Pharmacologic effects of polyinosinic• polycytidylic acid in man

Abstract

Twenty-four patients with cancer and concomitant infections with either herpes virus hominis or varicella zoster virus were treated with polyinosinic-polycytidylic acid (rIn.rCn) to determine: 1) the reliability of rIn.rCn to induce interferon production, and 2) the toxicity of the drug. Seven additional patients with herpes zoster were observed as controls. Two lots of rIn.rCn were used; Lot 1 was consistently effective in stimulating serum interferon at doses of 9 and 12 mg/kg, whereas Lot 2 was effective at doses of 3-12 mg/kg. There was no correlation between rIn.rCn doses within these ranges and the resultant interferon levels. Generally, peak serum interferon occurred within the first day. Toxicity to rIn.rCn consisted of fever in 21/24 patients, mild elevation of liver enzymes in 8/24 patients, and laboratory abnormalities of coagulation in 9 patients. The coagulation abnormalities appeared linearly related to the dose of rIn.rCn used. All these abnormalities were reversible, and none were considered severe of life-threatening. Since rIn.rCn was effective in stimulating interferon and since toxicity was considered acceptable, a randomized double-blind study was initiated to determine whether rIn.rCn is effective in the treatment of herpes zoster.

The microbial mimic poly IC induces durable and protective CD4+T cell immunity together with a dendritic cell targeted vaccine

“…Poly IC is recognized by endosomal TLR3 expressed by DEC ϩ DCs (33) and by MDA5 cytosolic receptors (34). Poly IC has been tested as a single therapeutic agent at high doses in patients with malignant disease (35)(36)(37), and it acts as an adjuvant for antibody immunity (38,39). Here, we show that poly IC alone is an effective adjuvant for a DC-targeted vaccine to yield CD4 ϩ T cell immunity that is quantitatively and qualitatively robust and also protective in a lung infection model.…”

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

“…The DCs were pulsed with the indicated antibodies or an EBNA1 peptide library as a positive control. After being matured with the TLR3/MDA-5 ligand poly(I:C), which has been explored for in vivo use in humans and could therefore be used as an adjuvant for clinical vaccination, 35 the DCs were cocultured with autologous PBMCs and EBNA1-specific T-cell expansion was monitored by both IFN-␥ production on day 9 ( Figure 1A top panel) as well as by proliferation on day 15 ( Figure 1A bottom panel) after restimulation with the EBNA1 peptide library on day 9. In 11 of the 17 individuals we studied, the frequency of IFN-␥ ϩ CD4 ϩ and/or CD8 ϩ T cells expanded by ␣DEC-205-EBNA1-pulsed DCs and specific for EBNA1 400-641 peptides was more than twice the number of T cells expanded as a result of isotype-EBNA1 stimulation ( Figure 1B).…”

Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft

“…In that study, the maximum tolerated doses of both rIL-2 (100000 U) and poly(I)-poly(C) (5 mg/kg) were used. Poly(I) -poly(C) has significant toxicity, while mismatched dsRNA is generally well tolerated [4,8,35] (Strayer DR, Hubbell HR, Brodsky I, et al, manuscript submitted). In our laboratory, repeated doses of up to 1000 ~tg/mouse mismatched dsRNA are well tolerated and can inhibit tumor cell growth (Hubbell, unpublished observations).…”