motolimod (VTX 2337) / Pfizer, BMS - LARVOL DELTA

Development of enhanced extracellular vesicle-based canine osteosarcoma cancer vaccines via metabolic labeling and click chemistry approach (AACR 2025) - "For the conjugation with EVs, a panel of toll-like receptor (TLR) agonists was selected, comprising imiquimod (TLR7 agonist), motolimod (TLR8 agonist), CpG oligodeoxynucleotides (TLR9 agonist), and polyinosinic:polycytidylic acid (poly(I:C), TLR3 agonist).Results and The selected TLR agonists were successfully conjugated with EVs. The selected TLR agonists were successfully conjugated with EVs. Notably, EVs conjugated with imiquimod demonstrated significantly enhanced activation of moDCs compared to EVs alone, imiquimod alone, or a simple mixture of EVs and imiquimod. These findings suggest that the conjugation of TLR agonists, particularly imiquimod, with EVs may potentiate the immunostimulatory effects on moDCs."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD14 • CSF2 • IL4 • TLR8

Iterative selection of lipid nanoparticle vaccine adjuvants for rapid elicitation of tumoricidal CD8⁺ T cells. (PubMed, Bioact Mater) - "Additional rounds of in vivo screening identified complementary adjuvants which targeted TLR4 (3D6A-PHAD adjuvant), TLR8 (motolimod), and inflammasome (QS-21) pathways and synergized to enhance cytokine secretion in antigen presenting cells and vaccine-elicited neoantigen-specific CD8⁺ T cells. Co-delivery of adjuvants and antigens led to effective immune responses which regressed large established tumors, synergized with immune checkpoint blockade, and inhibited lung nodules in an experimental metastasis model, without overt toxicity or reactogenicity. We conclude that iterative adjuvant screening, performed in mice in vivo, can identify useful adjuvant combinations that hold potential for therapeutic cancer vaccine research."

Journal • Oncology • Solid Tumor • TLR2 • TLR4 • TLR8

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis. (PubMed, Rheumatology (Oxford)) - "TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis."

Journal • Dermatitis • Fibrosis • Immunology • Inflammation • Scleroderma • Systemic Sclerosis • IL1B • IL6 • TLR8

Integrative multiomics analysis of poor risk AML rationalizes differential drug responses in cases with mature and primitive molecular landscapes (EACR 2023) - "Classification of AML cases into primitive (n=12) and mature (n=10) revealed that primitive cells were more sensitive to 22 compounds including azacitidine and navitoclax. In contrast, mature cells were preferentially sensitive to 17 compounds including the MLC1 inhibitor A-1210477, the TLR8 agonist motolimod, the ROS inducer auranofin and 4 IAPs inhibitors...Mature cells increased the phosphorylation of stress response proteins like ASK1, P38A, JNK1 at and ATF7 at regulatory sites, but were more resistant to the P38 and JNK inhibitors ralimetinib and tanzisertib, respectively.ConclusionThe higher activity of the stress response pathway in mature cells could be the reason for their higher sensitivity to compounds that either induce (Auranofin) or modulate (IAPs inhibitors) the stress response. Overall, our integrative analysis is a rich source of molecular information to rationalize specific drug sensitivities of poor risk AML cases with mature and primitive phenotypes...."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • MAPK8 • TLR8

TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia. (PubMed, Biomed Pharmacother) - "In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AMPK • CASP3 • STK11 • TLR8

A Study to Evaluate Immune Biomarker Modulation in Response to VTX-2337 in Combination With an Anti- PD-1 Inhibitor in Head and Neck Cancer (clinicaltrials.gov) - P1b | N=15 | Terminated | Sponsor: Celgene | Completed ➔ Terminated; Business objectives have changed

Biomarker • Combination therapy • Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Identification of new potent agonists for toll-like receptor 8 by virtual screening methods, molecular dynamics simulation, and MM-GBSA. (PubMed, J Biomol Struct Dyn) - "Previous studies have shown that TLR8 agonists e.g. Motolimod can be used to treat patients with last-stage cancer...As the RMSD results showed that compound A has very good flexibility, in terms of energy calculated using the MM-GBSA method, complex B and TLR8 showed the lowest energy level compared to the rest of the complexes. These observations suggest that these two compounds could be used as TLR8 agonists with the desired pharmacological features in future experimental studies.Communicated by Ramaswamy H. Sarma."

