Phase 1 trial of TLR9 agonist lefitolimod in combination with CTLA-4 checkpoint inhibitor ipilimumab in advanced tumors.

Abstract

TPS2669 Background: Drugs targeting pathogen associated molecular patterns are an attractive strategy to stimulate the immune system. Toll-like receptors (TLR) have generated significant interest as an effective means of stimulating the immune system that result in the killing of tumor cells. TLR-9 agonists can function to promote an early immune response and are an appealing partner for combination with checkpoint blockade to improve immune activation. Lefitolimod (MGN1703) is a covalently closed dumbbell-shaped DNA molecule that functions as a TLR-9 agonist. We developed a clinical trial combining lefitolimod with ipilimumab (anti-CTLA4) in patients with advanced malignancies. In the dose-escalation phase 19 patients were enrolled and no DLTs were encountered. Safety data and maximum planned dose level of lefitolimod at 120mg weekly and ipilimumab 3mg/kg every 3 weeks was previously presented. Adverse events related to the combination included fatigue, appetite loss, rash, and anemia. Methods: This trial (NCT02668770) was designed to evaluate the safety profile and maximum tolerated dose of lefitolimod with ipilimumab. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. Lefitolimod is administered via subcutaneous (SC) injection weekly while ipilimumab is given at 3mg/kg intravenous on day 8 of each 3 week cycle. Lefitolimod starting dose was 15mg SC weekly with 3 dose level escalations up to 120mg SC weekly. Patients receive treatment for 4 cycles (total 12 weeks) with the combination, and those with stable disease or response were eligible to remain on lefitolimod therapy for up to 1 year. Eligible patients have a metastatic or unresectable solid tumor refractory to standard therapies, ECOG ≤ 2, and normal organ and bone marrow function. Patients are allowed to have received prior checkpoint blockade agents. Enrollment in expansion cohorts in ongoing. To better understand relevant immunologic changes associated with treatment, paired pre- and post-treatment biopsies of target lesions and peripheral blood collection during treatment is required for target expansion cohort patient populations. In addition to evaluating target patient populations at the combination dose established during escalation, an expansion cohort for patients with cutaneous metastases involves combination treatment with intratumoral delivery of lefitolimod. Clinical trial information: NCT02668770.

Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics

“…Previous studies have investigated the effects of oligonucleotide ligands of various immune receptors, STING agonists, and even biological agents such as bacteria and viruses (22)(23)(24)(25)(26)(27). Several of these candidates have advanced to various stages of clinical trials with varying degrees of success (28)(29)(30)(31)(32), including a recently announced failure to meet the primary endpoint in a randomized phase III trial of an engineered TLR9 agonist (33). Thus far, minimally effective outcomes have been the primary reports arising from these efforts, and it appears that impediments to nucleotide delivery to optimal physical sites may be responsible for the low-level efficacy observed (34), generating great interest…”

Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors

“…In fact, a clinical trial in melanoma patients with a combination of lefitolimod and ipilimumab is ongoing and has shown encouraging first data on increase of tumor-infiltrating lymphocytes and a favorable safety profile, and no dose-limiting toxicities have been encountered at any dose level of lefitolimod together with ipilimumab. 38 a b Lefitolimod induced an increase of immune cells within the tumors, shown for T cells as well as for macrophages. Moreover, the ratio of anti-tumoral M1 vs pro-tumoral M2 macrophages 39,40 was increased after treatment with lefitolimod.…”

Toll-like Receptor 9 in breast carcinoma is a good prognostic marker in patients treated with neoadjuvant chemotherapy

“…A phase II immunotherapeutic maintenance treatment in small cell lung cancer using TLR9 agonists Lefitolimod have positive overall survivability [2 9]. Another phase I clinical trial using lefitolimod in combination with CTLA-4 checkpoint inhibitor ipilimumab in advanced malignancies is under progress [30]. The possible reason for using TLR9 agonists in cancer therapy was based on their ability to activate the inflammatory response to activate the immune system.…”