Skip to main content
Premium Trial:

Request an Annual Quote

Preclinical Data In Hand, City of Hope to Study Anti-TAG72 CAR T-Cell Therapy for Ovarian Cancer

NEW ORLEANS – Based on encouraging preclinical findings, a team of researchers from City of Hope are gearing up to launch a Phase I clinical trial of a TAG72-targeting autologous CAR T-cell therapy for advanced epithelial ovarian cancer patients.

In multiple presentations during the American Association for Cancer Research's (AACR) annual meeting this week, researchers presented on the upcoming Phase I trial and the preclinical research supporting the strategy.

The study, sponsored by Duarte, California-based City of Hope with collaboration from the National Cancer Institute, is designed to evaluate the safety, tolerability, recommended dose, and preliminary efficacy of the TAG72-targeting CAR T cells as treatment for roughly 33 epithelial ovarian cancer patients who have not responded to platinum-based chemotherapy.

Importantly, to be eligible for the trial, patients' tumors need to express the tumor-associated glycoprotein 72, or TAG72, in more than 1 percent of their tumor cells, according to immunohistochemistry staining. According to prior research, the protein is overexpressed in most epithelial ovarian cancers, but as Tanya Dorff, head of the genitourinary cancers program at City of Hope, explained in a Wednesday AACR session, it's important to "make sure that your patient has what you're trying to target," even when the antigens are fairly ubiquitous.

This is especially true given the high cost and potential toxicities associated with CAR T-cell therapy. Even if few epithelial ovarian cancer patients will not express the target antigen, it's important to appropriately weigh potential treatment benefit against the risks and screen these patients out.

Immunohistochemistry is not a perfect solution for target screening, but other methods may be on the horizon. "Another form of selecting patients for antigen expression would definitely be preferable in my view," Dorff said, suggesting PET tracers, which have been useful in selecting prostate cancer patients for radiopharmaceutical therapy based on their prostate-specific membrane antigen (PSMA) expression, could "eventually be something that we look at for selecting [patients for] CAR T-cell therapy as well."

Earlier this year, City of Hope researchers from the institution's molecular imaging and therapy department published preclinical research in the Journal of Nuclear Medicine suggesting that screening for TAG72 with a targeted radioligand might be feasible.

City of Hope investigators hope to begin enrolling patients into the planned Phase I TAG72-targeted CAR T-cell trial this year. Researchers led by gynecologic oncology professor Lorna Rodriguez plan to look into a number of secondary outcomes beyond safety and tolerability, including tumor response and patients' overall survival and progression-free survival rates. They'll also measure whether, and for how long, the CAR T cells expand and persist once administered.

This last part is important since, historically, CAR T-cell persistence has been a major barrier to bringing cell therapy to the solid tumor space. Part of the reason for this is that T cells are more likely to become exhausted when trying to infiltrate solid tumors. Strategies for overcoming this barrier have been top of mind in the field, leading researchers and drugmakers alike to experiment with new constructs for engineering the cells and new methods of administering them, perhaps in combination with other immunotherapies.

In the preclinical work supporting the upcoming study, researchers including Eric Lee from City of Hope's cellular immunotherapy center, suggested that one way to help these CAR T cells persist in the patient's body once infused would be to counteract the immunosuppressive tumor microenvironment using interleukin-12. Lee showed in an AACR poster session that this strategy of incorporating an IL-12 construct in the CAR T cells during the engineering stage could amplify cytokine pathways and, in turn, overcome the tumor microenvironment. When Lee and his team took the IL-12 endowed TAG72-targeting CAR T cells to mouse models, they "greatly improved the effectiveness of TAG72-CAR T cells."

The researchers selected IL-12 specifically over IL-15 due to the toxicities they saw in the mouse models with the latter. When they used the engineered T cells with the IL-12, on the other hand, the treatment "not only demonstrated safe and superior therapeutic responses but also allowed the regional administration of CAR T cells to address systemic disease." In other words, they could infuse the CAR T cells locally — around the cancer tumors themselves — to access the cancer more directly.

This is exactly what the investigators plan to do with the Phase I clinical trial: infuse the CAR T cells directly into the area around the ovaries, dubbed the peritoneal cavity, via local infusion. According to Dorff, this strategy could also limit side effects. "One way to get around the on-target, off-tumor toxicity would be to put the CAR T right where the tumor is," she said.

This strategy isn't unique to ovarian cancer, nor to CAR T-cell therapy, but rather has been picking up steam as one of the myriad ways researchers are trying to move cell therapy into the solid tumor space. In a separate AACR presentation on Tuesday, Christopher Cole, a senior medical oncology fellow in the NCI's women's malignancies branch, presented on a first-in-human trial of administering interferon-activated autologous monocytes directly into ovarian cancer patients' peritoneal cavity.

Beyond ovarian cancer, City of Hope investigators, in partnership with the drugmaker Mustang Bio, are trying this strategy in brain cancer patients by delivering IL13Rα2-specific CAR T-cell therapy directly into the cerebrospinal fluid to directly access the brain.

Even in blood and lymphoid cancers, where CAR T-cell therapy has had a clear and durable benefit, there are myriad factors that can lead to resistance and relapse, making it crucial for researchers in the solid tumor cell therapy space to keep tabs on these differences from the onset. As such, within the ovarian cancer CAR T-cell trial, researchers will dive deeper into potential markers of response and resistance by analyzing immune and tumor-infiltrating lymphocyte cell phenotypes, gene-expression patterns via RNA sequencing of circulating tumor cells, circulating cell-free DNA using whole-exome sequencing, and changes in the patients' microbiome in stool samples.