Several MAGE Antigens Proposed as Targets for Epithelial Ovarian Cancer Immunotherapy

Dr. Kunle Odunsi

Kunle Odunsi, MD, PhD, FRCOG, FACOG

A new study¹has recommended priority targets for immunotherapy in epithelial ovarian cancer (EOC) by profiling the expression of certain tumor-associated antigens (TAA), called MAGE cancer-testis antigens (CTA), in a large panel of tumor samples. The study’s authors have also implicated that three of the MAGE proteins might serve as prognostic biomarkers for the disease.

EOC is the most lethal gynecologic cancer in women with a relapse rate of 85% and a 5-year survival rate of 20 to 30%. This study examined the expression of five MAGE genes in a large panel of tumors from 400 patients and the immunogenicity of those antigens in a subset of 285 patients.

“The MAGE family of proteins is part of a class of CTAs that may serve as a target for directed immunotherapy in ovarian cancer and other types of cancer,” senior author Kunle Odunsi, MD, PhD, FRCOG, FACOG, M. Steven Piver Professor of Gynecologic Oncology and executive director of the center for immunotherapy at Roswell Park Cancer Institute (RPCI) noted in a statement.²“To achieve the important goal of tumor-directed immunity for ovarian cancer immunotherapy, it is critical to determine the extent to which this family of CTA molecules is expressed in these tumor cells.”

The authors assayed the expression of MAGE CTAs in the tumors using reverse transcription-PCR and immunohistochemical staining. They found aberrant expression of MAGE-A1 in 15% of the samples, MAGE-A3 in 36% of samples, MAGE-A4 in 47% of samples, MAGE-A10 in 52% of samples, and MAGE-C1/CT7 in 16% of samples.

The results also revealed that the most significantly co-expressed antigen pairs were MAGE-A1 and MAGE-A4, MAGE-A1 and MAGE-C1, and MAGE-A4 and MAGE-A10. Overall, approximately 78% of samples were found to express one or more of the five CTAs examined.

The researchers then examined the relationship between MAGE expression and patient survival. The expression of both MAGE-A1 and MAGE-A10 was associated with poor progression-free survival (PFS), while MAGE-C1/CT7 expression was correlated with improved clinical outcomes. The improvement in PFS conferred by MAGE-C1/CT7 was reduced, however, by co-expression of MAGE-A1 or MAGE-A10.

These results suggest that MAGE-A1, MAGE-A10, and MAGE-C1/CT7 are possible prognostic biomarkers in ovarian cancer. Furthermore, the authors recommend MAGE-A1 and MAGE-A10 as priority targets for the development of immunotherapy in EOC due to their correlation to poor patient outcomes.

In the paper, MAGE-A4 is also proposed as a priority target for immunotherapy. This recommendation is based on the relatively high frequency of MAGE-4A expression in the tumor panel and because the researchers’ analysis suggest that MAGE-A4 is a central gene that directs the expression profile of the other antigens.

Lastly, the study examined anti-MAGE humoral immunity in a subset of the patient panel. Serum samples from 285 patients were tested for reactivity against recombinant versions of the five MAGE antigens using ELISA. Spontaneous immunity was found in 9% of patients and predicted poor overall survival.

The authors hypothesize that the patients who develop a spontaneous immune response are those with more advanced disease and therefore a worse prognosis. They predict, however, that these patients are still likely to benefit from MAGE-directed immunotherapy.

Researchers at RPCI are also conducting separate vaccination and adoptive cell therapy trials, using another CTA known as NY-ESO-1. “Because not all ovarian tumors express NY-ESO-1, it is critical to identify other potential targets for immunotherapy,” Odunsi noted. “The current study supports the development of MAGE-directed immunotherapies to provide alternative modalities for patients whose tumors do not express NY-ESO-1 or whose responses against NY-ESO-1-expressing tumors are no longer sufficient.”

References:

1. Daudi S, Eng KH, Mhawech-Fauceglia P, Morrison C, et al. Expression and Immune Responses to MAGE Antigens Predict Survival in Epithelial Ovarian Cancer.PLoS One. 2014;9(8):e104099.
2. RPCI Researchers Identify Priority Targets for Immunotherapy in Epithelial Ovarian Cancer. Roswell Park Cancer Institute. https://www.roswellpark.org/media/news/rpci-researchers-identify-priority-targets-immunotherapy-epithelial-ovarian-cancer. Accessed August 16, 2014.