Immune checkpoint inhibitors in gynecologic cancers with lessons learned from non-gynecologic cancers

ABSTRACT

Introduction: The immune system plays a critical role in controlling cancer through a dynamic relationship with cancer cells. Immunotherapy can establish a sustained immune response against recurring cancer cells leading to long-term remissions for cancer patients. The use of immune checkpoint inhibitors, which work by targeting molecules that regulate immune responses, might be a promising avenue of immunotherapeutic research in gynecologic cancers.

Areas covered: This review focuses on the use of immune checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and the programmed death receptors such as PD-1 and PD1-ligand in gynecologic cancers. Combinatorial approaches utilizing immunotherapeutic agents with conventional treatments as well as immune-related response criteria and the adverse effects arising due to checkpoint inhibitor immunotherapy have been also discussed in the review.

Expert opinion: After years of very little success, a better understanding of the pivotal role of the tumor microenvironment in suppressing anticancer immunity and the exploration of treatment regimens using immune checkpoint inhibitors alone or in combination have finally led to the development of effective cancer immunotherapies and to improve survival of patients with certain types of advanced cancers. While the clinical experience with immune checkpoint inhibitors in gynecologic cancer patients remains limited, early signal of clinical activity strongly suggest that immunotherapy will play a significant role in the year to come in at least a subset of gynecologic cancer patients.

KEYWORDS:

• Immunotherapy
• gynecologic cancer
• checkpoint inhibition
• anti-cytotoxic T-lymphocytes
• anti-programmed death agents
• anti-program death ligands

Article highlights

• An increased understanding of the critical role of the immune system in cancer development and progression has led to new treatment strategies using various immunotherapies.

• It is now recognized that established tumors have numerous mechanisms of suppressing the antitumor immune response including production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of co-inhibitory receptors known as immune checkpoints.

• Under normal physiologic conditions, the immune checkpoints serve to inhibit immune responses against self-antigens, thereby preventing unwanted autoimmunity.

• Immune checkpoints play critical roles in cancer-associated immune suppression and immune evasion by inhibiting immune responses.

• Immune checkpoints control the balance of co-stimulatory and co-inhibitory signals that have essential roles in maintaining self-tolerance and in regulating the amplitude and duration of T-cell responses.

• Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions.

• Studies to identify biomarkers and other factors predictive of response and resistance to immunotherapy, and combination trials of immunotherapy with chemotherapy, targeted therapy, or multiple immune-modulators are underway to further define the role of this treatment modality for cancer.

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Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.