olivier; Boussiotis, Vassiliki A.; Reynolds, Hazel; Fisher, David C.; Szot, Agnieszka; Abbeele, Annick Van den; Freedman, Arnold S.

doi:10.1080/10428190801950033

Cited by 10 publications

(6 citation statements)

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“…In some tumors associated with chronic inflammation, TNF inhibition may be protective, such as follicular lymphoma [27], and as demonstrated in a mouse model of dextran sulfate sodium and azoxymethase-induced colitis and colon cancer [28]. Conversely, TNF may be an important inhibitor in the melanoma microenvironment [29].…”

Section: Discussionmentioning

confidence: 99%

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports

et al. 2013

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BackgroundMalignancy risk may be increased in chronic inflammatory conditions that are mediated by tumor necrosis factor (TNF), such as juvenile idiopathic arthritis (JIA), but the role of TNF in human cancer biology is unclear. In response to a 2011 United States Food & Drug Administration requirement of TNF blocker manufacturers, we evaluated reporting rates of all malignancies in patients ≤30 years old who received the TNF blocker etanercept.MethodsAll malignancies in etanercept-exposed patients aged ≤30 years from the Amgen clinical trial database (CTD) and postmarketing global safety database (PMD) were reviewed. PMD reporting rates were generated using exposure information based on commercial sources. Age-specific incidence rates of malignancy for the general US population were generated from the Surveillance Epidemiology and End Results (SEER) database v7.0.9.ResultsThere were 2 malignancies in the CTD: 1 each in etanercept and placebo/comparator arms (both in patients 18–30 years old). Postmarketing etanercept exposure was 231,404 patient-years (62,379 patient-years in patients 0–17 years; 168,485 patient-years in patients 18–30 years). Reporting rates of malignancy per 100,000 patient-years in the PMD and incidence rates in SEER were 32.0 and 15.9, respectively, for patients 0–17 years and 46.9 and 42.1 for patients 18–30 years old. Reporting rates were higher than SEER incidence rates for Hodgkin lymphoma in the 0-17 years age group. PMD reporting rates per 100,000 patient-years and SEER incidence rates per 100,000 person-years for Hodgkin lymphoma were 9.54 and 0.9, respectively, for patients 0–17 years and 1.8 and 4.2 for patients 18–30 years old. There were ≥5 cases of leukemia, lymphoma, melanoma, thyroid, and cervical cancers. Leukemia, non-Hodgkin lymphoma, melanoma, thyroid cancer, and cervical cancer rates were similar in the PMD and SEER.ConclusionsOverall PMD malignancy reporting rates in etanercept-treated patients 0–17 years appeared higher than incidence rates in SEER, attributable to rates of Hodgkin lymphoma. Comparison to patients with similar burden of disease cannot be made; JIA, particularly very active disease, may be a risk factor for lymphoma. No increased malignancy reporting rate in the PMD relative to SEER was observed in the young-adult age group.

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Section: Discussionmentioning

confidence: 99%

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports

et al. 2013

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“…ELISPOTS evaluating T‐cell activity, and peripheral blood flow cytometry failed to detect significantly enhanced T‐cell responses in the time period evaluated. Given the provocative findings in the few tumours we successfully obtained for study after exposure to 1018 ISS, we suggest that, in future trials, focused evaluation on local immune responses to TLR‐9 agonists and other agents designed to manipulate the microenvironment (Friedberg et al , 2008) will be more informative than evaluating PBMC. Other biological approaches with cytokines to improving rituximab therapy in follicular lymphoma have been studied in humans, including IL‐2 (Friedberg et al , 2002; Gluck et al , 2004), IL‐12 (Ansell et al , 2002), granulocyte‐macrophage colony‐stimulating factor (Cartron et al , 2008) and interferon‐alpha (Davis et al , 2000b).…”

Section: Discussionmentioning

confidence: 99%

Phase II study of a TLR‐9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma

et al. 2009

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SummaryToll-like receptor-9 (TLR-9) agonists have pleotropic effects on both the innate and adaptive immune systems, including increased antigen expression, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and T helper cell type 1 shift in the immune response. We combined a TLR-9 agonist (1018 ISS, 0AE2 mg/kg sc weekly · 4 beginning day 8) with standard rituximab (375 mg/m 2 weekly · 4) in patients (n = 23) with relapsed/ refractory, histologically confirmed follicular lymphoma, and evaluated immunological changes following the combination. Treatment was welltolerated with no significant adverse events attributable to therapy. Clinical responses were observed in 48% of patients; the overall median progressionfree survival was 9 months. Biologically relevant increases in ADCC and circulating CD-3 positive T cells were observed in 35% and 39% of patients, respectively. Forty-five percent of patients had increased T cells and dendritic cells in skin biopsies of 1018 ISS injection sites 24 h post-therapy. Pre-and post-biopsies of tumour tissue demonstrated an infiltration of CD8 + T cells and macrophages following treatment. This group of patients had favourable clinical outcome despite adverse prognostic factors. This study is the first to histologically confirm perturbation of the local immune microenvironment following systemic biological therapy of follicular lymphoma.

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“…17β-estradiol promotes accumulation of MDSCsbeen shown to be effective in treating patients with several diseases [44,45]. However, the mechanism by which TNF-α and its corresponding antagonists regulate the host's immune system remains unclear.…”

Section: Discussionmentioning

confidence: 99%

17β-estradiol contributes to the accumulation of myeloid-derived suppressor cells in blood by promoting TNF-α secretion

Dong

You

Fan

et al. 2015

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Estrogens are strongly implicated in gender differences in immune responses by influencing the development and activation of immune cells. Recent studies have shown that myeloid-derived suppressor cells (MDSCs), derived from CD11b + Gr-1 + myeloid cells under pathological conditions, play vital roles in modulating immune responses. However, it is still unknown the effects of estrogens on MDSCs. In the present study, we investigated the effects and mechanisms of estrogens on regulating the accumulation of MDSCs. It was found that, compared with male patients with systemic lupus erythematosus (SLE), female patients with SLE showed a higher frequency of MDSCs in peripheral blood mononuclear cells and a higher level of tumor necrosis factor α (TNF-α) in serum. Notably, estradiol level in the serum of female patients with SLE was positively correlated with the frequency of MDSCs. Moreover, 17β-estradiol could promote TNF-α-induced accumulation of MDSCs in vivo by increasing the fundamental frequency of CD11b + Gr-1 + cells. Furthermore, 17β-estradiol promoted the secretion of TNF-α in vivo, which contributed to the increase of the frequency of CD11b + Gr-1 + cells. In addition, it was also found that female mice showed a higher frequency of CD11b + Gr-1 + cells and a higher TNF-α level in blood than the age-matched male mice. These data indicate that 17β-estradiol contributes to the accumulation of MDSCs in blood by promoting TNF-α secretion, which increases the fundamental frequency of CD11b + Gr-1 + cells. Our findings provide a new insight into the mechanism of gender difference in the prevalence of inflammation and autoimmune diseases.

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Targeting the follicular lymphoma microenvironment through blockade of TNFα with etanercept

Cited by 10 publications

References 30 publications

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports

Phase II study of a TLR‐9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma

17β-estradiol contributes to the accumulation of myeloid-derived suppressor cells in blood by promoting TNF-α secretion

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Targeting the follicular lymphoma microenvironment through blockade of TNFα with etanercept

Cited by 10 publications

References 30 publications

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports

Phase II study of a TLR‐9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma

17&beta;-estradiol contributes to the accumulation of myeloid-derived suppressor cells in blood by promoting TNF-&alpha; secretion

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17β-estradiol contributes to the accumulation of myeloid-derived suppressor cells in blood by promoting TNF-α secretion