telratolimod (MEDI9197) / Bausch Health, AstraZeneca - LARVOL DELTA

Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies (AACR 2018) - P1; "We further demonstrate in vitro that combining MEDI9197 with durvalumab (anti-PD-L1) augments cytokine production (e.g. IL-2, IFN-) in a co-culture of human DCs and allogenic T cells. These data showcase MEDI9197 as a potent modulator of the innate and adaptive immune system in the fight against cancer and support the rationale for evaluating MEDI9197 in combination with checkpoint blockade and costimulatory agonists in the clinic. MEDI9197 is currently being evaluated in human clinical trials for safety and efficacy ."

Biomarker • IO biomarker • PD(L)-1 Biomarker • Tumor microenvironment • Oncology

Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment and holds potential for combination with immune checkpoint inhibitors (AACR 2017) - P1; "These preclinical data demonstrate that MEDI9197 can modulate both the myeloid and lymphoid immune compartments to mediate anti-tumor activity and combines productively with immune checkpoint blockade. MEDI9197 is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials (NCT02556463)."

Checkpoint inhibition • Biosimilar • Oncology

Adipocytes Encapsulating Telratolimod Recruit and Polarize Tumor-Associated Macrophages for Cancer Immunotherapy. (PubMed, Adv Sci (Weinh)) - "Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8 T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes."

Journal • Melanoma • Oncology • Solid Tumor

Safety and pharmacodynamic activity of MEDI9197, a TLR 7/8 agonist, administered intratumorally in subjects with solid tumors (AACR 2017) - P1; "Analysis of whole blood microarray data demonstrated increases (>2 fold) in TH1 and Type 1 IFN gene expression signatures with a transient decrease (>2 fold) in CD8A transcript expression suggesting trafficking of T cells in at least 4/6 pts treated with 0.037 mg of MEDI9197. In conclusion, IT administration of MEDI9197 was feasible and had AEs as well as local and systemic PD effects consistent with its expected mechanism of action."

P1 data • Biosimilar • Immunology • Oncology • Pain

Co-immunomodulation of tumor and tumor-draining lymph node during in situ vaccination promotes antitumor immunity. (PubMed, JCI Insight) - "The peritumoral delivery of micellar MEDI9197 (mcMEDI), a toll-like receptor 7/8 agonist, induced significantly stronger innate and adaptive immune responses than those on conventional dosing...The combination of local mcMEDI therapy significantly improved the efficacy of systemic anti-programmed death receptor-1 therapy. These data suggest that rerouting adjuvants to tumors and TDLNs can augment the therapeutic efficacy of in situ vaccination."

Journal • Immune Modulation • Immunology • Inflammation • Oncology

An injectable superior depot of Telratolimod inhibits post-surgical tumor recurrence and distant metastases. (PubMed, Acta Biomater) - "In the long-lasting treatment, the melanoma and breast cancer immunotherapeutic effect significantly enhanced and the risk of cancer metastasis and relapse was reduced. Crucially, for some immune agonists, a superior release control can significantly reduce adverse effects which was decisive for the availability of the drugs."

Journal • Breast Cancer • Inflammation • Melanoma • Oncology • Solid Tumor

Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses. (PubMed, Nature) - "Here, we show that macaque immunization with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052/Alum elicited cross-neutralizing antibody (cross-nAb) responses against batCoVs, SARS-CoV-1, SARS-CoV-2, and SARS-CoV-2 variants B.1.1.7, P.1, and B.1.351...Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD also induced SARS-CoV-1 and batCoV cross-nAbs, albeit at lower titers. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV vaccines."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

[VIRTUAL] 3M’s immune response modifiers: Discovery and development of small molecules that activate the immune system (ACS-Sp 2021) - "3M’s Immune Response Modifiers (IRMs) are small molecules that trigger an immune response by activating Toll-like receptors (TLRs). This talk will cover the history of IRM development by former 3M Pharmaceuticals and Drug Delivery Systems Divisions highlighting recent studies sponsored by 3M Corporate Research Laboratory involving the TLR 7/8 agonist 3M-052 as a vaccine adjuvant."

[VIRTUAL] SARS-CoV-2 VACCINES INDUCE DURABLE NEUTRALIZING ANTIBODIES IN INFANT RHESUS MACAQUES (CROI 2021) - "The S-2P-3M-052-SE and mRNA-LNP vaccines were well-tolerated and highly immunogenic in infant Rhesus Macaques, with persistent IgG binding and neutralization responses that are comparable to those reported for adult RMs and humans. Our results provide proof-of-concept that a pediatric SARS-CoV-2 vaccine could induce long term protection against SARS-CoV-2."

