lefitolimod (MGN1703) / Mologen, Feng Biosciences, iPharma, Gilead - LARVOL DELTA

Combination immunotherapy induces post-intervention control of HIV. (PubMed, Res Sq) - "Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD8 • IL12A

Lefitolimod in Combination with Ipilimumab in Patients with Advanced Solid Tumors: A Phase I Trial. (PubMed, J Immunother Precis Oncol) - P1 | "The combination of lefitolimod (administered subcutaneously or intratumorally) and ipilimumab was safe and well tolerated but demonstrated modest antitumor activity in patients with advanced cancers. ClinicalTrials.gov ID: NCT02668770."

Journal • P1 data • Dermatology • Fatigue • Oncology • Pruritus • Solid Tumor • CD8

Factors influencing time to viral rebound during analytical treatment interruptions in HIV cure trials (AIDS 2024) - "The trials investigated the following interventions alone or in combination: broadly neutralizing antibodies (bNAb) (3BNC117, 10-1074), histone deacetylase inhibitors (HDACi) (romidepsin, panobinostat), HIV-1 peptide vaccine (Vacc-4x) and toll-like receptor 9 (TLR9) agonist (MGN1703). Our findings shed new light on factors influencing time to viral rebound as well as loss of virologic control. These findings can inform the design of novel cure trials but also highlight the potential impact of early bNAb treatment on virological control during ATI."

Late-breaking abstract • Human Immunodeficiency Virus • Infectious Disease • CD4

Post-Intervention HIV Control Linked to Early In Vivo CD8+ T-Cell Proliferative Response to Rebound (CROI 2024) - P=N/A, P1/2 | "To determine the relevance of this relationship in vivo, we studied early T cell proliferation in response to reactivating virus in two prospective studies with an analytic treatment interruption (ATI).We previously reported a higher-than-expected rate of post-intervention control after a single-arm combination clinical trial (NCT04357821) in which people with treated HIV received a DNA/MVA vaccine regimen, followed by two bNAbs (10-1074, VRC07-523LS) plus a TLR-9 agonist (lefitolimod), then two bNAbs at the time of ATI. To our knowledge, these studies are the first to demonstrate a relationship between the early in vivo CD8+ T cell proliferative response to viral reactivation and HIV control post-ART. The results support continued focus on developing HIV cure strategies that enhance HIV-specific CD8+ T cell proliferative capacity."

Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD8 • IFNG

Effect of Broadly Neutralizing Antibody Exposure on HIV Rebound Following Combination Immunotherapy (CROI 2024) - P1/2 | "In this pharmacokinetic/pharmacodynamic (PK/PD) analysis, we evaluated the impact of bNAb exposure, susceptibility, and antidrug antibody (ADA) formation on rebound kinetics following combination immunotherapy with a boosted DNA vaccine, lefitolimod, and bNAbs (10-1074 and VRC07-523LS) (NCT04357821), in which 7/10 individuals exhibited altered post-intervention rebound dynamics.We described plasma bNAb PK using population PK modeling approaches in Monolix software. Higher bNAb exposure (e.g., AUC, Cmax) was consistently associated with delayed viral rebound. Our results suggest that post-treatment setpoint was not driven by bNAb susceptibility and that the association of IQ90 and setpoint is driven by higher VRC07-523LS levels at the time of rebound in those who rebounded earlier and had higher setpoints. Overall, bNAb PK-PD is likely not responsible for lower observed post-treatment setpoints during this trial, suggesting the effect is likely attributable to..."

Human Immunodeficiency Virus • Infectious Disease

Ipilimumab (Immunotherapy) and MGN1703 (TLR Agonist) in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: May 2024 ➔ May 2025 | Trial primary completion date: May 2023 ➔ May 2025

Metastases • Trial completion date • Trial primary completion date • Melanoma • Oncology • Prostate Cancer • Solid Tumor

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. (PubMed, Nat Med) - P2a | "Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 ."

Journal • P2a data • Human Immunodeficiency Virus • Infectious Disease

Lefitolimod (TLR agonist) and ipilimumab in patients with advanced solid tumors: A phase I trial. (ASCO 2023) - "The combination of high subcutaneous doses or intra-tumoral administration of lefitolimod in combination with ipilimumab is safe and well tolerated in patients with advanced cancers, with preliminary antitumor activity observed. Clinical trial information: NCT0266877."

Clinical • Metastases • P1 data • Dermatology • Fatigue • Oncology • Pruritus • Solid Tumor • CD8

TITAN: Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV (clinicaltrials.gov) - P2a | N=47 | Completed | Sponsor: University of Aarhus | Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4

Patient characteristics after completion of recruitment from the phase 3 IMPALA study with lefitolimod in metastatic colorectal carcinoma (ESMO-IO 2017) - P3; "The median age is 65 years both in the lefitolimod and the control arm. Age group distribution showed also a similar pattern: 12 vs 7 patients from 24-43 yo, 112 vs 114 from 44-63 yo, 56 vs 55 from 64-68 yo, 37 vs 46 from 69-73 yo, 35 vs 37 from 74-78 yo, 19 vs 15 from 79-83 yo and 3 vs 1 from 84-88 yo in the lefitolimod vs the control arm as pre-requisite to guide maintenance therapy in the future."

Clinical • P3 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Top-line data from the randomized phase 2 IMPULSE study in small-cell lung cancer (SCLC): Immunotherapeutic maintenance treatment with lefitolimod (ESMO 2017) - P2; "The IMPULSE study showed (1) the expected pharmacodynamic response to lefitolimod, (2) positive efficacy signals in two pre-defined and clinically relevant subgroups regarding OS and (3) a favorable safety profile. This data provides significant guidance for defining patient populations most likely to benefit from treatment with lefitolimod."

Clinical • P2 data • Small Cell Lung Cancer

REBOUND DYNAMICS FOLLOWING IMMUNOTHERAPY WITH AN HIV VACCINE, TLR9 AGONIST, AND bNAbs (CROI 2023) - " We performed a single-arm proof-of-concept study to evaluate the efficacy of a combination approach involving (1) Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost vaccination, followed by (2) a combination of two broadly neutralizing antibodies (bNAbs; 10-1074, VRC07-523LS) and a TLR-9 agonist (lefitolimod) and then (3) two bNAbs given at the time of treatment interruption. The majority of individuals who received combination immunotherapy exhibited evidence of virologic control post-ART. Treatment-mediated virologic and immunologic factors may have contributed to this outcome."

Late-breaking abstract • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4 • CD8 • IFNG • IL12A

THE IMPACT OF 3BNC117; 10-1074; AND LEFITOLIMOD ON HIV-1 PERSISTENCE: THE TITAN TRIAL (CROI 2023) - No abstract available

Human Immunodeficiency Virus • Infectious Disease

CD169 (Siglec-1) as a Robust Human Cell Biomarker of Toll-Like Receptor 9 Agonist Immunotherapy. (PubMed, Front Cell Infect Microbiol) - "Finally, in a clinical trial in HIV-infected individuals receiving immunotherapy treatment with MGN1703, we observed a uniform upregulation of CD169 on monocytes after dosing with 97% of classical monocytes positive for CD169 (p=0.002). Hence, in this comprehensive evaluation ex vivo, in an animal model, and in a clinical trial, we find increases in the percentage of CD169 positive monocytes to be a reliable and robust biomarker of immune activation following TLR9 agonist treatment."

