Results of a double-blind placebo-controlled study of the double-stranded RNA drug polyI:PolyC12U in the treatment of HIV infection

Thompson, Kenneth; Strayer, David R.; Salvato, Patricia; Thompson, Craig; Klimas, Nancy G.; Molavi, Abdolghader; Hamill, A. K.; Zheng, Zhihua; Ventura, Daniel; Carter, W. A.

doi:10.1007/bf01709367

Cited by 85 publications

(57 citation statements)

References 18 publications

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“…Although poly(I:C) is not used clinically because of its demonstrated toxicities in mice and humans (42,43), poly(I:C)-like agents are available for therapeutic use. As examples, poly-ICLC (Hiltonol), poly I: poly C 12 U (Ampligen, Oragen, atvogen), and poly I-mercapto poly C (polyI:MPC) have well-characterized side effects and safety profiles (44)(45)(46)(47)(48)(49). Rituximab-induced cellular cytotoxicity against tumor targets is improved significantly by the addition of poly I: poly C 12 U to in vitro blood cell cultures (50).…”

Section: Discussionmentioning

confidence: 99%

Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice

Horikawa¹,

Minard‐Colin²,

Matsushita³

et al. 2011

J. Clin. Invest.

164

131

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Current therapies for non-Hodgkin lymphoma commonly include CD20 mAb to deplete tumor cells. However, the response is not durable in a substantial proportion of patients. Herein, we report our studies in mice testing the hypothesis that heterogeneity in endogenous tissue CD20 + B cell depletion influences in vivo lymphoma therapy. Using highly effective CD20 mAbs that efficiently deplete endogenous mature B cells and homologous CD20 + primary lymphoma cells through monocyte-and antibody-dependent mechanisms, we found that lymphoma depletion and survival were reduced when endogenous host B cells were not depleted, particularly a rare IL-10-producing B cell subset (B10 cells) known to regulate inflammation and autoimmunity. Even small numbers of adoptively transferred B10 cells dramatically suppressed CD20 mAb-mediated lymphoma depletion by inhibiting mAb-mediated monocyte activation and effector function through IL-10-dependent mechanisms. However, the activation of innate effector cells using a TLR3 agonist that did not activate B10 cells overcame the negative regulatory effects of endogenous B10 cells and enhanced lymphoma depletion during CD20 immunotherapy in vivo. Thus, we conclude that endogenous B10 cells are potent negative regulators of innate immunity, with even small numbers of residual B10 cells able to inhibit lymphoma depletion by CD20 mAbs. Consequently, B10 cell removal could provide a way to optimize CD20 mAb-mediated clearance of malignant B cells in patients with non-Hodgkin lymphoma.

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Section: Discussionmentioning

confidence: 99%

Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice

Horikawa¹,

Minard‐Colin²,

Matsushita³

et al. 2011

J. Clin. Invest.

164

131

View full text Add to dashboard Cite

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“…PEI-complexed pppRNAs reduced the counts of leukocytes and platelets but not of erythrocytes, presumably due to systemic IFN induction, but no other obvious toxicities were observed (43). While pppRNA is a relatively new compound, poly(I:C) has been known for decades and was tested in multiple clinical trials for cancer therapy (44). However, only in the last few years has it become evident that there are at least 3 distinct receptors involved in the recognition of poly(I:C): PKR, TLR3, and MDA-5.…”

Section: Figurementioning

confidence: 99%

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

Besch¹,

Poeck²,

Hohenauer³

et al. 2009

J. Clin. Invest.

304

436

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The retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs.Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-I-and MDA-5-initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-x L rescued nonmalignant, but not melanoma, cells from RIG-I-and MDA-5-mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-I and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-x L , results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis.

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“…The safety profile of Ampligen ® , also known as polyI:polyC12U [5'-Inosinic acid, homopolymer, complexed with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)] has been established in the context of HIV therapy, and was found to be generally well-tolerated. 132 Poly[I:C(12)U] was found to be effective in inducing optimal phenotypic (elevated levels of MHC-Class I/Class II, CD83, CCR7, CD86 and CD40 molecules) and functional maturation of human DC in vitro, and capable of promoting the production of the T H 1-type cytokine IL-12. 133 The production of Type I IFN is thought to be crucial in enhancing the primary antibody response to soluble proteins, and in the stimulation of the production of all subclasses of IgG, and consequent induction of long-lived antibody production and immunological memory.…”

Section: Intracellular Tlr3 Activation: Dsrna and Poly (I:c)mentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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Results of a double-blind placebo-controlled study of the double-stranded RNA drug polyI:PolyC12U in the treatment of HIV infection

Cited by 85 publications

References 18 publications

Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice

Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

Potential adjuvantic properties of innate immune stimuli

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