urelumab (BMS-663513) / BMS, Ono Pharma - LARVOL DELTA

Rationale and feasibility of a rapid integral biomarker program that informs immune-oncology clinical trials: the ADVISE trial. (PubMed, J Immunother Cancer) - P1 | "Actualization of a patient-specific I-O combination treatment selection strategy is feasible, however, determination of de novo integral biomarker thresholds of novel I-O targets to facilitate effective treatment of PD-1-refractory cancer remains fraught. These data emphasize the difficulty of integral biomarker development for I-O in translating from immunotherapy treatment-naïve biospecimens to the selection of patients in the PD-1-refractory state."

Biomarker • IO biomarker • Journal • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • CD8 • CSF1R • FOXP3 • IDO1 • LAG3 • PD-L1 • TNFA

PF-08046049 synergizes with checkpoint inhibitors to drive CD8+ T cell effector differentiation and tumor clearance in an IO-resistant model (AACR 2025) - "Additionally, while the combination therapy of anti-CTLA-4 and anti-PD-1 (Ipilimumab-Nivolumab) improves response rate and overall survival compared to monotherapies, it also leads to increased toxicity and immune-related adverse events...However, nontargeted 4-1BB signaling poses a risk of widespread peripheral immune activation and liver toxicity, as was the case for the 4-1BB agonist Urelumab...We found that while anti-PD-1 and anti-CTLA-4 can target and expand stem-like CD8+ T cells in both the tumor-draining lymph node and TME, BB228 is able to drive the differentiation of those stem-like cells into effectors, resulting in tumor killing. These data illustrate that BB228 has a distinct and complementary mechanism of action from the current melanoma SOC treatments."

Checkpoint inhibition • Melanoma • Oncology • Solid Tumor • CD8 • MELTF • MELTF

Anti-VEGF x 4-1BB bifunctional AND-Body combines VEGF blockade and allosteric 4-1BB mechanism for sustained activation of adaptive and innate anti-tumor immunity (AACR 2025) - "This represents a new approach to bifunctional cancer therapeutics. The VEGF x 4-1BB bifunctional was evaluated in humanized 4-1BB transgenic mice harboring MC38 or B16F10 tumors and compared to aflibercept and urelumab... Anti-VEGF x 4-1BB AND-Body represents a novel bifunctional agent, combining established benefits of VEGF blockade with an allosteric 4-1BB agonist. Potent anti-tumor activity with high therapeutic index was achieved in preclinical models by localizing immune responses via a unique mechanism of action. These studies support advancement to the clinic as a potentially first-in-class candidate for cancer immunotherapy, both as a monotherapy and in combinations."

Oncology

Multabodies: A next-generation approach for cancer immunotherapy and 4-1BB agonist therapy (AACR 2025) - "However clinical development has been hindered by severe liver toxicity (i.e., urelumab), or insufficient single agent activity, as seen with utomilumab. Furthermore, RBT101 also provided long-term protection in a tumor rechallenge study, suggesting generation of a durable immunological memory response driven by RBT101. These data suggest the Multabody™ platform provides a novel approach to delivering a 4-1BB therapeutic with a differentiated profile to address an unmet clinical need in cancer immunotherapy for patients with solid malignancies."

Oncology • Solid Tumor • TNFRSF9

Platform Study of Neoadjuvant and Adjuvant Immunotherapy for Patients With Resectable Adenocarcinoma of the Pancreas (clinicaltrials.gov) - P2 | N=76 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Aug 2026 ➔ May 2026

IO biomarker • Trial completion date • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Development of a tumor-region-selective activation monoclonal antibody targeting the 4-1BB receptor for enhanced therapeutic efficacy and safety. (PubMed, Int J Biol Macromol) - "Additionally, Pro-Urelumab achieved 77 % tumor growth inhibition (TGI), compared to 45 % with Urelumab, and significantly increased T cell activation within the tumor. This study underscores the potential of tumor-selective 4-1BB activation for enhancing both the efficacy and safety of immuno-oncology therapies."

Journal • Hepatology • Oncology • CD8 • MMP2 • MMP9

Platform Study of Neoadjuvant and Adjuvant Immunotherapy for Patients With Resectable Adenocarcinoma of the Pancreas (clinicaltrials.gov) - P2 | N=76 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2025 ➔ Aug 2026 | Trial primary completion date: Dec 2024 ➔ Aug 2025

IO biomarker • Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD8 • GZMB • IL17A • PD-1 • TNFRSF9

Use of 4–1BB agonist (Urelumab) during TIL pre-REP promotes tumor-reactive like T cells (SITC 2024) - "ID of the aproval: CEI-0026-20. The participans gave informed consent before taking part of the study."

IO biomarker • Lung Cancer • Melanoma • Oncology • Solid Tumor • CCR7 • CD69 • CD8 • ENTPD1 • IFNG • IL2 • ITGAE • PD-1 • TNFA

A CD8 T Cell Radiomics Score Correlates with Local Failure in Patients Undergoing Combined SBRT and Immune Checkpoint Inhibition in a Pooled Analysis of Three Phase I Trials (ASTRO 2024) - "ICI agents included pembrolizumab or nivolumab combined with either ipilimumab, cabiralizumab, or urelumab. Our results support the prognostic utility of this CD8 T cell RS in patients undergoing SBRT+ICI. Future work will investigate using the RS for treatment selection in patients with advanced solid tumors."

Checkpoint inhibition • IO biomarker • P1 data • Retrospective data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8

Local and Marginal Failures in Spinal and Non-Spinal Osseous Metastases Receiving SBRT and Immunotherapy: A Secondary Analysis of Phase I Trials (ASTRO 2024) - "Materials/ Between 2016 and 2020, patients with widely metastatic solid malignancies were treated on three phase I trials (n = 213) combining multi-site SBRT with immunotherapy (regimens included pembrolizumab, ipilimumab with nivolumab, urelumab with nivolumab, or cabiralizumab with nivolumab; administered concurrently or sequentially). In widely metastatic patients receiving immunotherapy, the rate of local failure was low and marginal failures were not observed after SBRT to bone metastases, even with 0mm CTV expansions for non-spine lesions. Both histology and lesion location were associated with local failure. These findings inform adequate target delineation for future trials utilizing SBRT to non-spine and spine bone metastases."

P1 data • Oncology • Solid Tumor

Safety of combined ablative radiotherapy and immune checkpoint inhibitors in three phase I trials. (PubMed, Eur J Cancer) - "This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints."

Checkpoint inhibition • Journal • P1 data • Oncology

Neoadjuvant Nivolumab With and Without Urelumab in Cisplatin-Ineligible or Chemotherapy-refusing Patients With Muscle-Invasive Urothelial Carcinoma of the Bladder (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Jul 2024 ➔ Jul 2025

Trial completion date • Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

THE RATIONALE OF REPROGRAMMING TREM2+ MACROPHAGES FOR OVERCOMING THE RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS IN PANCREATIC ADENOCARCINOMA (APCM 2024) - "We also examined the relationship between TREM2 expression and effector T cells in surgically resected human PDAC collected from a previous clinical trial treated with the neoadjuvant combination therapy of nivolumab(anti-PD-1 antibody), urelumab(antiCD137 agonist antibody), and the pancreatic cancer GVAX vaccine... Our study demonstrates the anti-tumor efficacy of anti-TREM2 antibody in combination with an immune checkpoint inhibitor in mouse PDAC. However, the analysis of human PDAC following neoadjuvant immunotherapy suggests that TREM2 on TAMs may be activated following the activation of effector T cells. Taken together, our results suggest that TREM2+ TAMs should be reprogrammed instead of being depleted in the design of anti-TREM2-based therapy for PDAC."

Checkpoint inhibition • IO biomarker • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • GZMB • TREM2

The rationale of reprogramming TREM2+ macrophages for overcoming the resistance to immune checkpoint inhibitors in pancreatic adenocarcinoma. (ASCO 2024) - "TREM2 was stained on slides which were previously obtained from surgically resected PDACs following the neoadjuvant combination treatment of nivolumab, urelumab, and GVAX and stained for multiple immune cell markers with a multiplex staining-striping immunohistochemistry (IHC) technique... Our study demonstrates the anti-tumor efficacy of anti-TREM2 antibody in combination with an immune checkpoint inhibitor in mouse PDAC. However, the analysis of human PDAC following neoadjuvant immunotherapy suggests that TREM2 on TAMs may be activated following the activation of effector T cells. Taken together, our results suggest that TREM2+ TAMs should be reprogrammed instead of being depleted in the design of anti-TREM2-based therapy for PDAC."

