A Phase I–II Trial of Multiple-Dose Polyriboinosinic-Polyribocytidylic Acid in Patients With Leukemia or Solid Tumors

Abstract

Polyriboinosinic-polyribocytidylic acid (poly I - poly C), an interferon inducer, was administered in multiple doses of 0.3-75 mg/m2 to 26 patients with a variety of solid tumors, 9 with acute leukemia, and 2 with chronic myelogenous leukemia in blast crisis. Forty-four separate drug trials were comprised of various schedules and routes of administration. Toxic reactions included fever (in 66% of the trials), transient elevation of serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase (25%), minimal laboratory evidence of coagulation abnormalities (59%), and hypersensitivity (5%). These toxic manifestations did not relate to dose level or magnitude of interferon induction. Poly I - poly C administered iv induced low serum concentrations of interferon in 24/38 trials (63%), but the correlation between drug dose and peak interferon titer was not linear. Poly I - poly C administered iv or im was not effective as an inducer of interferon in the cerebrospinal fluid. Similarly, poly I - poly C administered im or by inhalation did not produce detectable serum levels of interferon. No patients experienced an objective tumor response to the administration of poly I - poly C, and most (76%) had progression of their disease while receiving the drug.

Activation of NF-κB by the dsRNA-dependent protein kinase, PKR involves the IκB kinase complex

“…We have addressed this issue using two strategies: the ®rst takes advantage of a VV recombinant that expresses PKR under regulation of the E. coli lacI operator/repressor system, the second is based on treating cells with a synthetic dsRNA polymer composed of alternating riboinosinic and ribocytidilic subunits (pIC), usually used as a model of viral infection or dsRNA-triggered processes. Characterizing this apoptosisinvolved pathway is of particular importance, since pIC is being used in dierent clinical trials for tumour treatments (Robinson et al, 1976;Salazar et al, 1996) and PKR has been invoked as a tumour suppresser gene (Meurs et al, 1993;Koromilas et al, 1992).…”

HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment

“…Here, we introduce a targeted therapy that selectively delivers synthetic dsRNA, pIC, into HER2-overexpressing breast tumor cells to induce targeted cell killing and promote an immune response against the tumor. Although it is a potent activator of the adaptive and innate immune responses (44), pIC caused severe toxicity when used systemically as naked pIC in clinical trials (45,46). The targeted delivery of pIC into HER2-overexpressing tumors is expected to abrogate the toxicity observed in previous trials, while stimulating an overall therapeutic effect.…”

Dual Role of TLR3 in Inflammation and Cancer Cell Apoptosis

“…It is known for long time that in human and primate, Poly(I:C) has a short half-life(~6min) because of rapid hydrolysis by RNase from serum, and its capacity to induce IFN production is weak compare to what is observed in mouse models [89,90]. Moreover, no GMP preparation are currently available and poly(I:C) has too much toxicity by causing fever, renal failure, coagulopathies and hypersensitivity reactions [90], indicating that Poly(I:C) can't be used in clinic.…”

“…Moreover, no GMP preparation are currently available and poly(I:C) has too much toxicity by causing fever, renal failure, coagulopathies and hypersensitivity reactions [90], indicating that Poly(I:C) can't be used in clinic. However, two type of Poly(I:C) analogues are currently evaluated in several clinical trials: Poly-ICLC that correspond to Poly(I:C) complexed with polylysine and carboxymethylcellulose, and Poly(I:C12U) or Ampligen (Hemispherx Biopharma of Philadelphia) which is a Poly(I:C) modified by introduction of unpaired bases (uracil).…”