GM.CD40L cell vaccine / AbelZeta Pharma, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida - LARVOL DELTA

Super-resolution high-speed video microscopy reveals rapid cytotoxicity and cooperative dynamics of folate receptor alpha CAR T cells against ovarian cancer (SITC 2025) - "Bystander CAR T cells would occasionally become activated during attacks and thereby amplify cytotoxicity.Conclusions This study captured a wide array of cell dynamics, revealing rapid target elimination, cooperative swarm-like behaviors, and on-site proliferation. These findings underscore the potential of high-resolution imaging to optimize CAR T-cell design for functionality and performance."

CAR T-Cell Therapy • Video • Oncology • Ovarian Cancer • Solid Tumor • FOLR1 • IL2

Initial phase 1 dose escalation data for emiltatug ledadotin (Emi-Le), a novel B7-H4-directed dolasynthen antibody-drug conjugate. (ASCO 2025) - P1 | "Emi-Le (XMT-1660) is a B7-H4-directed Dolasynthen ADC designed with a proprietary auristatin F-HPA microtubule inhibitor payload with controlled bystander effect... Based on the initial reported data, Emi-Le appears to have encouraging clinical activity and tolerability in a heavily pretreated population. Further clinical development is ongoing in the EXP portion of the trial at a dose of 67.4 mg/m2 Q4W in pts with advanced/metastatic TNBC who have received 1-4 prior lines of systemic therapy, including at least one topo-1 ADC. Dose exploration is ongoing to identify a potential second higher EXP dose."

P1 data • Adenoid Cystic Carcinoma • Fatigue • Interstitial Lung Disease • Neutropenia • Oncology • Optic Neuritis • Pain • Pulmonary Disease • Renal Disease • Respiratory Diseases • Thrombocytopenia • Triple Negative Breast Cancer • HER-2 • VTCN1

Emiltatug ledadotin (Emi-Le): A B7-H4-directed dolasynthen antibody-drug conjugate (ADC) being investigated in phase 1 dose expansion in patients with triple negative breast cancer who received at least one prior topoisomarase-1 inhibitor ADC. (ASCO 2025) - P1 | "Emiltatug ledadotin (Emi-Le; XMT-1660) is a B7-H4-directed Dolasynthen ADC designed with a precise, target-optimized drug-to-antibody ratio (DAR 6) and a proprietary auristatin F-HPA microtubule inhibitor payload with controlled bystander effect...The protocol includes the option for multiple additional indications, including HR+/HER2- breast cancer, endometrial cancer, ovarian cancer, and ACC-1. NCT05377996"

Clinical • P1 data • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2 • VTCN1

A phase 1b study of tbio-4101 (autologous selected and expanded tumor-infiltrating lymphocytes [TILs]) with pembrolizumab in patients with anti-PD-1–resistant, advanced head and neck squamous cell carcinoma (aHNSCC). (ASCO 2024) - P1 | "Non-tumor-reactive bystander T cells, which may negatively impact treatment efficacy via product dilution, and typically account for ≥90% of bulk TIL, are substantially reduced by this process. Thereafter, patients receive ≤6 doses of IL-2 (600,000 IU/kg) every 8h, and pembrolizumab (200 mg) every 3 weeks until disease progression. The trial is currently open, with a target enrollment of 15 patients (NCT06236425)."

Clinical • IO biomarker • Metastases • P1 data • Tumor-infiltrating lymphocyte • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8

An open-label, multicenter, phase 2 study to evaluate the safety and efficacy of BB-1701, a novel antibody drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2), in previously treated patients with HER2-positive (HER2+) or HER2-low unresectable or metastatic breast cancer (BC). (ASCO 2024) - P2 | "BB-1701 is an ADC consisting of a monoclonal antibody targeting HER2 with eribulin (microtubule inhibitor) as a payload that is capable of exerting a bystander effect...Randomization will be stratified by HER2 status (HER2+ vs. HER2-low) documented prior to T-DXd treatment...In both study parts, exploratory objectives will include evaluation of biomarkers of response to BB-1701 and BB-1701 immunogenicity; other efficacy measures (i.e., PFS on the next line of therapy) and population pharmacokinetics will be analyzed in the dose-expansion part only. Pt enrollment is currently open."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma (clinicaltrials.gov) - P2 | N=43 | Completed | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting ➔ Completed

