Advancement in Gynecologic Cancer Treatment Using Immune Checkpoint Inhibitors

Dr. Hye Sook Chon is a gynecologic oncologist in the Gynecologic Oncology program at Moffitt Cancer Center. She provides medical and surgical care to women with gynecologic malignancies and pre-invasive disease of the lower genital tract. Dr. Chon has a special interest in minimally invasive surgery, including robotic-assisted laparoscopy, for appropriate patients with gynecologic malignancies.

What is immune checkpoint inhibitor immunotherapy?

Immune checkpoint inhibitor is a type of drug that blocks certain proteins made by some types of immune system cells, such as T cells, and some cancer cells. These proteins help keep immune responses in check and can keep T cells from killing cancer cells. When these proteins are blocked, the "brakes" on the immune system are released and T cells can kill cancer cells better.

What are some advantages of immune checkpoint inhibitor for gynecologic cancers?

Immune checkpoint inhibitor provides possible long duration of responses in patients. It is also well tolerated in most patients, except that it has a unique side effect of "inflammatory reactions" in various systems. With immune checkpoint inhibitor, patients can avoid the side effects that usually come with conventional chemotherapy.

Where are we with the ability to use immune checkpoint inhibitor in solid tumors, particularly to treat gynecologic cancers?

Human papillomavirus (HPV) infection is the cause of more than 90% of cervical cancers and PD-L1 has been shown to be a solid biomarker of HPV infection of the cervix.

PD-L1 is significantly up-regulated in cervical cancer and detectable by immunohistochemistry in tumor cells, squamous cervical cancer between 54%- 80% according to different series and adenocarcinoma: 14%. PD-L1 expression reduces the immune response since it can bind to PD1 on T lymphocytes, thereby inhibiting their function. These findings provide background of therapeutic utility of checkpoint inhibitor targeting the PD-1/PD-L1 pathway in the treatment of cervical cancer.

For ovarian cancer, there are several tumor-specific antigens that have provided the foundation for designing successful immunotherapies. However, there’s still barrier to overcome the immune escape of the tumor or cancer immunoediting. Enough evidence indicates that ovarian cancer is indeed immunogenic tumors and is an excellent candidate for immunotherapy. Both passive and active immunotherapeutic modalities have shown potential clinical benefit in at least a subset of ovarian cancer patients. Several clinical trials using immune checkpoint inhibitor in combination with other type of treatment are on the frontline treatment for recurrence ovarian cancer.

Endometrial cancer cells can activate programmed death-1 (PD-1) signaling, by overexpressing PD-L1 and PDL-2, which can bind PD-1 receptors, expressed on tumor-infiltrating CD4 and CD8 T cells and inactivate them in the tumor microenvironment. Endometrial cancer cells overexpress PD-1 (present in 75% of cases) and PD-L1 (in 25%–100% of cases) the most among other gynecological cancers. For this reason, targeting this pathway seems a promising strategy to enhance antitumor immune response. A couple of immune checkpoint inhibitors have proven clinically effective in the treatment of endometrial cancer.

What are some of checkpoint inhibitor clinical trials currently available?

• A Two-arm, Randomized, Non-comparative, Phase 2 Trial of AGEN2034 (anti-PD-1) as a Monotherapy or Combination Therapy with AGEN1884 (anti-CTLA4) or with Placebo in Women with Recurrent Cervical Cancer (Second Line) – RaPiDS (MCC20175).
• Phase II study of stereotactic body radiation therapy and atezolizumab in the management of recurrent, persistent, or metastatic cervical cancer (MCC19662).
• A Randomised, Multicentre, Double-blind, Placebo-controlled, Phase III Study of First-line Carboplatin and Paclitaxel in Combination with Durvalumab, Followed by Maintenance Durvalumab with or without Olaparib in Patients with Newly Diagnosed Advanced or Recurrent Endometrial Cancer (DUO-E) (MCC#20529).

What are you most excited about the future of immune checkpoint inhibitor?

I am most excited about the potential long duration of response to treatment and long-term tolerability in certain patients compared to conventional chemotherapy.  In clinical trials, immune checkpoint inhibitors provide promising and complete response in recurrent cervical cancer. I’m optimistic that we will be able to provide better treatment options for patients with gynecologic cancers in the near future.

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