Journal • Oncology • TLR8

Ginsenoside Rh2 Ameliorates Neuropathic Pain by inhibition of the miRNA21-TLR8-MAPK axis. (PubMed, Mol Pain) - "Finally, intrathecal injection of TLR8 agonist VTX-2337 reversed the analgesic effect of Rh2. These results indicated that Rh2 relieved SNI-induced neuropathic pain via inhibiting the miRNA-21-TLR8-MAPK signaling pathway, thus providing a potential application of Rh2 in pain therapy."

IO biomarker • Journal • Neuralgia • Oncology • Pain • IL6 • MIR21 • TLR8 • TNFA

Generation of humanized TLR8 mice for the evaluation of human TLR8 agonists (AACR 2022) - "TLR8 agonists (e.g. VTX-2337) are undergoing clinical trials as immune stimulants in combination therapy for some cancers...We observed TNFα secretion in B-hTLR8 mice but not in wild-type mice. Therefore, B-hTLR8 mouse model is a promising model for preclinical in vivo studies to evaluate TLR8 agonists and antibody-conjugated TLR8 agonists."

Preclinical • Oncology • MYD88 • TLR7 • TLR8 • TNFA

Intratumoral Microdosing of Motolimod in HNSCC (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: Presage Biosciences | N=12 ➔ 1 | Recruiting ➔ Terminated; Partner Termination

Combination therapy • Enrollment change • Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CASP3 • CD163 • CD68 • CD8 • CD86 • GZMB • NCAM1

A Study to Evaluate Immune Biomarker Modulation in Response to VTX-2337 in Combination With an Anti- PD-1 Inhibitor in Head and Neck Cancer (clinicaltrials.gov) - P1b | N=15 | Completed | Sponsor: Celgene | Recruiting ➔ Completed | N=72 ➔ 15 | Trial completion date: Aug 2022 ➔ Jan 2022 | Trial primary completion date: May 2022 ➔ Jan 2022

Biomarker • Combination therapy • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

DTX@VTX NPs synergy PD-L1 immune checkpoint nanoinhibitor to reshape immunosuppressive tumor microenvironment for enhancing chemo-immunotherapy. (PubMed, J Mater Chem B) - "The core-shell small-molecule nanomedicine DTX@VTX NP (DTX: Docetaxel and VTX: VTX-2337 or Motolimod) was used to reverse immunosuppressed TME through the depletion of myeloid-derived suppressor cells (MDSCs) and the polarization of macrophages from an M2-like phenotype to M1-like phenotype. Combining BMS-1 NPs with DTX@VTX NPs, synergistic chemo-immunotherapy of 4T1 tumors was performed, and the results indicate that the inhibition rates of primary and rechallenge tumors achieved 90.5% and 94.3%, respectively. These results indicate that DTX@VTX NPs can synergize PD-L1 nanoinhibitor BMS-1 NPs to reshape the immunosuppressive tumor microenvironment for enhancing the anti-tumor effect of chemo-immunotherapy for breast."

Biomarker • Journal • Tumor microenvironment • Immune Modulation • Inflammation • Oncology • Solid Tumor • CD8

Phase 1/2 Study of Motolimod, Doxorubicin, and Durvalumab in Recurrent, Platinum-Resistant Ovarian Cancer (clinicaltrials.gov) - P1/2; N=53; Completed; Sponsor: Ludwig Institute for Cancer Research; Active, not recruiting ➔ Completed

Clinical • Trial completion • Oncology • Ovarian Cancer • Solid Tumor

Intratumoral Microdosing of Motolimod in HNSCC (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Presage Biosciences; Trial completion date: Aug 2021 ➔ Mar 2022; Trial primary completion date: Aug 2021 ➔ Dec 2021

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CASP3 • CD163 • CD68 • CD8 • CD86 • GZMB • NCAM1

Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists. (PubMed, Pharmacol Res) - "The phenomena of pattern-recognition receptor tolerance and reprogramming and their implications for immunotherapy are discussed. Finally, novel delivery systems that target the immune-stimulating drugs to the tumor or the tumor-draining lymph nodes to enhance their efficacy and safety are presented."

Journal • Review • Immune Modulation • Inflammation • Oncology

Phase 1/2 Study of Motolimod, Doxorubicin, and Durvalumab in Recurrent, Platinum-Resistant Ovarian Cancer (clinicaltrials.gov) - P1/2; N=53; Active, not recruiting; Sponsor: Ludwig Institute for Cancer Research; Trial completion date: Jun 2020 ➔ Jun 2021

Clinical • Trial completion date • Oncology • Ovarian Cancer • Solid Tumor

Intratumoral Microdosing of Motolimod in HNSCC (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Presage Biosciences; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CASP3 • CD163 • CD68 • CD8 • GZMB • NCAM1

A Study to Evaluate Immune Biomarker Modulation in Response to VTX-2337 in Combination With an Anti- PD-1 Inhibitor in Head and Neck Cancer (clinicaltrials.gov) - P1b; N=72; Recruiting; Sponsor: Celgene; Trial primary completion date: Dec 2020 ➔ May 2022

Biomarker • Clinical • Combination therapy • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent. (PubMed, Sci Rep) - "Depletion of CD4+ T cells, CD8+ T cells and NK cells were all able to abolish the anti-tumor effect of VTX-2337+ cetuximab. Altogether, VTX-2337 remains promising as an adjuvant for cetuximab-based therapy however patients with high TLR8 expression may be more likely to derive benefit from this drug combination compared to patients with low TLR8 expression."

Combination therapy • IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • EGFR • IFNG • TLR8

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice. (PubMed, Neurosci Bull) - "Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity...These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP."

IO biomarker • Journal • Immunology • Inflammation • Neuralgia • Pain • Peripheral Neuropathic Pain

Preclinical study of a novel TLR8 selective agonist for cancer immunotherapy (AACR 2018) - "Recent reports of motolimods clinical data indicated that ISR was strongly correlated with substantial survival benefit in cancer patients whereas there was no survival benefit when motolimod failed to induce ISR. Therefore, DN-A1 holds great potential as the best-in-class TLR8 selective immunotherapeutic drug candidate poised for human clinical trials."

Preclinical • Leukemia

A concise review of bioanalytical methods of small molecule immuno-oncology drugs in cancer therapy. (PubMed, Biomed Chromatogr) - "The bioanalytical methods reported for each drug were briefly discussed and tabulated for easy access. Our review indicates that LC-MS/MS is a versatile and reliable tool for the sensitive, rapid and robust quantitation of IO drugs."

Journal • Oncology

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications. (PubMed, Oncoimmunology) - "Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines. Here, we summarize preclinical and clinical evidence recently collected to support the development of resiquimod and motolimod and other TLR7/TLR8 agonists as anticancer agents."

Journal • Review • Actinic Keratosis • Dermatology • Immune Modulation • Inflammation • Oncology

A Study to Evaluate Immune Biomarker Modulation in Response to VTX-2337 in Combination With an Anti- PD-1 Inhibitor in Head and Neck Cancer (clinicaltrials.gov) - P1b; N=72; Recruiting; Sponsor: Celgene; Trial completion date: Jan 2021 ➔ Aug 2022

Trial completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Celgene: Preliminary FY 2015 Results (Celgene) - Anticipated data from P2 trial (NCT01836029) of motolimod + cetuximab for head and neck cancer in 2016

Anticipated P2 data • Biosimilar • Head and Neck Cancer • Oncology