Trial completion • Tumor cell • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • IFNG

XMT-1660: A phase 1b trial of a B7-H4 targeted antibody drug conjugate (ADC) in breast, endometrial, and ovarian cancers. (ASCO 2023) - P1 | "XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. NCT05377996. Clinical trial information: NCT05377996."

P1 data • Breast Cancer • HER2 Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CDK4 • ER • HER-2 • VTCN1

Phase II clinical study evaluating the efficacy and safety of disitamab vedotin in patients (pts) with HER2-expressing urothelial carcinoma (RC48G001) (ESMO 2022) - P2 | "Nearly half of all pts cannot tolerate standard cisplatin-based first line (1L) chemotherapy and opportunity still exists to improve outcomes in both 1L and later lines of therapy...DV elicits antitumor activity through MMAE-directed cytotoxicity and bystander effect (Li 2020)...Secondary endpoints include ORR assessed by investigator, duration of response, progression-free survival, disease control rate, overall survival, safety, and pharmacokinetic parameters. Enrollment for cohorts A and B is ongoing in North America and EU, and planned in LATAM, APAC, and Israel."

Clinical • P2 data • Bladder Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Urothelial Cancer • HER-2

Combination IFNβ and membrane-stable CD40L maximize tumor dendritic cell activation and lymph node trafficking to elicit systemic T-cell immunity. (PubMed, Cancer Immunol Res) - "Oncolytic viral therapies induce direct killing of tumor cells and activation of conventional dendritic cells (cDCs); however, cDC activation has not been optimized with current therapies. An oncolytic adenovirus (MEM-288) expressing MEM40+IFNβ in phase 1 clinical testing induced cancer cell loss concomitant with enhanced T-cell infiltration and increased systemic presence of tumor T-cell clonotypes in NSCLC patients. This approach to simultaneously target two major DC-activating pathways has potential to significantly impact the solid tumor immunotherapy landscape."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD40LG • CD8 • IFNB1

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma (clinicaltrials.gov) - P2 | N=43 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2022 ➔ Jul 2023

Preclinical • Trial completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • IFNG

CD3 engagement as a new strategy for allogeneic "off-the-shelf" T cell therapy. (PubMed, Mol Ther Oncolytics) - "BiTE-T cells down-regulated CD3ε/TCRαβ on bystander T cells by releasing BiTEs...Co-expressing co-stimulatory factors or T cell-promoting cytokines enhanced BiTE-T cells. Our study suggests CD3ε engagement could be a new strategy for allogeneic T cell therapy worthy of further evaluation."

IO biomarker • Journal • Graft versus Host Disease • Immunology • Oncology

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma (clinicaltrials.gov) - P2; N=43; Active, not recruiting; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Trial completion date: Jul 2021 ➔ Jul 2022

Preclinical • Trial completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • IFNG

The Calcitriol/Vitamin D Receptor System Regulates Key Immune Signaling Pathways in Chronic Lymphocytic Leukemia. (PubMed, Cancers (Basel)) - "To this end, we performed expression analysis of the vitamin D pathway molecules; complemented by RNA-Sequencing analysis in primary CLL cells that were treated in vitro with calcitriol, the biologically active form of vitamin D. In addition, we examined calcitriol effects ex vivo in CLL cells cultured in the presence of microenvironmental signals, namely anti-IgM/CD40L, or co-cultured with the supportive HS-5 cells; and, CLL cells from patients under ibrutinib treatment. This finding was also supported by our finding of preserved calcitriol signaling capacity in CLL patients under ibrutinib treatment. Overall, our results indicate a relevant biological role for vitamin D in CLL pathophysiology and allude to the potential clinical utility of vitamin D supplementation in patients with CLL."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD40LG

