Modified T Cells May Be New Hope in Fight Against Ovarian Cancer

August 29, 2011

The most lethal reproductive cancer in women, ovarian cancer, is estimated to affect 12.8 per 100,000 women in the United States. As such, researchers continue to look into novel ways to eradicate the disease. Armed with the knowledge that almost all (90%) ovarian cancers can be characterized by their expression of alpha-folate receptor, Dr De-Gang Song, postdoctoral investigator in the Perelman School of Medicine at the University of Pennsylvania, and colleagues attempted to engineer T cells to see if they would help shrink the cancer tumors.

The most lethal reproductive cancer in women, ovarian cancer, is estimated to affect 12.8 per 100,000 women in the United States. As such, researchers continue to look into novel ways to eradicate the disease. Armed with the knowledge that almost all (90%) ovarian cancers can be characterized by their expression of alpha-folate receptor, Dr De-Gang Song, postdoctoral investigator in the Perelman School of Medicine at the University of Pennsylvania, and colleagues attempted to engineer T cells to see if they would help shrink the cancer tumors.

Researchers have known that the alpha-folate receptor is expressed on the surface of the cancer cells; these proteins have a high affinity for folic acid, which helps feed the cancer cells. Previous attempts with human cells engineered to express an antibody fragment specific for the alpha-folate receptor protein were unsuccessful in the clinic. While these engineered cells showed antitumor activity against epithelial cancers in the laboratory setting, they were unable to persist and home to tumors in the human body. Song and colleagues further modified T cells and sought to determine if these T cells that expressed chimeric antigen receptor, an engineered fusion protein, outfitted with CD137 costimulatory motif in tandem would be more successful against the tumors.

First, the researchers took the modified T cells and expanded them in the laboratory for 2 weeks. The modified T cells were then exposed to human ovarian cancer cells to determine their efficacy. To further determine effectiveness, cytokine production by the T cells was measured, which is a sign of inflammation produced by the T cells as it is killing the cancer cells.

This new approach to modification allowed the T cells to multiply and survive as well as to recognize and kill ovarian tumors. In comparison to the older technology, the researchers further found that fewer new T cells died when exposed to cancer cells. Indeed, T cells increased over time in test tube experiments and a mouse model, which they believe is evidence that the new T cells were able to multiply and survive better when compared to those from the older technology.

One of the coauthors of this study is planning a clinical trial using these modified T cells. Dr George Coukos, director of the Ovarian Cancer Research Center at the University of Pennsylvania Medical Center, plans to recruit as many as 21 patients with advanced recurrent ovarian cancer with tumors that express the alpha-folate receptor. The trial is currently pending; thus far, the University of Pennsylvania is the only study site.

“This technology represents a promising advancement for the treatment of women with ovarian cancer,” Dr Daniel J. Powell Jr, research assistant professor of pathology and laboratory medicine at Perelman School of Medicine at the University of Pennsylvania and corresponding author of the study, said in a statement to the press. “We will continue to work around the clock to improve this approach using other costimulatory portions and antibody-like proteins to make this the most powerful and safe approach for the treatment of the greatest number of women with this horrible disease.”

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References

Song DG, Ye Q, Carpenito C, et al. In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res. 2011;71(13):4617-4627.
Penn News. Penn study finds more effective approach against "Achilles' heel" of ovarian cancer. University of Pennsylvania Press Release. August 5, 2011.