Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial

Abstract

Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells. In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood. Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (<grade 2). In the patient with clinical benefit, IHC analysis of tumor showed increased CD4, CD8, PD1, and PD-L1 levels compared with patients with progressive disease. RNA-seq analysis of the same patient's tumor and peripheral blood mononuclear cells showed dramatic changes in response to poly-ICLC treatment, including upregulation of genes associated with chemokine activity, T-cell activation, and antigen presentation. Poly-ICLC was well tolerated in patients with solid cancer and generated local and systemic immune responses, as evident in the patient achieving clinical benefit. These results warrant further investigation and are currently being explored in a multicenter phase II clinical trial (NCT02423863). .

Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

“…While tumor-induced T cell exhaustion may be partially reversed by checkpoint inhibitors, current treatments fail to show clinical benefits in a significant portion of the patients. With novel techniques of DC generation being developed [2,10], and combination regimes with other therapies, such as checkpoint inhibitors, being evaluated in preclinical and clinical settings [11][12][13][14], DC vaccination is still viewed as an opportunity to foster immunity against tumors [15][16][17][18].…”

Poly(I:C) stimulation is superior than Imiquimod to induce the antitumoral functional profile of tumor‐conditioned macrophages

“…Different TLR agonists have been tested in experimental mouse tumors models [22][23][24][25] and are being investigated in early clinical trials to assess their safety and efficacy in cancer patients, most frequently in combination with conventional or target therapies [26][27][28]. Here, we have studied the TLR7 agonist Imiquimod (IMQ), one of the few approved by FDA for the treatment of nonmelanoma skin cancers [26,29], and the TLR3 agonist Poly(I:C), a dsRNA analog under study in the clinic as adjuvant in antitumor vaccines [27,[30][31][32].…”

Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome

“…Less than two decades after the first reports characterizing the role of RLRs in immunity, we are closer than ever to having RLR ligands in clinical applications. Pilot trial and ongoing clinical trials in humans are yielding promising results, notably for cancer immunotherapy [67][68][69]85]. Although we have come a long way and key milestones have been reached, there are still significant knowledge gaps that need to be filled by use of molecular, cellular, and structural biology approaches to not only be able to design exclusive and potent RIG-I or MDA5 ligands but also to decide on the most appropriate target for use in antiviral, vaccine adjuvant, or cancer immunotherapeutic applications (see Outstanding Questions).…”