poly-ICLC Research Articles

Poly ICLC induces anti-IC antibodies in mice and rabbits.

Poly ICLC is an interferon (IFN) inducer and antiviral, antitumor, radioprotective, and immunoregulatory agent. We show that administration of poly ICLC to mice and rabbits also results in the presence of anti-IC antibodies in their serum.

Bimodal effects of MVE-2 on cytotoxic activity of natural killer cell and macrophage tumoricidal activities

Maleic anhydride divinyl ether of molecular weight 15,500 (MVE-2) increased the tumoricidal activity of NK cells and Mφ in a dose-dependent manner with the peak response of both effector cells occurring 3 days following treatment. Both effector cell responses were sustained for over 7 days following one injection. However, repeated injections with MVE-2 led to a hyporesponsiveness of NK cells whereas Mφ activity remained high. Poly ICLC, but not C. parvum, reconstituted NK cell activity in mice hyporesponsive to MVE-2. Significant antitumor response was achieved when tumor cells were inoculated at the peak time of effector cell response, indicating the in vivo role of NK and/or Mφ in exerting a tumoricidal effect.

Antitumor effect of Corynebacterium parvum and poly ICLC on experimental brain tumors

Corynebacterium parvum (C. parvum) or stabilized poly I: C complex (poly ICLC) was administered to C57BL/6 mice with malignant gliomas induced by 20-methylcholanthrene. The results were as follows. 1) When C. parvum was administered intracerebrally, growth of the brain tumor was significantly inhibited compared with intraperitoneal administration. Inhibition of tumor growth was obtained in proportion to the dose of C. parvum. Natural cytotoxic (NC) activity of brain mononuclear cells against malignant glioma cells was most enhanced when C. parvum was administered intracerebrally and that of peritoneal exudate cells was most enhanced when it was administered intraperitoneally in a 15 hour 51Cr release assay. Enhanced NC activity of brain mononuclear cells was found to reach a peak 5 days after intracerebral administration, and to depend on the administered dose. 2) When poly ICLC was administered intracerebrally, tumor growth was more inhibited than when it was administered intraperitoneally. Four administrations of poly ICLC at 4-day intervals showed significant inhibition of tumor growth compared with single administration. Enhanced NC activity of brain mononuclear cells against malignant glioma cells was found to reach a peak 1 day after intracerebral administration of poly I:C, and to depend on the frequency of intracerebral administration of poly ICLC. 3) Enhanced NC cells in the brain after administration of C. parvum and poly ICLC were observed mainly in the adherent cell fraction. 4) Tumor cell growth was inhibited when tumor cells were co-cultured with 250 μg/ml of C. parvum, but poly ICLC had no influence on tumor cell growth. 5) Interferon was not induced after intracerebral administration of C. parvum. High titers of interferon were observed after single intracerebral administration of poly ICLC, but much lower titers of interferon were observed after plural administration at 4-day intervals. From these results, it was suggested that local administration of C. parvum or poly ICLC is effective in inhibiting the growth of brain tumors, that natural cytotoxicity of brain mononuclear cells is enhanced by intracerebral administration of C. parvum or poly ICLC with little interaction of interferon, and that there is a possibility of direct cytotoxic effects of C. parvum.

Prostaglandin E synthesis and release by murine macrophages and human monocytes after in vitro treatment with biological response modifiers.

