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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In addition to drug delivery, the ClearPointTM system has been used in clinical trials for the delivery of gene therapies directly to brain tumors. For example, the Toca-511/Toca-FC treatment (vocimagene amiretrorepvec) is a combination of a replicating, non-lytic retroviral vector containing a gene encoding for the enzyme cytosine deaminase (CD) and a prodrug Toca FC, an extended-release formulation of the antifungal agent 5-fluorocytosine. The latter is a prodrug of 5-fluorouracil, a known anticancer agent that does not cross the blood–brain barrier whereas 5-fluorocytosine does. Used after a brain tumor has been removed, Toca-511 is injected into the tissues lining the cavity from which the tumor was removed using the ClearPointTM system. The virus replicates only in cells that are dividing such as any cancer cells left behind after the surgery, whereas healthy brain cells are either non-dividing or very slow dividing. The 5-fluorocytosine prodrug is then administered orally and, after crossing the blood–brain barrier and reaching the tumor site, is converted into the cytotoxic 5-fluorouracil in those dividing cells expressing cytosine deaminase. At the time of writing, the Toca-511/Toca-FC therapy is still in clinical trials.
Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer
Published in Expert Opinion on Biological Therapy, 2021
Sara A. Collins, Ashish H. Shah, Derek Ostertag, Noriyuki Kasahara, Douglas J. Jolly
Inability to induce an adequate antitumor immune response: As noted above, an inadequate number of prodrug cycles was associated with failure to fully eradicate orthotopic gliomas in syngeneic immunocompetent animal models, and reduced survival in the Phase III clinical trial (Figure 3c). Presumably this is because initial tumor transduction and vector replication at early time points are restricted to areas immediately surrounding injection sites. Accordingly, the extent of direct tumor cell killing (and hence tumor antigen release) and local bystander toxicity to MDSC and TAM populations (and hence alleviation of immunosuppression) are initially low, but increase with each successive cycle of RRV replication from viral ‘reservoir’ cells and subsequent prodrug treatment. Hence, without an adequate number of prodrug cycles, antitumor immunity may not be fully activated. Nonetheless, there are certainly other immunological parameters that may influence the ability of Toca 511/Toca FC treatment to induce a robust antitumor immune response. These may include: paucity of immunogenic tumor antigens, loss or impaired function of antigen-presenting cells, inhibition of T cell activation or induction of T cell anergy by non-myeloid cells (e.g. T regulatory cells) or signaling pathways (e.g. TGF-β). Further detailed characterization of antitumor immune responses that develop after Toca 511/Toca FC treatment, especially within the microenvironment of patient gliomas, is needed.