CpG oligodeoxynucleotide-induced immunity prevents growth of germinal center-derived B lymphoma cells

Ponzio, Nicholas M.; Cutro, Scott; Hu, Junmei; Marzouk, Atara; Marshall, Jason D.

doi:10.1016/j.intimp.2006.08.008

Cited by 4 publications

(4 citation statements)

References 48 publications

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“…Single‐agent 1018 ISS has been evaluated in a murine model of B‐cell lymphoma (Ponzio et al , 2006). Growth inhibition of B lymphoma cells (RCS line) was observed, as well as the demonstration of tumour‐specific cytotoxic T lymphocyte (CTL) responses, suggesting significant immunostimulatory activity.…”

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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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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“…In addition, at various times before and after weaning offspring were subjected to various immunological tests, including FACS analysis to enumerate lymphocyte subpopulations, as well as in vitro responses to mitogens, syngeneic B lymphoma cells, and allogeneic spleen cells to detect functional parameters. We have reported the details of the methods for these assays in previous publications 28–31 …”

Section: Methodsmentioning

confidence: 99%

“…We have reported the details of the methods for these assays in previous publications. [28][29][30][31] The offspring were also subjected to behavioral tests (such as, exploration in a novel environment, frequency of rearing and grooming, and classical conditioned eyeblink response) when they were 3-5 months of age. 25,26,32,33…”

Section: Prenatal and Postnatal Testing Parametersmentioning

confidence: 99%

Cytokine Levels during Pregnancy Influence Immunological Profiles and Neurobehavioral Patterns of the Offspring

Ponzio

Servatius

Beck

et al. 2007

Annals of the New York Academy of Sciences

106

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The underlying causes of autism spectrum disorders (ASD) are unknown, but clinical and experimental studies indicate immune mechanisms, in general, and cytokine dysregulation, in particular, as contributing factors in their etiology. We developed a prenatal mouse model of autism to demonstrate that circulating levels of defined cytokines in pregnant dams could influence fetal development and behavioral characteristics in their offspring. We administered daily injections of murine IL-2 (0.4 mug in phosphate-buffered saline [PBS]) to pregnant mice during mid-gestation, and analyzed their offspring (IL-2 pups) in comparison to offspring of pregnant mice injected with vehicle only (PBS pups). Significant levels of IL-2 were present in amniotic fluid and tissues from embryos of dams given radiolabeled IL-2, indicating that the injected IL-2 crossed the placenta and entered the fetuses. Lymphocytes from IL-2 pups demonstrated accelerated T cell development, with a skewing toward TH1 cell differentiation. IL-2 pups also showed in vitro proliferative and cytotoxicity responses that were significantly higher than control PBS pups when stimulated with syngeneic B lymphoma cells or allogeneic spleen cells. In addition to their previously shown increases in open-field activity, grooming and rearing behavior, offspring of IL-2-injected (vs. PBS-injected) dams also displayed abnormal new motor learning as assessed through acquisition of the classically conditioned eyeblink response. These results suggest that increases in maternal levels of IL-2 during pregnancy induce in their offspring long-lasting increased vulnerability to neurobehavioral abnormalities associated with autism, and provide a valid animal model to determine the underlying immunological mechanisms.

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“…The administration of 1018 ISS to simian immunodeficiency virus (SIV)-infected macaques reportedly results in massive activation of plasmacytoid DCs, IL-12 production and accumulation of IFNγ-secreting SIV-specific T cells 223 . Along similar lines, ISS 1018 has been shown to trigger an IL-12-dependent cytotoxic immune response that efficiently prevents the growth of spontaneous B-cell lymphomas in SJL mice 224 . Following early clinical trials that demonstrated its safety, 225 ISS 1018 has been extensively tested as part of a vaccine against the hepatitis B virus (HEPLISAV TM ) 226 .…”

Section: Tlr9 Agonistsmentioning

confidence: 98%

Trial Watch

et al. 2012

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Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.

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CpG oligodeoxynucleotide-induced immunity prevents growth of germinal center-derived B lymphoma cells

Cited by 4 publications

References 48 publications

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

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

Cytokine Levels during Pregnancy Influence Immunological Profiles and Neurobehavioral Patterns of the Offspring

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