Biomarker • IO biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease • Oncology • IFNA1

TITAN: Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV (clinicaltrials.gov) - P2a | N=47 | Active, not recruiting | Sponsor: University of Aarhus | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4

Ipilimumab (Immunotherapy) and MGN1703 (TLR Agonist) in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | N=55 ➔ 28

Enrollment change • Melanoma • Oncology • Solid Tumor

Ipilimumab (Immunotherapy) and MGN1703 (TLR Agonist) in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1; N=55; Active, not recruiting; Sponsor: M.D. Anderson Cancer Center; Trial completion date: May 2021 ➔ May 2024; Trial primary completion date: May 2021 ➔ May 2023

Clinical • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor

Phase 1 trial of TLR9 agonist lefitolimod in combination with CTLA-4 checkpoint inhibitor ipilimumab in advanced tumors. (ASCO 2019) - P1; "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"

Checkpoint inhibition • Combination therapy • P1 data • Oncology

Combination of subcutaneously administered TLR9 agonist lefitolimod with CTLA-4 checkpoint inhibitor ipilimumab - A phase I trial in patients with advanced solid tumors (SITC 2018) - P1; "Conclusions The combination is safe and well tolerated in patients with advanced cancers. Expansion cohorts with intratumoral administration are ongoing."

Checkpoint inhibition • Clinical • IO biomarker • P1 data • PD(L)-1 Biomarker • Neuroendocrine Tumor

Lefitolimod vs standard of care (SOC) for patients with metastatic colorectal cancer (mCRC) responding to first-line standard treatment: Results from the randomized phase III IMPALA trial (ESMO 2019) - P3; "Lefitolimod did not show superiority to standard of care as a single agent maintenance treatment in patients with mCRC. Limited add-on toxicity confirmed the favorable safety and tolerability profile of lefitolimod. Hence, and given its mode of action, lefitolimod will be evaluated in combination with other anti-cancer immunotherapies."

Clinical • Late-breaking abstract • P3 data

Maintenance treatment with the TLR9 agonist lefitolimod in extensive-stage small-cell lung cancer (ES-SCLC): Final results from the randomized phase 2 IMPULSE study (ESMO 2018) - P2; "The IMPULSE study showed (1) the expected pharmacodynamic response, (2) positive efficacy signals in two pre-defined subgroups regarding OS and (3) a favorable safety profile. This data provides significant guidance for defining patient populations most likely to benefit from lefitolimod treatment."

Clinical • P2 data • Small Cell Lung Cancer

Current status of intralesional agents in treatment of malignant melanoma. (PubMed, Ann Transl Med) - "This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid..."

Journal • Review • Gene Therapies • Immune Modulation • Inflammation • Melanoma • Oncology • Solid Tumor • CD40 • IL12A • MAGEA3 • TYRP1

TITAN: Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV (clinicaltrials.gov) - P2a; N=48; Recruiting; Sponsor: University of Aarhus; Trial completion date: Feb 2021 ➔ Feb 2023; Trial primary completion date: Jul 2020 ➔ Jul 2022

Clinical • Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4

Ipilimumab (Immunotherapy) and MGN1703 (TLR Agonist) in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1; N=55; Active, not recruiting; Sponsor: M.D. Anderson Cancer Center; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Melanoma • Oncology • Prostate Cancer • Solid Tumor

TLR9 activation cooperates with T cell checkpoint blockade to regress poorly immunogenic melanoma. (PubMed, J Immunother Cancer) - "In the setting of the immunogenic B16-Ova (Ovalbumin) expressing melanoma model, local injection of the CpG oligonucleotide TLR9 agonist ODN1826 combined with systemic CTLA-4 blockade cured 45% of mice of both their treated and an untreated tumor on the opposite flank demonstrating the synergistic potential of this combination. Using both a TLR9 agonist (MGN1703) and a CTLA-4 antibody (9D9-IgG2a) of increased potency cured 50% of bi-lateral B16-F10 melanoma. These findings suggest that intra-tumoral TLR9 agonists can improve sensitivity of poorly immunogenic tumors to T cell checkpoint blockade, and that newer, higher potency TLR agonists and checkpoint antibodies can raise the therapeutic ceiling for this combination therapy."

Checkpoint inhibition • IO Biomarker • Journal • Melanoma • Oncology • Solid Tumor