Late-breaking abstract • Infectious Disease • Novel Coronavirus Disease • Pediatrics • Respiratory Diseases • CD27 • CD4 • IFNG • IL17A • IL2 • TNFA

[VIRTUAL] Induction of neutralization breadth and broadly neutralizing antibody lineage responses in HIV envelope BG505 SOSIP immunized infant macaques (HIVR4P 2021) - "Therefore, the goal of our study was to assess the ability of a B cell lineage-designed HIV Env trimer to induce bnAb lineages in early life. Infant rhesus macaques (RMs) received 50mg of either the BG505 wild type (WT) or germline-targeting (GT1.1) SOSIP trimer (n=5/group) with the 3M-052-SE adjuvant at 0, 6, and 12 weeks of age... A multi-dose immunization regimen in infants with bnAb lineage designed SOSIP trimers is a promising strategy for inducing protective HIV bnAb responses in childhood prior to adolescence, when sexual HIV exposure risk begins."

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

New GMP manufacturing processes to obtain thermostable HIV-1 gp41 virosomes under solid forms for various mucosal vaccination routes. (PubMed, NPJ Vaccines) - "The HIV-1 gp41-derived antigens anchored in the virosome membrane, along with the adjuvant 3M-052 (TLR7/8 agonist) on the same particle, served as a candidate vaccine for the proof of concept for establishing manufacturing processes, which can be directly applied or adapted to other virosomal vaccines or lipid-based particles...Virosome integrity was also preserved during exposure to <-15 °C, mimicking accidental freezing conditions. These "ready to use and all-in-one" thermostable needle-free virosomal HIV-1 mucosal vaccines offer the advantage of simplified logistics with a lower dependence on the cold chain during shipments and distribution."

Journal • Human Immunodeficiency Virus • Infectious Disease • Respiratory Diseases

A TLR7/8 Agonist-Including DOEPC-Based Cationic Liposome Formulation Mediates Its Adjuvanticity Through the Sustained Recruitment of Highly Activated Monocytes in a Type I IFN-Independent but NF-κB-Dependent Manner. (PubMed, Front Immunol) - "We find here that the incorporation of the synthetic TLR7/8 ligand 3M-052 in a cationic DOEPC-based liposome formulation shifts immunity toward T1 responses and elicits strong and long-lasting germinal center and follicular T helper cell responses in adult mice...We further show that this adjuvanticity is independent of type I IFN but NF-κB-dependent. Overall, our data identify TLR7/8 agonists incorporated in liposomes as promising and effective adjuvants to enhance T1 and germinal center responses."

Clinical • Journal

Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors. (PubMed, J Immunother Cancer) - P1 | "IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations."

Clinical • Combination therapy • IO Biomarker • Journal • Fatigue • Hematological Disorders • Liver Cancer • Oncology • Solid Tumor

Intratumoral administration of the Toll-like receptor 7/8 agonist 3M-052 enhances interferon-driven tumor immunogenicity and suppresses metastatic spread in preclinical triple-negative breast cancer. (PubMed, Clin Transl Immunology) - "3M-052 action was demonstrated via dendritic cell activation and production of type I IFN and other pro-inflammatory cytokines to initiate a T-cell-inflamed TME and promote tumor cell antigen presentation. This work supports neoadjuvant TLR agonist-based immunotherapeutics as realistic options for immune activation in the TME and long-term metastatic protection in TNBC."

Journal • Preclinical • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • IFNAR1

Effects of cationic adjuvant formulation particle type, fluidity and immunomodulators on delivery and immunogenicity of saRNA. (PubMed, J Control Release) - "We tested both liposomal and emulsion based CAFs with solid and fluid phase lipids, with or without the TLR agonists R848 and 3M-052, for in vitro transfection efficiency and cytotoxicity...MOMP-encoding saRNA complexed with CAFs resulted in both MOMP-specific cellular and humoral immunity, and while there was a slight enhancement of IFN-γ T-cell responses when R848 was incorporated into the formulation, the self-adjuvanting effects of RNA appeared to dominate the immune response. These studies establish that CAFs are efficient delivery vehicles for saRNA both for in vitro transfections and in vivo immunogenicity and generate cellular and humoral responses that are proportionate to protein expression."

Clinical • Journal • Immune Modulation • Inflammation

Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies. (PubMed, J Immunother Cancer) - "Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists."

Biomarker • Journal • Tumor microenvironment • Immune Modulation • Inflammation • Oncology

[VIRTUAL] Intradermal MVA vaccinations provide superior protection compared to intramuscular MVA vaccinations against a homologous tier 2 SHIV challenge (AIDS 2020) - "Soluble BG505-SOSIP.664 trimer protein plus 3M-052 adjuvant encapsulated in nanoparticles was used as a protein boost... Both groups (ID and IM) showed strong binding antibody response to BG505-SOSIP.664 gp140 in serum/vaginal secretions, and some animals generated autologous neutralizing antibody response against BG505.664 Env but these were comparable between the groups... These results demonstrate that MVA-ID vaccination is superior to MVA-IM vaccination for protection against HIV and the route of MVA vaccination markedly influences the quality of T helper response and innate activation that are associated with difference in protection outcome."

