Challenges and Opportunities for Immunotherapies in Gynecologic Cancers

January 15, 2016

The advent of immunotherapy presents us with new treatment approaches in gynecologic cancers, with preliminarily promising outcomes. Multiple clinical trials are currently being conducted to better define the role of immunotherapy. Further investigation is warranted to develop and identify predictive biomarkers.

Breakthrough successes within the last 5 years have brought immunotherapy to the forefront of cancer therapy.[1,2] The development of immune checkpoint inhibition, which targets T-cell regulatory pathways and enhances antitumor immune responses by reversing T-cell exhaustion, has led to important clinical advances in the treatment of melanoma, lung cancer, and renal cell cancer.[2] Consistent with this, Bourla and Zamarin have described modulation of the host immune response to tumors, which is now recognized as an exciting new therapeutic target in gynecologic malignancies.[3] The major challenges to this strategy include the limited activity of single-agent immunotherapy and the lack of reliable biomarkers to predict patient response. The clinical evaluation of immunotherapy has focused on single agents to date.[1] The single-agent activity of immune checkpoint inhibitors in recurrent ovarian cancers is associated with objective response rates of approximately 15%.[4] Hence, it may be necessary to target other pathways to augment the checkpoint blockade and to address the dynamic events underlying the host immune response.[5]

Active therapeutic targets in recurrent ovarian cancer include DNA damage repair and vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) signaling pathways. Emerging data indicate that the VEGF and VEGFR pathways modulate immune response by increasing DNA damage and tumor mutational loads.[6,7] Mutational load, leading to increased potential neoantigen expression, has been associated with clinical response to immune checkpoint inhibitors in colorectal cancer and melanoma.[8,9] Approximately 50% of high-grade epithelial ovarian cancers have acquired or inherited dysfunction in homologous recombination, high-fidelity DNA double-strand break repair.[10] All high-grade epithelial ovarian cancers have genomic instability that is partially associated with loss of normal p53 function.[6]

Poly (ADP-ribose) polymerase (PARP) 1 has many roles in DNA damage repair, including repair of single-strand DNA breaks via the base excision repair pathway.[11] Preclinical studies have shown that PARP inhibitors promote local antigen release, resulting in systemic antitumor response after tumor exposure to radiation or DNA-damaging agents or secondary to spontaneous or heritable defects in DNA.[5,12] Increased DNA damage resulting from PARP inhibitors or exposure to other DNA-repair inhibitors would thus yield greater mutational burden and expand the neoantigen microenvironment.[13]

PARP inhibitors are also associated with immunomodulation. Huang et al reported that talazoparib (BMN 673) increased the number of peritoneal CD8+ T cells and natural killer cells, and increased production of interferon γ and tumor necrosis factor α in a BRCA1-mutated ovarian cancer xenograft model.[14] These data suggest that PARP inhibitors may be complementary to immune checkpoint modulation in yielding clinical benefit in recurrent ovarian cancer. Currently a phase I/II study of the programmed death (PD) ligand 1 (PD-L1) inhibitor MEDI4736 (durvalumab) in combination with olaparib is being conducted in patients with solid tumors and recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT02484404).

Angiogenesis pathways interact with both immune response and DNA repair mechanisms. Tumor hypoxia induces downregulation and decreased expression of genes and proteins involved in DNA damage repair, leading to further DNA damage, genomic instability, and cell death.[15-17] VEGF has been shown to reduce the antitumor immune response in preclinical and clinical models, including suppression of dendritic cell maturation, inhibition of T-cell responses, and an increase in regulatory T cell proliferation and accumulation of myeloid-derived suppressor cells (MDSCs).[18-21] In addition, PD-L1 expression was upregulated under hypoxic conditions in a panel of mouse and human tumor cell lines,[22] as well as in splenic MDSCs,[23] through a hypoxia-inducible factor-1α–dependent mechanism. Angiogenesis inhibitors are active in gynecologic cancers; bevacizumab[24,25] and the oral VEGFR1-3 tyrosine kinase inhibitor cediranib[26,27] have been associated with improved progression-free survival. Thus, angiogenesis inhibition may lead to increased mutational load and potential neoantigens, and may promote an antitumor immune response. Ongoing and new clinical trials will investigate this hypothesis in gynecologic cancers.

It is crucial to identify biomarkers that can predict the response to immunotherapies, particularly with the new checkpoint blockade agents. The overexpression of PD-L1 is an important and widely explored biomarker for response to immune checkpoint inhibitors.[28] However, PD-L1 expression as demonstrated by immunohistochemistry fails to accurately select all patients who are suitable for PD-1/PD-L1 pathway blockade. A phase II study in patients with ovarian cancer recently reported by Hamanishi et al indicated that the expression of PD-L1 did not significantly correlate with objective response.[4] Primary tumor samples may not represent the dynamic processes present in the immune milieu in recurrent disease. The expression of PD-L1 may be altered by prior treatment or by inflammatory changes at tumor sites. Optimization and harmonization of diagnostic and fit-for-purpose assays and examination of parallel and related pathways are needed to better guide patient selection and therapeutic choices.

Tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment, and their characterization by PD-L1 and expression of other immune biomarkers, may be important in predicting the clinical benefit of checkpoint blockade.[28,29] The clinical benefit of immune checkpoint inhibition is seen when immunogenic tumors and tumors with increased neoantigen production are treated with these inhibitors.[4]

Tumors with DNA damage repair deficiencies are recognized to have high(er) mutational loads, and thus potentially to express more neoantigens.[6,30] Suppressor (CD8+) and helper (CD4+) T cells recognize mutated peptides resulting from tumor-specific DNA mutations; neoantigen-specific T-cell responses have been associated positively with clinical response to immune checkpoint inhibition.[9] Le et al reported that administration of the PD-1 inhibitor nivolumab resulted in a higher response rate in mismatch repair (MMR)-deficient colorectal cancer compared with MMR-proficient colorectal cancer (40% vs 0%, respectively).[8] The high numbers of somatic mutations and neoantigens in MMR-deficient colorectal cancer correlated with longer progression-free survival.

Howitt et al also reported that polymerase ε–mutated and microsatellite-instable (MSI) endometrial cancers are associated with high neoantigen loads and numbers of TILs, which is counterbalanced by overexpression of PD-1 and PD-L1.[31] Patch et al recently showed that germline BRCA1 mutation–associated ovarian cancer has a higher mutational load and quantity of neoantigens compared with BRCA wild-type ovarian cancer.[6] Patients with these types of ovarian or endometrial cancer may be particularly suited for therapy with PD-1/PD-L1 inhibition.

The advent of immunotherapy presents us with new treatment approaches in gynecologic cancers, with preliminarily promising outcomes. Multiple clinical trials are currently being conducted to better define the role of immunotherapy. Further investigation is warranted to develop and identify predictive biomarkers. Determining the optimal timing or sequencing of immune-modulatory interventions will also be important, given the crucial role of the dynamics of immune reactions; this may require novel or adaptive trial designs. Assessing how to incorporate immunotherapies into current standard-of-care treatment protocols is essential to progress in the treatment of gynecologic malignancies.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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