Checkpoint inhibition • IO biomarker • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD8 • GZMB • TREM2

CB307: A dual targeting costimulatory Humabody® VH therapeutic for treating PSMA-positive tumors (AACR 2024) - "The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumour toxicities. CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T cell activation thereby alleviating toxicological concerns against unrestricted CD137 agonism."

Colorectal Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

A novel anti-4-1BB antibody with no liver toxicity and its application in a bi-specific antibody (AACR 2024) - "However, the development of 4-1BB agonist antibodies has encountered challenges, with limited clinical efficacy (e.g., utomilumab) or dose-dependent liver toxicity (e.g., urelumab)...Furthermore, we've developed HLX34, a Her2x4-1BB bispecific antibody, derived from Trastuzumab and HLX25...These results provide evidence that our novel anti-4-1BB antibody activates proper 4-1BB signaling through tumor-enriched FcgRIIB or tumor-associated antigen-mediated clustering, inhibiting tumor growth with good safety in both in vitro and in vivo settings. This underscores HLX34 as a promising alternative therapeutic strategy for next-generation cancer immunotherapy."

Oncology • CD8 • HER-2 • TNFA • TNFRSF9

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors. (PubMed, Clin Cancer Res) - "The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism."

Journal • Colorectal Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors. (PubMed, J Immunother Cancer) - P1/2, P1b | "Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer."

Combination therapy • IO biomarker • Journal • Metastases • Colorectal Cancer • Dermatitis • Dermatology • Fatigue • Gastrointestinal Cancer • Head and Neck Cancer • Immunology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • CXCL9 • GZMB

Development of a c-MET x CD137 bispecific antibody for targeted immune agonism in cancer immunotherapy. (PubMed, Cancer Treat Res Commun) - "Overall, the c-MET x CD137 BsAb exhibits a promising developability profile as a tumor-targeted immune agonist by minimizing off-target effects while effectively delivering immune agonism. It has the potential to overcome resistance to anti-PD-(L)1 therapies."

Journal • Hepatology • Oncology • MET • TNFRSF9

Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. (PubMed, J Immunother Cancer) - P2 | "TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy."

Journal • Tumor-infiltrating lymphocyte • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Refractory Ovarian Cancer • Solid Tumor • CD8 • ENTPD1

Neoadjuvant Nivolumab With and Without Urelumab in Cisplatin-Ineligible or Chemotherapy-refusing Patients With Muscle-Invasive Urothelial Carcinoma of the Bladder (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

M9657 is a bispecific tumor-targeted anti-CD137 agonist that induces MSLN-dependent antitumor immunity without liver inflammation. (PubMed, Cancer Immunol Res) - "Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by FcγR ligand-dependent CD137 activation, respectively. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity."

IO biomarker • Journal • Hepatology • Oncology • CD8 • MSLN

Neoadjuvant Nivolumab With and Without Urelumab in Cisplatin-Ineligible or Chemotherapy-refusing Patients With Muscle-Invasive Urothelial Carcinoma of the Bladder (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Jul 2023 ➔ Jul 2024

Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

DECOSTARTM, a novel platform for TNF receptor superfamily agonism (SITC 2023) - "Background Immune checkpoint inhibitors (ICIs) such as Pembrolizumab and Atezolizumab have been approved as first-line treatment for some advanced solid tumors. When administered IT, DB202 more effectively inhibits the growth of subcutaneous (SQ) MC38 tumors in h4-1BB transgenic mice compared to Urelumab, without evidence of enhanced liver toxicity. Conclusions In summary, DECOSTAR TM can facilitate higher-order receptor clustering, potentially expanding the therapeutic window for agonist immunotherapy when compared to monoclonal antibodies."

IO biomarker • Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • TNFA

PBMC humanized mouse model with clinical relevance in assessing the safety profile of 4–1BB agonist, urelumab, in 5 donors (SITC 2023) - "Two 4–1BB agonists, urelumab and utomilumab, investigated in clinical trials showed different safety profiles. Furthermore, the differing toxicity profiles from the five PBMC donors illustrate the value of using PBMC humanized mouse models for preclinical safety assessments. Data from multiple PBMC donors can be used as a tool to evaluate how therapeutics will be tolerated in the greater population as well as used as a tool to assess individual patient responses."

Preclinical • Oncology • CCL4 • CXCL8 • IFNG • TNFA