Infectious Disease • CD14 • CD8 • IFNG

[VIRTUAL] HIV envelope BG505 SOSIP immunization induces autologous virus and CD4 binding site-specific B cell lineage antibody precursor responses in infant rhesus macaques (AIDS 2020) - " Infant rhesus macaques (RMs) received 50mg of either the BG505 wild type (WT) SOSIP trimer or the BG505 germline-targeting (GT1.1) SOSIP trimer (n=5/group) with the 3M-052-SE adjuvant at 0, 6, and 12 weeks of age... A multi-dose immunization regimen in infants with a B cell lineage designed SOSIP trimer is a promising strategy for inducing HIV bnAbs throughout childhood to elicit protective HIV immunity prior to adolescence, when sexual HIV exposure risk begins."

Late-breaking abstract • Preclinical • Gene Therapies • Infectious Disease • Pediatrics

3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates. (PubMed, Sci Immunol) - "Adjuvanting Env with 3M-052 also induced robust activation of blood monocytes, strong plasmablast responses in blood, germinal center B cells, T follicular helper (T) cells, and persistent Env-specific plasma cells in draining lymph nodes. Overall, these results demonstrate efficacy of 3M-052 in promoting high magnitude and durability of antibody responses via robust stimulation of innate immunity and BM-resident LLPCs."

Journal • Gene Therapies • Infectious Disease • TLR4

AstraZeneca: Q3 FY 2016 Results (AstraZeneca) - Anticipated completion of enrollment in P1 trial (NCT02556463) for solid tumor in 2017; Anticipated top-line results from P1 trial for solid tumor in 2018

Anticipated enrollment status • Anticipated P1 data • Oncology

New GMP manufacturing processes to obtain thermostable HIV-1 gp41 virosomes under solid forms for various mucosal vaccination routes. (PubMed, NPJ Vaccines) - "The HIV-1 gp41-derived antigens anchored in the virosome membrane, along with the adjuvant 3M-052 (TLR7/8 agonist) on the same particle, served as a candidate vaccine for the proof of concept for establishing manufacturing processes, which can be directly applied or adapted to other virosomal vaccines or lipid-based particles...Virosome integrity was also preserved during exposure to <-15 °C, mimicking accidental freezing conditions. These "ready to use and all-in-one" thermostable needle-free virosomal HIV-1 mucosal vaccines offer the advantage of simplified logistics with a lower dependence on the cold chain during shipments and distribution."

Journal • Gene Therapies • Infectious Disease

Neonatal vaccination primes persistent HIV Env-specific antibodies that are augmented by a single booster immunization in late infancy (IMMUNOLOGY 2020) - "Two groups of neonatal rhesus macaques were immunized with a clade C HIV Env protein adjuvanted with 3M-052 stable emulsion (SE) vaccine (Env Only) alone or together with a modified vaccinia Ankara (MVA) vector expressing HIV Env and SIV Gag (MVA/Env) at 0, 6, and 12 weeks of age...Our data from the Env Only vaccine regimen are consistent with the induction of Env-specific antibody responses in human infants. These results support the idea that early life vaccination is an effective means to induce persistent HIV Env-specific IgG responses that can be boosted in infancy and could be exploited to drive protective immunity against HIV acquisition prior to sexual debut."

Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques. (PubMed, JCI Insight) - "To test this hypothesis, we immunized 3 groups of nonhuman primates: (a) Group 1, which includes sequential immunization regimen involving heterologous viral vectors (HVVs) comprising vesicular stomatitis virus, vaccinia virus, and adenovirus serotype 5-expressing SIVmac239 Gag; (b) Group 2, which includes immunization with a clade C HIV-1 envelope (Env) gp140 protein adjuvanted with nanoparticles containing a TLR7/8 agonist (3M-052); and (c) Group 3, which includes a combination of both regimens...This protection correlated with the magnitude of the serum and vaginal Env-specific antibody titers on the day of challenge. Thus, vaccination strategies that induce both CD8+ T cell and antibody responses can confer enhanced protection against infection."

Journal

Evaluating the Safety and Immunogenicity of HIV-1 BG505 SOSIP.664 gp140 With TLR Agonist and/or Alum Adjuvants in Healthy, HIV-uninfected Adults (clinicaltrials.gov) - P1; N=105; Recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Active, not recruiting ➔ Recruiting

Clinical • Enrollment open

Evaluating the Safety and Immunogenicity of HIV-1 BG505 SOSIP.664 gp140 With TLR Agonist and/or Alum Adjuvants in Healthy, HIV-uninfected Adults (clinicaltrials.gov) - P1; N=105; Active, not recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed