Q&A: Will Ovarian Cancer be the Next Target for Gene Therapy?

January 8, 2018

Jinghe Lang, MD, PhD, of the Department of Obstetrics and Gynecology at Peking Union Medical College Hospital, and colleagues recently published a study entitled, “CAR-T cell therapy in ovarian cancer: from the bench to the bedside.” The study, published in Oncotarget, examined how gene therapy can be used to treat ovarian cancer—and what hurdles have to be jumped before we see gene therapy for ovarian cancer in clinical practice.

We spoke with Dr Lang about his researcher to catch up manage care professionals up with the possibility of a gene therapy for ovarian cancer in the coming years.

Can you tell me about the potential that CAR-T holds for treating ovarian cancer?

As is mentioned in our paper, although clinical pilot trials have just begun in ovarian cancer, the potential of this form of CAR-T-cell immunotherapy is becoming increasingly evident. Solid tumors often employ multiple mechanisms to attenuate the validity of T-lymphocyte-mediated attacks by in turn downregulating MHC class I (MHC-I) or other molecules related to the antigen-processing machinery in order to evade immune responses. The downregulation of MHC-I on the surface of a cancer cell restrains the homing of T lymphocytes because the interaction between the TCR and peptide-MHC is a prerequisite for T-lymphocyte activation. Nevertheless, CARs bypass the immune escape mechanism of cancer cells because they endow T lymphocytes with cytotoxic effector features in an MHC unrestrictive manner. This is particularly important for ovarian cancer, in which the advanced stage is correlated with MHC downregulation. These findings imply that patients with ovarian cancer may benefit from CAR-T cells in clinical practice. Up to now, there are several kinds of antigens targeted by CARs in ovarian cancer including MUC16, folate receptor-α(FRα), mesothelin, and HER2 and so on. CAR-T-cell immunotherapy in ovarian cancer is promising.

What are the on-target adverse reactions  associated with treating ovarian cancer with CAR-T?

Tumor associated antigens were expressed not only in tumor cells but also in normal cells. When tumor-associated antigens are used as targeting molecules for CAR-T-cell therapies, normal cells can also be distinguished and attacked by lymphocytes, causing damage to normal tissue (referred to as on-target, off-tumor toxicity). A case report detailed a serious “on-target” adverse event following the application of T cells transduced using a CAR recognizing ERBB2 (HER2) in colon cancer. Since numerous tumor-associated antigens can be targeted by CARs in ovarian cancer including MUC16, folate receptor-α(FRα), mesothelin, and HER2, we speculate that the similar on-target, off-tumor toxicity is also in ovarian cancer.

Is it likely CAR-T will be expanded to treat ovarian cancer in the near-future?

With the development of immunology and oncology, it is likely that CAR-T will be expanded to treat ovarian cancer in the near-future.

What barriers are there to overcome before CAR-T can be used for ovarian cancer?

We think that the potential side effects and cytotoxicities including the CRS effect and “on-target” adverse events must still be considered and resolved before this novel and promising approach can be broadly applied to treat patients with ovarian cancer.

Are costs expected to match that of other recently approved gene therapies for cancer?

We think the costs match that of other recently approved gene therapies for cancer.

David Costill