MB-108 / Fortress, UAB University - Birmingham - LARVOL DELTA

Enhanced Cytotoxicity of Anti-ROR1 CAR NK Cells Against Glioblastoma via Combined Treatment with Oncolytic Virus and NKTR-255 (SITC 2025) - "Our group has successfully ex vivo expanded functional peripheral blood NK cells (exPBNK) and electroporated with anti-ROR1 CAR mRNA.3 Oncolytic herpes simplex viruses C134, a neurovirulent deleting γ134.5 and expressing the human cytomegalovirus IRS1, is a promising experimental therapy.4 We previously demonstrated enhanced cytotoxicity against neuroblastoma using HSV expressing human IL-21(HSV C021) in combination with ROR1.CAR.5 NKTR-255 is an investigational IL-15Rα-dependent, polymer-conjugated IL-15 agonist that promotes NK cell expansion. Increased IFNγ secretion was also confirmed by ELISA assay (p < 0.05) (figure 1C).Conclusions The combination of HSV C021 with NKTR-255 significantly enhanced ROR1.CAR cytotoxicity against GBM in vitro, accompanied by elevated IFNγ secretion. In vivo evaluation using humanized NSG models is currently underway."

IO biomarker • Oncolytic virus • Brain Cancer • Glioblastoma • Neuroblastoma • Oncology • Solid Tumor • GZMB • IFNG • IL15 • IL21 • ROR1

oHSV-IL27 expression improves survival and induces protective immune memory in a CD4 T cell dependent mechanism in a preclinical murine glioma model (SITC 2025) - "To test this, CT-2A MG brain tumors were orthotopically established in (C57BL/6) mice and treated 7d later with equivalent virus dose of C027 (C134+IL27) or parent virus (C134) or vehicle control...Within this CD4 depleted cohort, ~10% survive in repeated studies but these LTS mice fail to reject their tumors on tumor rechallenge, unlike CD4-intact C027-LTS mice, suggesting CD4 T cells are essential for the development of durable immune memory. IL-27 expression by oHSV is a promising approach to enhance anti-glioma activity and immune memory formation.Ethics Approval All animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) at Nationwide Children's Hospital (AR16-00057, AR21-00145)."

IO biomarker • Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • CD4 • IFNG • IL27

Zoonotic potential of methicillin-resistant Staphylococcus aureus isolated from pets and their owners in Bangladesh. (PubMed, Sci Rep) - "The MRSA isolates exhibited resistance to penicillin (94.9%), azithromycin (82%), and ciprofloxacin (53.9%), in addition to their intrinsic resistance to cefoxitin. Multidrug resistance was observed in 94.9% of MRSA isolates, though all were sensitive to amikacin, clindamycin, linezolid, and vancomycin...Two pairs of isolates, C134-P134 and C185-P185, showed clonality based on whole genome and core genome SNP analysis, and other genetic parameters, suggesting clonal transmission between the pets and their respective owners...The detection of diverse MRSA lineages, including human lineages ST80, ST88, and ST6-t304 in pets, underscores their zoonotic potential and emphasizes the necessity for targeted MRSA surveillance and effective infection control measures. A collaborative One Health approach is therefore imperative to address the spread of MRSA between pets and their owners, thereby mitigating associated risks."

Journal • Infectious Disease • Septic Shock

A Phase IB 2 Dose Trial of IRS-1 HSV C134 (IND 17296) Administered Intratumorally in Patients With Recurrent Malignant Glioma (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: James Markert, MD | Not yet recruiting ➔ Active, not recruiting | Initiation date: Jan 2026 ➔ Jun 2025

Enrollment closed • Trial initiation date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Gliosarcoma • High Grade Glioma • Oncology • Sarcoma • Solid Tumor

C134-HSV-1: Trial of C134 in Patients With Recurrent GBM (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: University of Alabama at Birmingham | Trial primary completion date: Apr 2025 ➔ Oct 2024

Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Gliosarcoma • High Grade Glioma • Oncology • Sarcoma • Solid Tumor

Single cell sequencing delineates immune features of oncolytic virus therapeutic response in murine high-grade gliomas (AACR 2025) - P1 | "Our labs developed OV C134, now under evaluation in a phase I clinical trial of recurrent glioblastoma (NCT03657576)...Further, cell type-specific immune signatures of C002 therapeutic responders as compared to nonresponders were identified, including responder-specific increases in major histocompatibility complex class II in macrophages/monocytes, interferon gamma in CD4+ and CD8+ T cells, tumor necrosis factor-alpha in CD4+ T cells, and a decrease in interferon gamma receptor 1 in T regulatory cells. Collectively, our findings contribute to the knowledge of how OV therapy alters tumor immune microenvironments and reveal prioritized candidates whose further study could advance the understanding of how to achieve positive responses to OV therapy in patients."

