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A combination therapy comprising **ISF35** (a gene therapy using an adenoviral vector encoding a chimeric CD154/CD40 ligand), **fludarabine** (a purine analog antimetabolite), **cyclophosphamide** (an alkylating agent), and **rituximab** (a monoclonal antibody targeting CD20). ISF35 acts as an immune stimulatory gene therapy designed to increase the immunogenicity of malignant B-cells, enhancing their susceptibility to immune clearance. The other three agents constitute a standard chemoimmunotherapy regimen for B-cell malignancies, with fludarabine and cyclophosphamide causing cytotoxicity through DNA damage and rituximab targeting B-lymphocytes via anti-CD20 activity. The combination has been investigated primarily for treatment of **chronic lymphocytic leukemia (CLL)** and possibly for other B-cell lymphomas, aiming to augment antitumor immune responses beyond standard chemoimmunotherapy. ISF35 is developed and originated by Memgen, and studies have involved academic collaborators such as UCSD Moores Cancer Center. ISF35 was discontinued as a stand-alone agent after phase 2.
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