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma (clinicaltrials.gov) - P2; N=43; Active, not recruiting; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Trial completion date: Dec 2020 ➔ Jul 2021

Trial completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • IFNG

Granzyme B Producing B-Cells Have Immunoregulatory Function and Are Diminished in Patients with ANCA-Vasculitis (KIDNEY WEEK 2016) - "In patients with inactive AAV, B-cells showed a diminished production of GrB upon IgG+IgM/CD40L stimulation in presence of IL-21 (AAV vs. HC; IgG+IgM: 21.1±17.8% vs. 29.4±15.2%,p=0.0427; CD40L: 3.4±2.6% vs. 6.5±3.8%,p=0.0111). Thus, GrBpos B-cells can be regarded as an additional Breg subpopulation. This GrBpos B-cell-population is diminished in patients with ANCA-vasculitis."

Biosimilar • Immunology

Combination Immunotherapy of GM.CD40L Vaccine With CCL21 in Lung Cancer (clinicaltrials.gov) - P1/2; N=76; Recruiting; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Trial primary completion date: Apr 2015 ->Dec 2015

Trial primary completion date • Biosimilar • Non Small Cell Lung Cancer • Oncology

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma (clinicaltrials.gov) - P2; N=43; Active, not recruiting; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Trial completion date: Dec 2019 ➔ Dec 2020

Trial completion date • IFNG

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma (clinicaltrials.gov) - P2; N=43; Active, not recruiting; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Trial completion date: Aug 2019 ➔ Dec 2019

Trial completion date

IS THERE A ROLE OF VITAMIN D IN THE PATHOPHYSIOLOGY OF CHRONIC LYMPHOCYTIC LEUKEMIA? (EHA 2019) - "...Following, in order to activate the calcitriol/VDR system, we cultured CLL cells with calcitriol as well as a combination of anti-IgM/CD40L/calcitriol for 24 hours and measured the protein expression of CYP24A1, a target gene of the activated VDR...In contrast, no differences in VDR+ cells were observed under the conditions described above.Conclusion We show that VDR is expressed at low levels in CLL cells compared to normal B cells, which can be further reduced by microenvironmental signals, indicating that the tumor microenvironment competes with VDR expression. However, calcitriol supplementation activates the VDR system suggesting that VDR is functional in CLL cells and can potentially induce the expression of target genes with antitumor activity."

IO Biomarker

Universal Granulocyte Macrophage-colony Stimulating Factor (GM-CSF)-Producing and GM.CD40L for Autologous Tumor Vaccine in Mantle Cell Lymphoma (clinicaltrials.gov) - P2; N=43; Active, not recruiting; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Trial completion date: Mar 2019 ➔ Aug 2019

Trial completion date

Control of Α2,6-sialylation in B-cells, and consequences of reduced B-cell sialylation in patients with rheumatoid arthritis (EWRR 2019) - "...PBMCs were also isolated from peripheral blood and T and B-cells activated using CD3/28 beads and anti-IgM/CD40L respectively, before measuring B-cell sialylation and expression of ST6Gal1 and NEU1 mRNA...Conclusions α2,6-sialic acid is upregulated on the surface of healthy control B-cells in response to activation in vitro, and may be downregulated by TNF. Further experiments will determine if the environment in which naïve/memory B-cells are activated determines plasmablast/plasma cell sialylation, and if B-cells from patients with RA undergo the same changes in response to stimuli."

Clinical

Combination Immunotherapy of GM.CD40L Vaccine With CCL21 in Lung Cancer (clinicaltrials.gov) - P1/2; N=73; Completed; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Active, not recruiting ➔ Completed; Trial completion date: Dec 2019 ➔ Feb 2019

Combination therapy • Trial completion • Trial completion date