IO biomarker • Oncolytic virus • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor • CD8 • HLA-DRB1 • IFNG • IFNGR1 • IL12A • PTPRC • TNFA

C134 - Tics/Tourette's and Paroxysmal Movement Disorders (AAN 2025) - "Learning Objectives Participants should understand the presentation and diagnosis of Tourette syndrome (TS) and other tic-related disorders; describe the history of tic-related conditions; analyze common myths associated with TS; compare and contrast tic-related treatments; and review the differential diagnosis for paroxysmal movement disorders, including the genetic etiologies. Recommended Audience Fellow, Resident, General Neurologist, Specialist Neurologist, Non-neurologist, Advanced Practice Provider, Medical Student Teaching Styles Didactic"

Movement Disorders • Tourette Syndrome

Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma. (PubMed, Mol Ther Oncol) - "Furthermore, the combination of C021 and anti-ROR1-CAR-NK cells significantly extended the survival of human NB xenografted NSG mice compared to controls (mock NK, ROR1-CAR-NK, C134, C021, C134+ROR1-CAR-NK, and C021+mock NK). Our results suggest that cytokine-secreting oncolytic virus in combination with CAR-NK cells is a novel, effective immunotherapeutic approach for high-risk NB."

Journal • CNS Tumor • Herpes Simplex • Neuroblastoma • Oncology • Solid Tumor • GZMB • IL21 • ROR1

A Phase IB 2 Dose Trial of IRS-1 HSV C134 (IND 17296) Administered Intratumorally in Patients with Recurrent Malignant Glioma (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: James Markert, MD | Trial completion date: Jan 2027 ➔ Jan 2028 | Initiation date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Jan 2026 ➔ Jan 2027

Trial completion date • Trial initiation date • Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Malignant Glioma • Oncology • Sarcoma • Solid Tumor

Re-Administration of C134 in Patients with Recurrent GBM (C134-HSV-1) (clinicaltrials.gov) - P1 | N=12 | Enrolling by invitation | Sponsor: University of Alabama at Birmingham | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Malignant Glioma • Oncology • Sarcoma • Solid Tumor

Oncolytic virotherapy changes tumor antigen landscapes in murine high-grade glioma models (SITC 2024) - P1 | "Methods Using the CT2A and GL261 models of HGG, we intracranially implanted tumors into C57BL/6 mice and treated them with vehicle control or oncolytic herpes simplex virus (oHSV) C134, which our group developed and is currently under study in a phase I clinical trial for glioblastoma (NCT03657576)...This work has the potential to reveal novel oHSV-modified HGG antigen targets and advances the understanding of how oHSVs may be harnessed to improve therapeutic outcomes for patients with glioblastoma. Ethics Approval All animal experiments were approved by the Nationwide Children's Hospital Institutional Animal Care and Use Committee (AR16-00057)."

IO biomarker • Oncolytic virus • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Oncolytic virotherapy changes tumor antigen landscapes in murine high-grade glioma models (SITC 2024) - P1 | "Methods Using the CT2A and GL261 models of HGG, we intracranially implanted tumors into C57BL/6 mice and treated them with vehicle control or oncolytic herpes simplex virus (oHSV) C134, which our group developed and is currently under study in a phase I clinical trial for glioblastoma (NCT03657576)...This work has the potential to reveal novel oHSV-modified HGG antigen targets and advances the understanding of how oHSVs may be harnessed to improve therapeutic outcomes for patients with glioblastoma. Ethics Approval All animal experiments were approved by the Nationwide Children's Hospital Institutional Animal Care and Use Committee (AR16-00057)."

IO biomarker • Oncolytic virus • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Mustang Bio Granted Orphan Drug Designation by U.S. FDA for MB-108 (HSV-1 oncolytic virus) to Treat Malignant Glioma (GlobeNewswire) - P1 | N=19 | NCT03657576 | "MB-108 (HSV-1 oncolytic virus) is active and well tolerated in patients with recurrent glioblastoma in ongoing Phase 1 clinical trial...Mustang Bio, Inc....announced that the U.S. Food and Drug Administration ('FDA') has granted Orphan Drug Designation to Mustang for MB-108, a herpes simplex virus type 1 ('HSV-1') oncolytic virus, for the treatment of malignant glioma."

Orphan drug • P1 data • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

A Phase IB 2 Dose Trial of IRS-1 HSV C134 (IND 17296) Administered Intratumorally in Patients With Recurrent Malignant Glioma (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: James Markert, MD

New P1 trial • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor

C134-HSV-1: Trial of C134 in Patients With Recurrent GBM (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: University of Alabama at Birmingham | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2025 ➔ Sep 2026 | Trial primary completion date: Sep 2024 ➔ Apr 2025

Enrollment closed • Trial completion date • Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor

A viral attack on brain tumors: the potential of oncolytic virus therapy. (PubMed, J Neurovirol) - "Furthermore, the discovery and creation of new OVs that can seamlessly integrate gene therapy strategies, such as cytotoxic, anti-angiogenic, and immunostimulatory, are promising advancements. This review presents an overview of the latest advancements in OVs transduction for brain cancer, focusing on the safety and effectiveness of G207, G47Δ, M032, rQNestin34.5v.2, C134, DNX-2401, Ad-TD-nsIL12, NSC-CRAd-S-p7, TG6002, and PVSRIPO. These are evaluated in both preclinical and clinical models of various brain tumors."

Journal • Oncolytic virus • Review • Brain Cancer • Gene Therapies • Oncology • Solid Tumor

Oncolytic virotherapy targeting high-grade glioma tumor antigens (AACR 2024) - P1 | "Our pVAC-Seq analysis revealed a conserved set of 1,264 tumor-exclusive variants expressed at the RNA level with high (ic50<500nm) predicted binding to mouse MHC. I will present details of C134-induced immune remodeling in syngeneic HGG models, and describe a plan to engineer C134 to express a prioritized set of neoantigens to evaluate how efficacy from OV therapy may be further enhanced in a patient-specific manner."

IO biomarker • Oncolytic virus • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CCL2 • JUN • PTPRC

C134 - Coding Update: Turning Coding into Dollars and Sense (AAN 2024) - "Learning Objectives Participants should become familiar with high-yield recent topics in coding to help them get reimbursed for the work they are doing, including an overview and key concepts from the 2021 Outpatient E/M changes, the 2023 Inpatient E/M changes, Critical Care, non-face-to-face codes, and important new codes and rules for 2024 (changes to split/shared billing and G2211 add-on code)."

Critical care

IL15 (N-803) and IL21 (oHSV-21) Significantly Enhance ROR1 CAR NK Cells Against Pediatric Neuroblastoma (TCT-ASTCT-CIBMTR 2024) - "The N-803 combined with dinutuximab and exPBNK cells significantly extended the survival of NB xenografts (Chu/Cairo, et al, JITC...C021 was generated by modifying C134 to express human IL21 gene... Our data demonstrated IL15 or IL21 based novel cytokine therapy (N-803 or C021) significantly enhanced the anti-tumor efficacy of ROR1 CAR NK targeting NB in vitro and in vivo"

Clinical • CNS Tumor • Herpes Simplex • Infectious Disease • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • GZMA • GZMB • IFNG • IL15 • IL21 • MYCN • ROR1

Re-Administration of C134 in Patients With Recurrent GBM (C134-HSV-1) (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: University of Alabama at Birmingham | Initiation date: Jan 2024 ➔ Aug 2025

Trial initiation date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor

Re-Administration of C134 in Patients With Recurrent GBM (C134-HSV-1) (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: University of Alabama at Birmingham

New P1 trial • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor

Mustang Bio Announces Amendment and Closing of Strategic Manufacturing Partnership Transaction with uBriGene (Boston) Biosciences (GlobeNewswire) - "Mustang Bio, Inc...today announced that, on July 28, 2023, it amended its previously announced asset purchase agreement with uBriGene (Boston) Biosciences Inc....closed the transaction under the terms of the amended asset purchase agreement...Per the terms of the amended agreement, at closing, uBriGene acquired all of Mustang’s assets primarily relating to the manufacturing and production of cell and gene therapies for upfront consideration of $6 million in cash....At closing, Mustang and uBriGene also entered into a manufacturing services agreement, under which Mustang contracted uBriGene to manufacture Mustang’s lead product candidates. This includes the manufacturing of MB-106..."

Licensing / partnership • M&A • Brain Cancer • Chronic Lymphocytic Leukemia • CNS Tumor • Glioblastoma • Glioma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Mustang Bio Provides CAR T Cell Therapy Portfolio Updates and 2023 Anticipated Milestones (GlobeNewswire) - "CAR T Candidate Portfolio Highlights: MB-106...In 2023, the Company anticipates dose escalation and reporting response data at a major medical meeting....Given this, Mustang plans to treat patients with WM in the Phase 1 portion of its multicenter clinical trial to support a fast-to-market Phase 2 strategy for this indication. Data from the Fred Hutch clinical trial also support the potential of MB-106 to be administered as outpatient therapy and provide a best-in-class immunotherapy option for patients treated previously with CD19-directed CAR T cell therapy. In 2023, Mustang anticipates the U.S. Food and Drug Administration granting Orphan Drug Designation in at least one additional CD20 positive malignancy....Phase 1 clinical trials of MB-101 at City of Hope and of MB-108 at the University of Alabama at Birmingham continue to enroll patients. Additionally, Mustang will advance the preclinical investigation of MB-109 and plans to file an IND for this treatment in 2023."

Enrollment status • IND • Orphan drug • P1 data • P1/2 data • Brain Cancer • CNS Tumor • Glioblastoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia

Ferulic acid derivatives block coronaviruses HCoV-229E and SARS-CoV-2 replication in vitro. (PubMed, Sci Rep) - "Among these ten drugs tested, five of them namely MBA112, MBA33, MBA27-1, OS4-1 and MBA108-1 were highly cytotoxic and did not warrant further testing...We then measured a reduction of the viral SARS-CoV2 replication by 46% with MBA28 (EC50 > 200 µM), by 58% with MBA140 (EC50 = 176 µM), and by 82% with LIJ2P40 (EC50 = 66.5 µM). Overall, the FAD LIJ2P40 showed a reduction of the viral titer on SARS-CoV-2 up to two logs with moderate cytotoxicity which opens the door to further evaluation to fight Covid-19."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

C134-HSV-1: Trial of C134 in Patients With Recurrent GBM (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Sep 2022 ➔ Sep 2024 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor