2:18 PM
Jul 11, 2018
 |  BC Extra  |  Preclinical News

Turning cancer cells against their own kind

To overcome hurdles facing cancer cell-based therapies such as self-toxicity and long-term persistence, researchers from Brigham and Women's Hospital and colleagues developed a two-part therapy by pairing tumor cells delivering a receptor-targeted anticancer agent with a suicide system.

Harnessing cancer cells as therapies is advantageous compared with stem cell-based therapies because the cancer cells have enhanced homing toward the primary tumor site and prolonged survival.

Previous self-targeted cancer therapies have had limited success ensuring the cells persist for just the right amount of time -- long enough to reach primary or metastatic tumor sites, but not too long to cause secondary tumor formation. In a Science Translational Medicine paper, the team's approach combines a previously established suicide system to eliminate therapeutic cells with receptor-targeted cancer cells to prevent premature cell death due to self-toxicity.

The researchers developed both allogeneic and autologous cancer cell therapies against tumors sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by delivering a secretable ligand that targets death receptors on cancer cells.

The researchers first engineered glioblastoma cells already TRAIL-resistant to secrete TRAIL, as resistant cells are less likely to die due to autotoxicity. The cells were also engineered to express herpes simplex virus thymidine kinase (HSV-TK), which coverts the prodrug ganciclovir into a toxic agent, inducing cell death.

In a mouse model of glioblastoma, the therapeutic cancer cells followed by ganciclovir led to tumor regression and a significant survival increase compared with vehicle.

To mimic an autologous therapy using a patient's own TRAIL-sensitive cells, the researchers changed the phenotype to TRAIL-resistant cells by using CRISPR to knock out two TRAIL receptors. The cancer cells followed by ganciclovir reduced tumor growth and increased survival in two mouse models of recurrent glioblastoma and a mouse model of breast cancer that metastasized to the brain.

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