Prostaglandins of the E series (PGE), produced by mononuclear phagocytes, have many biological activities and are involved in the regulation of myelopoiesis and of the cytotoxic activities of macrophage (M phi) and natural killer (NK) cells. Since one of the possible effects of biological response modifiers (BRMs) on immune regulation might be modulation of PGE production, resident peritoneal murine M phi (mM phi) and elutriated human blood monocytes (hM) were incubated with BRMs and the supernatants were then assayed for PGE. Control mM phi produced about 4.9 ng PGE/10(5) mM phi over a 24 hr period. Lipopolysaccharide (LPS, 1-5 micrograms/ml), polyinosinic-polycytidylic acid complexed with poly-L-lysine (Poly ICLC, 0.1-10 micrograms/ml) and murine alpha, beta-interferon, (IFN, 10-1000 U/ml) all caused a highly significant increase in PGE-secretion. BM41.332, a 2-cyanoaziridine (25-50 micrograms/ml), was found to be less stimulatory, whereas the pyran copolymer MVE-2 (25-50 micrograms/ml), and Azimexone (25-50 micrograms/ml) had marginal effects on PGE-production. Kinetic studies showed that the plateau of PGE-production by mM phi occurred during the first 24 hr of incubation, and mM phi which were washed after a 24 hr incubation period could not be restimulated to produce more PGE. PGE release by hM was increased after stimulation with LPS, Poly IGLC and BM41.332, whereas human IFNs (alpha and beta) induced a slight decrease in PGE production. As in the murine studies, Azimexone and MVE-2 had no detectable effect. The ability of some BRMs to augment PGE-secretion by mM phi and hM may contribute to their negative effects on host responses, such as suppression of NK cell activity.

Phase I Trial with the Interferon Inducer Poly I:C/Poly-L-Lysine (Poly ICL)

Poly I:C/poly-L-lysine (poly ICL) was previously shown to be a potent inducer of interferon (IFN) production in nonhuman primates. In this limited trial in five patients with advanced cancer, poly ICL stimulated primarily leukocyte interferon (IFN-α) with peak titers of 40 to 160 units/ml, usually at 24 hours after poly ICL administration. Treatments were regularly followed by fever, usually maximum at 5-7 after drug administration. Other side effects included chills, fatigue, malaise, and headache. Hypotension did not occur. One patient experienced bronchospasm and another developed urticaria immediately following poly ICL injection. These two patients and a third patient (who did not experience any allergic reactions) were found to have developed serum antibodies reactive with poly ICL. In addition, two patients treated with poly ICL using carbomethylcellulose (CMC) as a solubilzing agent (poly ICLC) without allergic reactions in a previous study were also found to have such antibodies. The relationship between apparent allergic reactions and the observed antibody responses remains uncertain. There were no clear therapeutic responses observed.

Pharmacokinetics of interferon in blood, cerebrospinal fluid, and brain after administration of modified polyriboinosinic-polyribocytidylic acid and amphotericin B.

Polyriboinosinic-polyribocytidylic acid (with a sedimentation coefficient of 9S) prepared in a complex with poly-L-lysine and carboxymethylcellulose (poly ICLC) was given intravenously to rabbits in a priming technique with two infusions 4 hr apart; and with low-dose amphotericin B (AmB, 0.5 mg) to trace the transfer of interferon (IFN) in serum to cerebrospinal fluid (CSF) and brain. Peak titers of IFN in serum were at 4 hr, but peak titers of IFN in CSF and brain occurred at 8 hr. At 4 hr, CSF IFN was 0.6%-2.7% of serum titers but at 8 hr had increased to 11.7%-51.1%. IFN was uniformly distributed to all areas of the brain and spinal cord at 8 hr. Titers of IFN in the brain were independent of CSF values, and varied from 5.9%-44.1% of the serum titers. When two injections of poly ICLC were given 4 hr apart, IFN titers in serum, CSF, and brain were significantly raised. Poly ICLC together with AmB increased serum IFN.

Treatment of recurrent laryngeal papillomatosis with anartificial interferon inducer (poly ICLC)

LARYNGEAL PAPILLOMATOSIS, although rare, is the most common proliferative lesion of the larynx in childrem The evidence to date suggests that a virus, presumably one of the papovavirus group, is responsible for the lesions. The clinical behavior is unpredictable. In children with early onset of the disease (under age 2 years) and in those with marked epithelial atypia on histologic examination, the tumor tends to have a more aggressive clinical course. ~ When disease is localized to the larynx, it can be controlled by surgery; in some patients, spontaneous regression occurs. However, in other cases the papillomas spread down the tracheobronchial tree to the lung parenchyma; then the prognosis for total eradication of disease is poor. Since these lesions may well be of viral origin and ince there was a preliminary report from Sweden of a favorable effect of exogenous interferon, ~ we elected to try a synthetic interferon inducer for therapy in two patients with a highly aggressive form of the disease.

