varlilumab (CDX 1127) / Celldex - LARVOL DELTA

DIAL: Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas (clinicaltrials.gov) - P2 | N=54 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2025 ➔ Oct 2026

Trial completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Burkitt Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Hodgkin Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type • Primary Mediastinal Large B-Cell Lymphoma • T Cell Histiocyte Rich Large B Cell Lymphoma • ALK • BCL2 • BCL6 • IRF4

CD27 agonist antibodies mediate clinical responses through intratumoral stimulation in B-cell malignancies: multicenter RiVa trial. (PubMed, Clin Cancer Res) - "Rituximab and varlilumab show modest activity. However, CD27 agonist antibodies may elicit meaningful anti-tumor responses when tumors express sufficient intratumoral targets and exhibit existing immune priming."

Journal • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD27 • CD4

CRISPR/Cas9-Mediated Knockouts of the ALG3 and GNTI in N. benthamiana and Their Application to Pharmaceutical Production. (PubMed, Plant Biotechnol J) - "To validate our N-glycoengineering approach, we expressed two model biopharmaceuticals, Varlilumab (anti-CD27 antibody) and β-glucocerebrosidase (GCase), in wild-type and mutant plants. While the antibodies expressed in alg3 and alg3gntI showed a certain level of glucosylated endoplasmic reticulum-type N-glycan, with increased non-N-glycosylated heavy chains, GCase exhibited a more consistent N-glycosylation profile, reflecting the engineered N-glycosylation pathway. Our findings provide valuable insights into N-glycan biosynthesis in N. benthamiana and demonstrate the potential of targeted N-glycoengineering for producing biopharmaceuticals with more homogeneous mannose-type N-glycan profiles."

IO biomarker • Journal • CD27

Reversibility of Immune Dysfunction Following Pediatric Thermal Injury. (PubMed, J Burn Care Res) - "Our hypothesis was immune suppression after pediatric thermal injury is reversible ex-vivo using immunomodulators recombinant human granulocyte macrophage-colony stimulating factor (GM-CSF) and varlilumab (CD27-agonist)...Samples co-incubated with GM-CSF significantly increased ex-vivo LPS-induced TNFα while samples containing CD27 increased PHA-induced IL-10 production capacity, in the first 72 h, compared to samples that did not receive immunomodulators. The results of our study identified key markers to discover those most at risk for development of NI and provided early evidence of immunomodulators that may enhance immune function early after pediatric burn injury."

IO biomarker • Journal • Infectious Disease • Oncology • Pediatrics • Thermal Injury • CD14 • CD27 • CSF2 • IL10 • TNFA

ETCTN 10476: Testing A New Combination of Anti-cancer Immune Therapies, Atezolizumab and CDX-1127 (Varlilumab) With or Without the Addition of a Third Anti-cancer Drug, Cobimetinib, for Advanced-Stage Biliary Tract Cancer (clinicaltrials.gov) - P2 | N=57 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jul 2025 ➔ Apr 2026

Trial completion date • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Liver Cancer • Oncology • Solid Tumor

DERIVe: DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab (clinicaltrials.gov) - P2 | N=43 | Active, not recruiting | Sponsor: Annick Desjardins, MD | Trial completion date: Mar 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CCL3 • MGMT

RiVa: A Combination of Rituximab and Varlilumab Immunotherapy in Patients with B-cell Lymphoma (clinicaltrials.gov) - P1/2 | N=26 | Completed | Sponsor: University Hospital Southampton NHS Foundation Trust | Active, not recruiting ➔ Completed | Phase classification: P2a ➔ P1/2 | Trial completion date: Mar 2024 ➔ Aug 2024

Phase classification • Trial completion • Trial completion date • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

DIAL: Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas (clinicaltrials.gov) - P2 | N=54 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2024 ➔ Oct 2025

Combination therapy • IO biomarker • Trial completion date • Tumor mutational burden • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type • Primary Mediastinal Large B-Cell Lymphoma • T Cell Histiocyte Rich Large B Cell Lymphoma • ALK • BCL2 • BCL6 • CD27 • IRF4 • TMB

Evaluation of safety and immunogenicity of a melanoma vaccine, with or without a systemic agonistic CD27 antibody (CDX-1127), in patients with stage II-IV melanoma (SITC 2024) - P1/2 | "All received 6MHP vaccine (200 mcg each) emulsified in an incomplete Freund's adjuvant + polyICLC on days (d)1, 8, 15, 36, 57, 78 plus a booster (without pICLC) on d176. The other site (Virginia Commonwealth University) has a reliance agreement in place with their IRB. This trial was also performed under FDA review (IND # 10825) All participants give written informed consent before participating in the study.Download figure Open in new tab Download powerpoint Abstract 1468 Figure 1 T cell response boost analyzed by direct ELISpot assay after vaccine on week 25 by study Arm.Arm A: 6MHP vaccine + CDX-1127, Arm B: 6MHP onlyDownload figure Open in new tab Download powerpoint Abstract 1468 Figure 2 Mean regulatory T cell proportions & total lymphocyte counts.PBMCs from Arm A (blue, 6MHP vaccine + CDX-1127) and Arm B (orange, 6MHP vaccine only) were isolated and analyzed by flow cytometry for Tregs (CD4+CD25+FOXP3+)"

Clinical • Late-breaking abstract • Melanoma • Oncology • Solid Tumor • CD27 • CD4 • FOXP3 • IFNG • IL2RA

A Phase I Trial of Atezolizumab and Varlilumab in Combination With Radiation in Patients With Metastatic NSCLC. (PubMed, JTO Clin Res Rep) - P1 | "Varlilumab in combination with atezolizumab and RT was safe and well tolerated; no additional signal was identified for toxicity. Clinical activity for the combination was modest with 25% of patients with stable disease as the best response."

Combination therapy • Journal • Metastases • P1 data • Gastroenterology • Gastrointestinal Disorder • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD27

ETCTN 10476: Testing A New Combination of Anti-cancer Immune Therapies, Atezolizumab and CDX-1127 (Varlilumab) With or Without the Addition of a Third Anti-cancer Drug, Cobimetinib, for Advanced-Stage Biliary Tract Cancer (clinicaltrials.gov) - P2 | N=56 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2024 ➔ Jul 2025 | Trial primary completion date: Sep 2024 ➔ Jan 2024

Metastases • Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG) (clinicaltrials.gov) - P1 | N=14 | Terminated | Sponsor: Nicholas Butowski | Active, not recruiting ➔ Terminated; Industry sponsor decision

Trial termination • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioma • Oligodendroglioma • Oncology • Solid Tumor • CD4 • CD8

A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without addition of cobimetinib in previously treated unresectable biliary tract cancer. (ASCO 2024) - P2 | "The combination of Atezolizumab and Varlilumab with or without Cobimetinib was safe but did not improve clinical outcomes in advanced stage BTC patients treated in later lines. Though not statistically significant, treatment with CAV demonstrated numerically favorable PFS/OS compared AV among immunotherapy-experienced patients."

Clinical • P2 data • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CD27 • CD8

Brief Report: A Phase I Trial of Atezolizumab and Varlilumab in Combination with Radiation in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC) (JTO Clinical and Research Reports) - P1 | N=16 | NCT04081688 | "15 patients were enrolled (1 patient did not start treatment). Median age was 64 years; 10 patients were female. Eight patients (57%) had at least one treatment-related adverse event (TRAE); 7 (50%) had at least one grade 3 or worse TRAE. There was only one grade 3 immune-related AE requiring steroids (1 diarrhea/colitis); there were no treatment-related deaths. Of the 12 patients evaluable for efficacy, 3 patients had stable disease (SD; 2 with SD > 4 months) and clinical benefit rate was 25%. Median PFS was 2.0 months and median OS was 6.4 months."

P1 data • Non Small Cell Lung Cancer

Enhancing the strength and durability of vaccine-induced anti-tumor immunity with CD27 agonism of CD4+ T cells (AACR 2024) - "To determine the potential impact of CD27 agonism in vaccination, we combined HER2 vaccination with an anti-CD27 agonist antibody (Varlilumab)...Collectively, our results support a central role for antigen-specific CD27+ CD4+ T cells in cancer vaccination. These data support the addition of CD27 agonism to improve the therapeutic index of cancer vaccines and potentially enhance responses to immune checkpoint blockade in refractory cancers."

