Long-term Treatment of Malignant Gliomas with Intramuscularly Administered Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose: An Open Pilot Study

Abstract

Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) (10-50 mcg/kg, administered intramuscularly one to three times weekly) was given for < or = 56 months to 38 patients with malignant gliomas. There was minimal or no toxicity. Twenty of 30 patients (66%) receiving at least twice weekly poly-ICLC showed regression or stabilization of gadolinium-enhancing tumor, as revealed by magnetic resonance imaging (median = 65% volume decrease). All but one patient with anaplastic astrocytomas who received continuous poly-ICLC remain alive, with a median progression-free survival of 54 months from diagnosis. Median Kaplan-Meier survival is 19 months for patients with glioblastomas who receive at least twice weekly poly-ICLC treatments. Tumor response was associated with 2',5' -oligoadenylate synthetase activation (P = 0.03) but not with serum interferon. We hypothesize clinical activation by poly-ICLC of a basic host tumor suppressor system. Prolonged, quality survival with tumor stabilization or regression confirmed by magnetic resonance imaging for most patients with anaplastic astrocytomas and glioblastomas suggests that more extensive laboratory and controlled clinical studies are warranted. The concept of long-term, broad spectrum stimulation of host defenses with nontoxic, inexpensive double-stranded ribonucleic acids, such as low-dose poly-ICLC, may be applicable to the treatment of other malignancies.

A phase II clinical trial of poly-ICLC with radiation for adult patients with newly diagnosed supratentorial glioblastoma: a North American Brain Tumor Consortium (NABTC01-05)

“…Fatigue, myalgia and pain at the injection site were the main adverse events; these events were not substantially different from the toxicities witnessed in the previous trial which utilized poly-ICLC in high-grade glioma patients. No patients went off-study because of toxicity [26]. …”

“…Twenty of 38 patients also received concurrent CCNU at 120mg/m2 once every six weeks while others received no chemotherapy. This study showed up to a 40-fold increase in serum OAS product and toxicity was mild [26]. 66% of patients (including all 11 newly diagnosed AA) receiving at least twice-weekly poly-ICLC showed regression or stabilization of gadolinium enhancing tumor volume on MRI for at least 6 months from study entry.…”

“…The enzyme systems activated by poly-ICLC include 2’5’oligoadenylate sythetase (OAS), protein kinase R (PKR), RIG-1 helicase, and melanoma differentiation associated gene MDA5, which along with the interferon and immune related responses may be responsible for its anti-neoplastic effects [25, 26]. OAS requires dsRNA as a cofactor in order to activate ribonuclease-L which then exerts anti-proliferative and proapoptotic activity in cells [27].…”

Pediatric Phase II Trials of Poly-ICLC in the Management of Newly Diagnosed and Recurrent Brain Tumors

“…In multiple previous reports it was shown that poly-ICLC induced greater activation of natural killer cells at 10 mcg/kg as compared with higher doses, and the most active biological dose of 20 mcg/kg was established in adult trials. 14,21 The FDA agreed with this plan to do a low-dose study without a phase I dose escalation.…”

“…The safety and tolerability of long-term, low-dose intramuscularly administered poly-ICLC in the dose range of 20 mcg/kg 2 to 3 times weekly, in adult patients with malignant gliomas was established. Prolonged, quality survival with tumor stabilization or regression confirmed by magnetic resonance imaging for most patients with anaplastic astrocytomas and glioblastomas prompted Salazar et al 14 to conclude that more extensive laboratory and controlled clinical studies with poly-ICLC are warranted. Other adult trials with recurrent and newly diagnosed glioblastoma found that poly-ICLC was well tolerated as a single agent and in combination, but did not improve progression-free survival.…”