830 TREATMENT OF RECURRENT LARYNGEAL PAPILLOMATOSIS WITH AN INTERFERON INDUCER

Papillomatosls is a potentially life-threatening proliferative lesion of the larynx; a viral etiology is postulated. Repeated recurrence can occur requiring frequent surgery for maintenance of a patent airway. The synthetic interferon inducer polylnosinic-polycytidillc acid stabilized with poly-L-lysine (Poly ICLC) was used l.v. In 6 patients. Doses ranged from 2.5 mg/m2 to 12 mg/m2 t.i.w. for a three month course. In all patients a marked decrease in the requirement for surgery was seen. No regression of pulmonary lesions was seen in 3/3 patients with such lesions. Toxiclty consisted of fever, nausea and headache; mild neutropenla lasting 1-3 days and transient transaminase elevations. Variable serum interferon titers ranging from 100-3000 units were seen 8 hours after each dose (peak titer). The dramatic decrease in the requirement for surgery in these patients suggests that additional studies of antiviral agents in papillomatous diseases are indicated. Supported in part by General Clinical Research Center-Pediatrics grant RR-0052 and General Research grant RR-0046.

Modified polyriboinosinic-polyribocytidylic acid complex: induction of serum interferon, fever, and hypotension in rabbits

The purposes of this study were to determine whether the febrile and hypotensive reactions to the administration of polyriboinosinic-polyribocytidylic acid [poly (I)-poly (C)] complexed with poly-L-lysine and carboxymethylcellulose (poly ICLC) (9S) encountered in humans could be duplicated in rabbits, and when such duplication was demonstrated, to ascertain whether these untoward reactions could be avoided by (i) administration of hydrocortisone (HC), (ii) alteration of the route of delivery, or (iii) administration of poly ICLC (4S) an interferon inducer of lower molecular weight. Responses to intravenous poly ICLC (9S) in rabbits reproduced adverse reactions in humans, namely fever and hypotension, and were accompanied by high titers of serum interferon. Continuing investigations showed that (i) intravenous pretreatment of rabbits with HC ameliorated hypotensive responses but markedly diminished interferon induction. When HC was given after poly ICLC (9S), both interferon and hypotension induction were likewise depressed. (ii) Intramuscular or subcutaneous poly ICLC (9S) produced neither high titers of serum interferon nor toxic effects. (iii) Poly ICLC (4S) induced high titers of serum interferon and fever, but no hypotension. Poly ICLC (4S) warrants further study.

Protective and toxic effects of a nuclease-resistant derivative of polyriboinosinic-polyribocytidylic acid on Venezuelan equine encephalomyelitis virus in rhesus monkeys.

Polyriboinosinic-polyribocytidylic acid, stabilized with poly-L-lysine and carboxymethylcellulose (poly ICLC), favorably alters the pathogenesis of Venezuelan equine encephalomyelitis virus infection in rhesus monkeys by decreasing the number of infected monkey that become detectably viremic and by delaying the onset of viremia in the remaining monkeys. Poly ICLC is known to induce high circulating levels of interferon in primates, and the interferon system is assumed to be the mechanism by which poly ICLC exerts its antiviral effect. Poly ICLC treatment was associated with a few deaths, but only under certain conditions of infection and handling. The death of some infected, treated monkeys in the absence of death in monkeys that were either infected and untreated or treated and uninfected suggests a synergistic toxicity resulting from the combination of infection, handling, and poly ICLC treatment, although other explanations are possible.