glucopyranosyl lipid A (G100) / Merck (MSD) - LARVOL DELTA

PEMBROSARC: Combination of MK3475 and Metronomic Cyclophosphamide in Patients With Advanced Sarcomas : Multicentre Phase II Trial (clinicaltrials.gov) - P2 | N=129 | Completed | Sponsor: Institut Bergonié | Active, not recruiting ➔ Completed | N=227 ➔ 129

Enrollment change • Trial completion • Oncology • Sarcoma • Solid Tumor

Synergistic anti-tumor effects of TLR4 agonist G100 and anti-OX40 antibody (SITC 2018) - P1/2; "Background Intratumoral injection of G100 (Glucopyranosyl Lipid A in stable emulsion) has shown potent anti-tumor effects...The survival mice rejected re-challenge with B16-ova and with wildtype B16-F10 tumors, indicating long-term memory responses. Conclusions Combination therapy using intratumoral injection of G100 with systemic delivery of anti-OX40 has synergistic anti-tumor effects in preclinical tumor models, which supports clinical evaluation."

Follicular Lymphoma • Indolent Lymphoma • Lymphoma • Melanoma • Non-Hodgkin’s Lymphoma • Oncology

Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab (ASH 2017) - "G100 is a well tolerated active agent in FL with 52% pts experiencing clinical benefit (26% PR, 26% MR). The addition of P did not result in unexpected toxicity, and may have an effect on the degree and duration of tumor reduction. Longer follow-up will be required to determine the durability and depth of these responses."

Adverse events • Combination therapy • Tumor-infiltrating lymphocyte • Biosimilar • Follicular Lymphoma • Immunology • Indolent Lymphoma • Renal Disease

Effect of intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist G100 on a clinical response and CD4 T-cell response locally and systemically. (ASCO-SITC 2018) - P1; "...G100 is under investigation in multiple clinical trials and contains a potent TLR4 agonist (oil-in-water emulsion of glucopyranosyl lipid A) that has been tested as vaccine adjuvant...IT G100 is a viable agent for local control of metastatic STS lesions. With or without RT, G100 appears to cause CD4 T cell mediated local and systemic response. Combination of G100 with other immunomodulators could induce clinically significant systemic responses, as seen in follicular NHL treated with G100."

Clinical • Non-Hodgkin’s Lymphoma • Sarcoma

Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma. (ASCO 2017) - P1/2; "G100 consists of glucopyranosyl lipid-A (GLA), a TLR-4 agonist in a specific formulation. G100 IT was safe, well-tolerated, induced CD8+ T cell infiltration and expansion of TIL clones. G100/RT treated and abscopal lesion regressions were observed signifying the induction or boosting of systemic anti-tumor immunity. The induction of immune responses, favorable safety profile and clinical activity indicate that G100 IT is an active agent that warrants further investigation."

Adverse events • Biosimilar • Immunology • Indolent Lymphoma • Neuroendocrine Tumor

Pembrolizumab combined with low-dose cyclophosphamide and intra-tumoral injection of the toll-like receptor 4 agonist G100 in patients with advanced pretreated soft tissue sarcoma: results from the PEMBROSARC basket study. (PubMed, J Hematol Oncol) - P2 | "We hypothesized that intra-tumoral G100 would induce a robust local and potentially systemic anti-tumor immune response in the microenvironment of TLS-negative sarcoma, leading to improved response to PD1 inhibition. However, clinical activity in combination with PD1 inhibition was limited and no clear correlation was observed between tumor shrinkage and increased inflammation. TLR4 stimulation might have both antitumor and pro-tumor consequences.Trial registration: This study was registered with ClinicalTrial.gov, number NCT02406781."

Journal • Pan tumor • Immune Modulation • Immunology • Inflammation • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD4 • CD8 • PD-L1 • TLR4

Nonclinical safety evaluation of two vaccine candidates for Herpes Simplex Virus type 2 to support combined administration in humans. (PubMed, J Appl Toxicol) - "Three repeated-dose toxicity studies, one in guinea pigs and two in rabbits, were conducted to assess systemic toxicity and local tolerance of HSV529, alone or adjuvanted with GLA-SE, or G103 containing GLA-SE. Data from these studies show that both vaccines are safe and well tolerated and support the ongoing HSV-2 clinical trial in which the two vaccine candidates will be given either sequentially or concomitantly to explore their potential synergistic and incremental effects."

