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

Tumor-localized monoclonal antibody targeting 4-1BB for superior safety and efficacy in cancer treatment (AACR 2026) - "These findings demonstrate that tumor-localized 4-1BB activation can uncouple efficacy from systemic toxicity. Lock-Urelumab represents a next-generation immune checkpoint agonist with strong potential to revitalize 4-1BB-targeted immunotherapy and broaden its clinical applicability."

Clinical • Oncology • CD8

Agonistic CD137 (4-1BB) anchored immunotherapy (ANK-203) elicits potent 4-1BBL signaling in vitro and therapeutic responses against established tumors without systemic toxicity in vivo* (AACR-IO 2026) - "CD137 agonistic monoclonal antibodies (mAbs) demonstrated preclinical anti-tumor activity, but clinical trials with first-generation CD137 mAbs were limited by dose-dependent hepatotoxicity (urelumab) or lack of efficacy (utomilumab). ANK-203 is the first anchored immunotherapy using a fully humanized CD137 mAb. ANK-203 was associated with enhanced CD137 signaling in vitro and generated significant therapeutic activity in a bilateral MC38 tumor model without signs of systemic toxicity. Further studies to elucidate the impact on immune responses are in progress and ANK-203 may warrant further development for clinical investigation."

IO biomarker • Preclinical • Oncology • CD4 • CD8 • FAM20C • TNFRSF9

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

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. (PubMed, Nat Commun) - P2 | "We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively...GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study."

Combination therapy • IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD8 • IL17A • PD-1

Expanding the horizons of cancer therapy with next-generation 4-1BB agonists: a review of molecular and clinical strategies to maximize efficacy and ensure safety. (PubMed, MAbs) - "Driven by the substantial limitations of first generation 4-1BB agonists urelumab and utomilumab, the field has shifted toward engineering next-generation molecules with improved therapeutic windows. Furthermore, we discuss strong rationale for combination strategies, emphasizing how 4-1BB signaling provides the crucial costimulatory signal necessary to sustain durable anti-tumor responses. In summary, this review elucidates the scientific basis of antibody engineering aimed at improving safety and tumor-selective activation of 4-1BB agonists and outlines future directions for optimizing their clinical application in cancer immunotherapy."

Journal • Review • Oncology

Safety, feasibility and pharmacodynamic activity of intratumoral injections of the agonist anti-CD137 (4-1BB) mAb urelumab in combination with nivolumab. (PubMed, Clin Cancer Res) - P1/2 | "Intratumoral delivery of urelumab is feasible, safe, and induces favorable immunopharmacodynamic effects in serial biopsies and in peripheral blood. Our results support the development of tumor-targeted next-generation CD137 (4-1BB) agonists."

IO biomarker • Journal • PK/PD data • Oncology • Solid Tumor • CD8

Development of a nanoparticle-based immunotherapy targeting CD137 for nasopharyngeal carcinoma treatment. (PubMed, Theranostics) - "Urelumab and utomilumab, are two agonistic anti-CD137 antibodies that are most advanced in clinical trials but suffer from liver toxicity and low potency, respectively. In contrast to ure-MSNs, rhCD137-MSN treatment did not induce liver damage, thereby demonstrating a more favorable safety profile than ure-MSNs. This study identifies a formulation of rhCD137L on MSNs that combines high potency with excellent safety."

IO biomarker • Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • CD8 • TNFRSF9

Platform Study of Neoadjuvant and Adjuvant Immunotherapy for Patients With Resectable Adenocarcinoma of the Pancreas (clinicaltrials.gov) - P2 | N=76 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Oct 2025 ➔ May 2026

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

The Multabody: A Next-Generation Approach for Cancer Immunotherapy and 4-1BB Agonist Therapy (SITC 2025) - "Here we describe a novel MULTi-specific, multi-Affinity antiBODY platform, the Multabody™, that exploits multi-valency to deliver an innovative 4-1BB agonist with broad therapeutic potential.Methods To understand the impact of epitope on 4-1BB agonism, we generated a panel of 4-1BB Multabodies to comprehensively evaluate potency of these molecules in comparison to the historical 4-1BB agonist, urelumab...By using multivalent clustering to multimerize receptors in an Fc-independent manner, Multabodies enable precise and tunable agonism that more closely mimic natural ligand biology. Our findings demonstrate that Multabodies represent an innovative approach to receptor agonism—combining precision, tunability, and safety—and support their continued development as promising therapeutics in oncology and beyond."

IO biomarker • Oncology • TNFRSF9

A multi-cohort Phase 1-2 clinical trial shows safety, feasibility and pharmacodynamic activity of intratumoral injections of the agonist anti-CD137 (4-1BB) mAb urelumab in combination with nivolumab (SITC 2025) - P1/2 | "E-F) Microphotographs of CD8 and CD137 expression, and changes over time. G) Comparison of disease control and CD8 increases"

Clinical • Combination therapy • IO biomarker • P1/2 data • PK/PD data • Oncology • Solid Tumor • CD8

Phase-2 clinical trial testing intratumoral injections of the agonist anti-CD137 (4-1BB) mAb urelumab in combination with systemic nivolumab (CICON 2025) - P1/2 | "CONCLUSIONS Intratumoral delivery of urelumab is feasible and safe, and induces favorable immunopharmacodynamic effects in serial biopsies and in peripheral blood. Our results support the development of next generation CD137 (4-1BB) agonists in ongoing and future phase-2/3 clinical trials especially considering those with concomitant PD(L)1 blockade."

Clinical • Combination therapy • P2 data • Oncology • Solid Tumor

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 2025 ➔ Dec 2026 | Trial primary completion date: Jul 2025 ➔ Jul 2026

IO biomarker • Trial completion date • Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

Platform Study of Neoadjuvant and Adjuvant Immunotherapy for Patients With Resectable Adenocarcinoma of the Pancreas (clinicaltrials.gov) - P2 | N=76 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting ➔ Active, not recruiting

Enrollment closed • IO biomarker • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

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

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