A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect

Abstract

PurposeTo determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant.MethodsPatients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic “danger” response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years.ResultsEighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS.ConclusionIntra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity.

Stereotactic Body Radiation Therapy–Induced Abscopal Effect on Hepatocellular Carcinoma After Treatment for Lung Cancer: A Case Report

“…(3) Studies seeking to capitalize on anticancer immunity to induce the abscopal effect hold the potential to increase the therapeutic ratio of radiotherapy to a diseased liver. (4) We describe a case of the abscopal effect after radiation to a second primary cancer. It is hypothesized that systemic immunologic reactions have the potential to cause spontaneous HCC regression.…”

Polysaccharide-based nanomedicines for cancer immunotherapy: A review

“…CpG oligodeoxynucleotide (CpG ODN) and polyinosinic-polycytidylic acid (Poly I: C) are both members of pathogen-associated molecule pattern (PAMP) families that could be recognized by TLR-9 and -3. The former is usually found in bacteria and the latter is a synthetic analogue of double-stranded RNAs from viral-infected mammalian cells [ [251] , [252] , [253] , [254] ]. The combination of these two substances was reported to demonstrate synergistic effects to stimulate T cell responses and thus were explored as promising immune adjuvants for immunotherapeutic vaccines [ 255 , 256 ].…”

Delivery routes matter: Safety and efficacy of intratumoral immunotherapy

“…One promising intratumoral approach is polyriboinosinic-polyribocytidylic acid-polylysine carboxymethylcellulose (poly-ICLC) targeting TLR3. Poly-ICLC has shown to be safe and tolerable after intratumoral administration in a Phase 1 clinical trial in patients with liver cancer [99]. Recently, intratumoral poly-ICLC entered a Phase 1 clinical trial in combination with FMS-like tyrosine kinase 3 ligand (Flt3L) and a low-dose of radiation therapy in order to investigate the response rate and the safety profile in low-grade lymphoma patients (NCT01976585).…”