Journal • CNS Disorders • Herpes Simplex • Human Immunodeficiency Virus • Infectious Disease

HVTN 135: Evaluating Safety and Immune Response to the HIV-1 CH505 Transmitted/Founder gp120 Adjuvanted With GLA-SE in Healthy, HIV-exposed Uninfected Infants (clinicaltrials.gov) - P1 | N=38 | Recruiting | Sponsor: HIV Vaccine Trials Network | Trial completion date: Oct 2022 ➔ Jun 2024 | Trial primary completion date: Oct 2022 ➔ Jun 2024

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

Synthesis of LDN carbohydrate antigens of Schistosoma mansoni (ACS-Sp 2022) - "Existing disease control comprises of mass and repetitive administration of the antihelminth drug praziquantel, however, drug resistance, high chances of reinfections and the lack of alternative therapies creates an urgent need for developing novel anti-schistosomiasis therapies. Regardless of the discovery and publications on antigens from S. mansoni and some extent from S. haematobium, only few vaccine candidates, named as BILHVAX (against sm14 antigen) and its combination with various adjuvant such as glucopyranosyl Lipid A (GLA), aqueous formulation of glucopyranosyl lipid (GLA-AF), glucopyranosyl lipid adjuvant–stable emulsion (GLA-SE) has entered clinical trials, but no promising result has been reported to date...In this communication, we present the progress of our synthetic work towards the synthesis of core LDN antigen and its analogues.Figure 1. Structures of targeted antignes"

Infectious Disease

HVTN139: Evaluating the Safety and Immunogenicity of HIV-1 Vaccines Based on Chimpanzee Serotypes of Ad Expressing Clade C gp140 and a CH505TF gp120 Protein Boost in Healthy, HIV- Uninfected Adult Participants (clinicaltrials.gov) - P1; N=34; Recruiting; Sponsor: HIV Vaccine Trials Network

Clinical • New P1 trial • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

Efficacy of an experimental gonococcal lipooligosaccharide mimitope vaccine requires terminal complement. (PubMed, J Infect Dis) - "An experimental peptide vaccine called TMCP2 that mimics an oligosaccharide epitope in gonococcal lipooligosaccharide, when adjuvanted with glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE), elicits bactericidal IgG and hastens clearance of gonococci in the mouse vaginal colonization model...In conclusion, TMCP2 vaccine efficacy in the mouse vagina requires membrane attack complex. Serum bactericidal activity may serve as a correlate of protection for TMCP2."

Clinical • Journal • Infectious Disease • TMC2

Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma. (PubMed, Leuk Lymphoma) - P1/2 | "G100 20 µg (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity."

Journal • P1/2 data • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology • TLR4

Intratumoral expression of IL-12 from lentiviral or RNA vectors acts synergistically with TLR4 agonist (GLA) to generate anti-tumor immunological memory. (PubMed, PLoS One) - "Furthermore, concurrent intratumoral administration of the synthetic TLR4 agonist glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE) induced systemic memory T cell responses that mediated complete protection against tumor rechallenge in all survivor mice (8/8 rechallenged mice), whereas only 2/6 total rechallenged mice treated with intratrumoral IL12 monotherapy rejected the rechallenge. Taken together, expression of vectorized IL12 in combination with a TLR4 agonist represents a varied approach to broaden the applicability of intratumoral immune therapies of solid tumors."

Journal • Immunology • Oncology • Solid Tumor • IL12A • TLR4

A respirable HPV-L2 dry-powder vaccine with GLA as amphiphilic lubricant and immune-adjuvant. (PubMed, J Control Release) - "A key feature of our engineering approach was the use of the amphiphilic endotoxin derivative glucopyranosyl lipid A (GLA) as both a coating agent enhancing particle de-aggregation and respirability as well as a built-in immune-adjuvant...Despite the very short-term immunization conditions employed for a preliminary vaccination experiment, the intratracheally administered dry-powder, but not the s.c. injected liquid-state, vaccine induced consistent HPV neutralizing responses. Overall, the present data provide proof-of-concept validation of a new formulation design to produce a dry-powder vaccine that may be easily transferred to other antigens."

Clinical • Journal • Oncology

Characterization of T cell responses to co-administered hookworm vaccine candidates Na-GST-1 and Na-APR-1 in healthy adults in Gabon. (PubMed, PLoS Negl Trop Dis) - P1 | "Two hookworm vaccine candidates, Na-GST-1 and Na-APR-1, formulated with Glucopyranosyl Lipid A (GLA-AF) adjuvant, have been shown to be safe, well tolerated, and to induce antibody responses in a Phase 1 clinical trial (Clinicaltrials.gov NCT02126462) conducted in Gabon...In Gabonese volunteers, hookworm vaccine candidate, Na-GST-1, induces detectable CD4+ T cell responses that correlate with specific antibody levels. As these CD4+ T cells express CTLA-4, and blocking this inhibitory molecules resulted in enhanced cytokine production, the question arises whether this pathway can be targeted to enhance vaccine immunogenicity."

Clinical • Journal • Hepatitis B • Hepatology • Immune Modulation • Infectious Disease • Inflammation • CD40LG • IL2

Higher dose single-agent intratumoral G100 (a TLR4 agonist) results in increased biomarker activity and improved clinical outcomes in patients with follicular lymphoma (SITC 2018) - P1/2; "...This ongoing phase 1/2 study demonstrated that intratumoral (IT) G100 alone or with pembrolizumab (P) was safe, induced systemic clinical responses in follicular lymphoma (FL) patients (pts) including relapsed/refractory (R/R) disease...Conclusions G100 20µg dose is safe and demonstrates an early trend toward better clinical responses. This dose induces greater changes in tumor biomarkers that are associated with clinical response (increase of TILs, decrease of CD20+ tumor cells) and supports further development of the 20µg dose of IT G100."

Biomarker • Clinical • IO biomarker • PD(L)-1 Biomarker • Follicular Lymphoma • Indolent Lymphoma

Phase 1b/2a Trial to Evaluate LEP-F1 + GLA-SE in Healthy Adults and Leprosy Patients (clinicaltrials.gov) - P1b/2a; N=54; Not yet recruiting; Sponsor: The Immunobiological Technology Institute (Bio-Manguinhos) / Oswaldo Cruz Foundation (Fiocruz); Trial completion date: Jun 2021 ➔ Sep 2024; Trial primary completion date: Jun 2021 ➔ Apr 2022

Clinical • Trial completion date • Trial primary completion date

A Clinical Trial in Healthy, HIV-1-Uninfected Adult Participants to Compare the Safety, Tolerability and Immunogenicity of CH505TF gp120 Produced From Stably Transfected Cells to CH505TF gp120 Produced From Transiently Transfected Cells (clinicaltrials.gov) - P1; N=30; Active, not recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Trial completion date: Mar 2021 ➔ Nov 2021; Trial primary completion date: Sep 2020 ➔ Mar 2021

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

Evaluating the Safety and Immunogenicity of Polyvalent DNA/gp120 HIV Vaccine in Healthy, HIV-uninfected Adults (clinicaltrials.gov) - P1; N=42; Recruiting; Sponsor: Worcester HIV Vaccine; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Human Immunodeficiency Virus • Infectious Disease • CD4 • PCR

Evaluating the Safety and Immunogenicity of Polyvalent DNA/gp120 HIV Vaccine in Healthy, HIV-uninfected Adults (clinicaltrials.gov) - P1; N=42; Not yet recruiting; Sponsor: Worcester HIV Vaccine

New P1 trial • Human Immunodeficiency Virus • Infectious Disease • CD4 • PCR

Evaluating the Safety and Immunogenicity of EnvSeq-1 and CH505 M5 gp120 Envs Adjuvanted With GLA-SE in Healthy, HIV-Uninfected Adults (clinicaltrials.gov) - P1; N=107; Recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Active, not recruiting ➔ Recruiting

Clinical • Enrollment open • Human Immunodeficiency Virus • Infectious Disease • CD4 • PCR

PEMBROSARC: Combination of MK3475 and Metronomic Cyclophosphamide in Patients With Advanced Sarcomas : Multicentre Phase II Trial (clinicaltrials.gov) - P2; N=227; Active, not recruiting; Sponsor: Institut Bergonié; Recruiting ➔ Active, not recruiting; Trial completion date: Jun 2023 ➔ Aug 2021; Trial primary completion date: Jan 2022 ➔ Nov 2020

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Oncology • Sarcoma • Solid Tumor • CD8 • IL2

Subunit vaccine protects against a clinical isolate of Mycobacterium avium in wild type and immunocompromised mouse models. (PubMed, Sci Rep) - "Due to this quietly emerging health threat, we evaluated the ability of a recombinant fusion protein ID91 combined with GLA-SE [glucopyranosyl lipid adjuvant, a toll like receptor 4 agonist formulated in an oil-in-water stable nano-emulsion] to confer protection in both C57BL/6 (wild type) and Beige (immunocompromised) mouse models...Importantly, both ID91 + GLA-SE and BCG vaccines significantly reduced pulmonary bacterial burden in both mouse strains. This work is a proof-of-concept study of subunit vaccine-induced protection against NTM."

Journal • Preclinical • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • TLR4

Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen. (PubMed, NPJ Vaccines) - "We then established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ effectively immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity, underscoring UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts."

Clinical • Journal • Infectious Disease • Malaria

Polymeric Pathogen-Like Particles-Based Combination Adjuvants Elicit Potent Mucosal T Cell Immunity to Influenza A Virus. (PubMed, Front Immunol) - "We generated micro particle PLPs loaded with TLR4 (glucopyranosyl lipid adjuvant, GLA) or TLR9 (CpG) agonists, and formulated them with and without a mucosal delivery enhancing carbomer-based nanoemulsion adjuvant (ADJ)...Further, balanced CD8 (Tc1/Tc17) and CD4 (Th1/Th17) recall responses were linked to effective influenza virus control. These studies provide mechanistic insights into vaccine-induced pulmonary T cell immunity and pave the way for the development of a universal influenza and SARS-CoV-2 vaccines."

Clinical • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CD4 • CD8 • TLR4