Graduate Student Emily Ankrom

"Adenoviral Vectors for Cancer Immunotherapy"

Cells of the immune system are usually able to detect and eliminate tumor cells as they arise. Abnormal proteins produced as a result of DNA damage are detected as “non-self” antigens by circulating white blood cells. In instances of immunosurveillance failure or when the immune response is not powerful enough to destroy cancer cells, tumorigenesis proceeds. Tumor cells rapidly divide and evolve to produce daughter cells with increasingly immune-suppressing qualities. The immunoevasive nature of tumor cells warrants the development of therapeutics that restore anti-tumor immunity, particularly following treatment with myelosuppressive chemotherapy.1 A developing body of evidence suggests oncolytic viruses, which selectively replicate and destroy cancer cells, may provide a form of cancer immunotherapy. Viral infection causes dying tumor cells to release damage-associated molecular patterns (DAMPs) that are processed by antigen-presenting cells. Subsequent activation of T-cells informs the immune system on where to initiate their cytotoxic attack. Additionally, pathogen-associated molecular patterns (PAMPs) produced by the virus may stimulate immunity against infected cells.2 Adenoviruses, the viral family associated with the common cold, are the most popular in preclinical and clinical virotherapy trials. The adenovirus platform, known as Conditionally Replicating Adenovirus (CRAd), is genetically modified to have cancer selectivity and enhanced anti-tumor properties. The recently identified immunogenic cell death pathways activated in adenovirus-infected cancer cells will be detailed in this seminar2, along with in vitro and in vivo studies demonstrating the efficacy of CRAd against chemotherapy resistant metastatic human breast carcinoma.3 Furthermore, the evidence for enhancement of CRAd cancer-killing properties by addition of a tumor-derived membrane will be discussed.4

References:

1. Emens, L.A. Chemoimmunotherapy. Cancer J. 16, 4, 295-303 (2010). https://doi.org/10.1097/PPO.0b013e3181eb5066
2. Ma, J., Ramachandran, M., Jin, C. et al. Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer. Cell Death Dis 11, 48 (2020). https://doi.org/10.1038/s41419-020-2236-3
3. Sakhawat, A., Ma, L., Muhammad, T. et al. A tumor targeting oncolytic adenovirus can improve therapeutic outcomes in chemotherapy resistant metastatic human breast carcinoma. Sci Rep 9, 7504 (2019). https://doi.org/10.1038/s41598-019-43668-8
4. Fusciello, M., Fontana, F., Tähtinen, S. et al. Artificially cloaked viral nanovaccine for cancer immunotherapy. Nat Commun 10, 5747 (2019). https://doi.org/10.1038/s41467-019-13744-8