IO biomarker • Oncology • CD27 • CD4 • CD8 • HER-2

Mel-65: Vaccination With 6MHP, With or Without Systemic CDX-1127, in Patients With Stage II-IV Melanoma (clinicaltrials.gov) - P1/2 | N=33 | Completed | Sponsor: Craig L Slingluff, Jr | Recruiting ➔ Completed

Trial completion • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • CD4

A phase I trial of atezolizumab and varlilumab in combination with radiation in patients with metastatic non-small cell lung cancer (NSCLC) (SITC 2023) - P1 | "Clinical activity for the trial combination was modest with 25% of patients with stable disease as the best response. Correlative biomarker analyses to guide further research will be presented."

Clinical • Combination therapy • IO biomarker • Metastases • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD27

DIAL: Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas (clinicaltrials.gov) - P2 | N=52 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=106 ➔ 52 | Trial completion date: Dec 2023 ➔ Oct 2024 | Trial primary completion date: Dec 2023 ➔ May 2023

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Histiocyte Rich Large B Cell Lymphoma • ALK • BCL2 • BCL6 • IRF4

RiVa: A Combination of Rituximab and Varlilumab Immunotherapy in Patients With B-cell Lymphoma (clinicaltrials.gov) - P2a | N=26 | Active, not recruiting | Sponsor: University Hospital Southampton NHS Foundation Trust | Trial completion date: Jan 2023 ➔ Mar 2024

Trial completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

A combinatory vaccine with IMA950 plus varlilumab promotes effector memory T-cell differentiation in the peripheral blood of patients with low-grade gliomas. (PubMed, Neuro Oncol) - "The combinational immunotherapy, including varlilumab, was well-tolerated and induced vaccine-reactive T-cell expansion in the peripheral blood but without a detectable response in the tumor. Further developments of strategies to overcome the blood-tumor barrier are warranted to improve the efficacy of immunotherapy for LGG patients."

Journal • Brain Cancer • CNS Tumor • Glioma • Hematological Malignancies • Oncology • Solid Tumor • CD27 • CD4 • CD8

ETCTN 10476: Testing A New Combination of Anti-cancer Immune Therapies, Atezolizumab and CDX-1127 (Varlilumab) With or Without the Addition of a Third Anti-cancer Drug, Cobimetinib, for Advanced-Stage Biliary Tract Cancer (clinicaltrials.gov) - P2 | N=64 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2023 ➔ Sep 2024 | Trial primary completion date: Sep 2023 ➔ Sep 2024

Metastases • Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Production and N-glycan engineering of Varlilumab in Nicotiana benthamiana. (PubMed, Front Plant Sci) - "Concomitantly, N-glycan profile analysis of IgG co-expressed with β1,3-GALT demonstrated that there was an increased efficiency of galactosylation and an enhancement in the formation of Lewis a structure in plant-derived antibodies. Taken together, our findings show that the first plant-derived Varlilumab was successfully produced with biantennary β1,4-galactosylated N-glycan structures."

IO biomarker • Journal • Oncology • CD27

FcγR requirements and costimulatory capacity of Urelumab, Utomilumab, and Varlilumab. (PubMed, Front Immunol) - "In the presence of Varlilumab the percentage of annexin V positive T cells was increased, indicating that this antibody mediated FcγR-dependent cytotoxic effects. Collectively, our data underscore the importance to perform studies in reductionist systems as well as in primary PBMC samples to get a comprehensive understanding of the activity of costimulation agonists."

Journal • Oncology • ANXA5 • CD27 • CD4 • CD8 • FCGR2A • FCGR2B • TNFA

DERIVe: DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab (clinicaltrials.gov) - P2 | N=43 | Active, not recruiting | Sponsor: Annick Desjardins, MD | Recruiting ➔ Active, not recruiting | N=80 ➔ 43

Enrollment change • Enrollment closed • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CCL3 • CD4 • FOXP3 • IL2RA • ISG20 • MGMT

ETCTN 10476: Testing A New Combination of Anti-cancer Immune Therapies, Atezolizumab and CDX-1127 (Varlilumab) With or Without the Addition of a Third Anti-cancer Drug, Cobimetinib, for Advanced-Stage Biliary Tract Cancer (clinicaltrials.gov) - P2 | N=64 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Active, not recruiting

Enrollment closed • Metastases • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor