Abstract
The presence of tumor infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICPI) have been approved for treating different types of malignancies. In this review, we assess the scanty data from literature and the perspectives of clinical research about the use of ICPI in gynecological cancers. These agents have obtained objective response rates ranging from 5.9% to 15% in early phase Ib-II trials, including patients with platinum-resistant ovarian cancer, whereas only anecdotal data are available for patients with recurrent, heavily pretreated endometrial cancer. Several ongoing trials are investigating ICPI alone or in combination with chemotherapy or with other biological agents in untreated and recurrent ovarian cancer, advanced and recurrent endometrial cancer, as well as advanced and recurrent cervical cancer. Breast cancer (BRCA)-mutated high-grade serous ovarian cancers, clear cell ovarian cancers with microsatellite instability (MSI), POLE ultramutated and MSI hypermutated endometrial cancers are likely to be sensitive to programmed cell death (PD-1)/PD-ligand 1 (PD-L1) pathway blockade, since these tumors show increased neoantigen load, increased CD8+ TIL number and PD-1 and PD-L1 overexpression. ICPI could have a role as maintenance treatment in patients with persistent, recurrent or metastatic cervical cancer in response after chemotherapy.
- Immune checkpoint inhibitor
- PD-1
- PD-L1
- CTLA
- epithelial ovarian cancer
- endometrial cancer
- cervical cancer
- review
There is a large body of evidence supporting the crucial role of tumor immune microenvironment in carcinogenesis (1). The presence of tumor infiltrating lymphocytes (TILs) correlates with the clinical outcome of patients with different malignancies, such as melanoma, breast cancer, prostate cancer, renal cell cancer, esophageal cancer and colorectal cancer (2-8). The pooled analysis of 33 studies including several types of cancer revealed that high CD3+ TIL number, high CD8+ TIL number and high CD8+TIL//CD4+CD25+FoxP3+ regulatory TIL (T-reg) ratio had a positive impact on overall survival (OS) with a hazard ratio (HR) of 0.58 (95% confidence interval (CI)=0.43-0.78), 0.71 (95%CI=0.62-0.82) and 0.48 (95%CI=0.34-0.68), respectively (9). T-reg cells are a type of CD4+ T cells that inhibit immune responses characterized by lack of expression of effector cytokines, such as interferon (IFN)-γ and the production of inhibitory cytokines, such as transforming growth factor (TGF)-β, interleukin (IL)-10 and IL-35 (10). Beside T-reg cells and type-2 tumor-associated macrophages (TAM), the blockade of the T-cell response against tumor cells may be caused by immune checkpoint receptors expressed on the T-cell surface, such as cytotoxic T lymphocyte-antigen 4 (CTLA-4) and programmed cell death (PD-1) receptor (10-14). CTLA4 counteracts the activity of the T cell co-stimulatory receptor CD28 for binding to the ligands B7.1 and B7.2 expressed on antigen-presenting cells and, therefore, CTL4 functions as a negative immune regulator. Similarly, the linkage between PD-1 on T cells and the programmed-death ligand (PD-L1) on tumor cell surface inhibits T-cell proliferation and increases T-reg cell number, thus resulting in Tcell function inhibition (11-14). Whereas CTLA-4 predominately regulates T cell activation within secondary lymphoid organs, PD-1 regulates T cell function within peripheral tissues and tumor microenvironment (10, 12, 15).
Monoclonal antibodies (mAbs) targetingPD-1 (i.e. pembro-lizumab and nivolumab) and PD-L1 (i.e. avelumab, atezolizumab and durvalumab), as well as mAbs targeting CTLA-4 (ipilimumab and tremelimumab), have been approved by Food and Drug Administration (FDA) for several malignancies, such as melanoma, non-small cell lung cancer, renal cell cancer, urothelial cancer and lymphoma (16-20). Anti-CTLA mAbs and anti-PD-1/PD-L1 mAbs cause immune-related adverse events (AEs) in 60% and 40% of cases, respectively, but severe AEs are more frequent with anti-CTLA therapy (21, 22). The management of these AEs depends on their severity and ranges from immune checkpoint inhibitor therapy suspensionto the administration of corticosteroids and, also, to the use of anti-tumor necrosis factor (TNF)-α mAbs, mycophenylate mofetil, tacrolimus and cyclosporine (23).
Four distinct patterns of response to immune checkpoint inhibition have been observed: (i) regression of baseline lesions; (ii) stable disease followed by a slow decline in tumor burden; (iii) delayed response after an initial increase in tumor burden; and (iv) response after the appearance of new lesions (24). The three latter patterns of response havenot been reportedwith chemotherapeutic agents (25). Novel immune-related response criteria, different from the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified World Health Organization (WHO) criteria (24), have been suggested for immune checkpoint inhibitors (25, 26).
Tumors can be classified into four groups based on PD-L1 expression and T cell infiltration (27). Type I tumors (PD-L1-positive, TILs+) exhibit an adaptive immune resistance and are likely to respond to immune checkpoint inhibitors, whereas type II tumors (PD-L1-negative, TILs−) display no detectable immune reaction and are likely to be unresponsive to single- agent checkpoint blockade. Type III tumors (PD-L1-positive, TILs−) exhibit intrinsic expression of PD-L1 with no immune reactivity, which suggests that PD-L itself is not apredictive biomarker of response to anti-PD-1/PD-L1 mAbs. Type IV tumors (PD-L1-negative, TILs+) may be amenable to targeting of other non-PD-1/PD-L1 checkpoint receptors.
The present manuscript reviews the few data availablein literature on the use of immune checkpoint inhibitors in the management of gynecological cancers.
Epithelial Ovarian Cancer
The number and type of TILs influence the clinical outcome of patients with epithelial ovarian cancer (EOC) (28-33). For instance, in the study of Zhang et al. (28), the presence of TILs was detected in 54.8% of 186 frozen specimens from women with this malignancy and found to be correlated with increased expression of IFN-γ, IL-2 and lymphocyte-attracting chemokines within the tumor. Median progression-free survival (PFS) and median OS were 22.4 months and 50.3 months, respectively, for patients whose tumors contained TILs versus 5.8 months and 18.0 months for those whose tumors did not contain TILs (p<0.001 for both). The meta-analysis of 10 studies, including 1,815 patients with EOC, confirmed that lack of intraepithelial TILs correlated with worse OS (pooled HR=2.24, 95% CI=1.71-2.91) (29).
High CD8+ T cell infiltration was an independent favorable prognostic factor in a series of 203 patients with EOC: the mortality risk decreased by 18% with each doubling of CD8+ T cell density (HR=0.82, 95%CI=0.73-0.92) (33). The immunohistochemical analysis of paraffin-embedded specimens from 117 women with EOC showed that patients with higher frequencies of intraepithelial CD8+ T cells had a better clinical outcome compared with those with lower frequencies (median OS=55 versus 26 months, HR=0.33, 95%CI=0.18-0.60) (31). It is noteworthy that median OS was 57.6 months for patients with high CD8+ T cell/T-reg cell ratios versus 22.6 months for those with low ratios (HR=0.31, 95%CI=0.17-0.58).
Hamanishi et al. (34) found strong immunostaining for PD-L1 in 68.5% of tissue samples from 70 patients with EOC. There was a significant inverse correlation between intraepithelial CD8+ T cell count and PD-L1 expression, thus suggesting that PD-L1 on tumor cells could block the intraepithelial invasion of tumor-specific CD8+ T cells.
Conflicting data emerge from the literature about the prognostic relevance of PD-1 and PD-L1 expression in EOC and these discordant results may reflect different techniques for PD-1 and PD-L1 assessment, different cut-off values for tumor cell staining, as well aspatients' heterogeneity (34-38).
PD-1/PD-L1 blockade caused tumor regression in a syngeneic EOC mouse model, thus supporting the relevance of this regulatory pathway in ovarian carcinogenesis (38).
Some phase Ib-II trials have investigated the activity and safety of anti-PD1 or anti-PD-L1 mAbs in platinum-resistant EOC, with objective response (OR) (complete response (CR)+ partial response (PR)) rates ranging from 5.9% to 15% (22, 39-41) and with grade (G)≥3 AE rates ranging from 3.8% to 40% (Table I). Nivolumab obtained an OR and a disease control (CR+PR+stable disease (SD)) in 15% and 45% of 20 patients who had received at least two prior chemotherapy lines (39) (Table I). Immunohistochemical expression of PD-L1 was high in 16 patients (80%) and low in 4 (20%); however, this variable did not correlate with OR rate.
Varga et al. (40) reported an OR rate of 11.5% and a disease control rate of 34.6% in 26 women with PD-L1-positive advanced EOC treated with pembrolizumab (Table I). Eighty-five per cent of the patients had received prior therapies for recurrent/metastatic disease, whereas 38.5% had received five or more therapies.
Avelumab achieved an OR in 9.7% and a disease control in 54.0% of 124 women with recurrent or refractory EOC (41) (Table I). PD-L1 expression was evaluable in 74 cases. Using a ≥1% cut-off for tumor cell staining, 57 women (77.0%) were PD-L1+, with OR rate being 12.3% in PD-L1-positive versus 5.9% in PD-L1-negative patients.
Phase I-II studies of anti-programmed cell death (PD)1 or anti-programmed cell death ligand (PD-L)1 antibodies in platinum-resistant epithelial ovarian cancer.
In a phase I trial, Brahmer et al. (22) administered the anti-PD-L1 mAbBMS-936559 to 207 patients with selected advanced cancers (Table I). Among the 17 women with EOC, 1 (5.9%) had a PR and 4 (23.5%) had a disease control, all at the 10-mg dose.
Combining the nivolumab and avelumab studies, it has been observed that 4 of the 5 patients who experienced durable responses had clear cell EOC (CCOC), which is a chemoresistant histologic type. Alterations of the phosphatidylinositol 3-kinase (PIK3CA)/AKT/mammalian target of rapamycin (mTOR) pathway have been detected in 15%-75% of CCOCs (42-49) and preclinical data from non-small cell lung cancer have suggested that activation of this pathway correlates with an increased expression of PD-L1 in tumor cells (50).
The administration of ipilimumab after vaccination with irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor showed antitumor effects also in patients with stage IV EOC (51). In a phase II study, 40 patients with recurrent platinum-sensitive EOC were scheduled to receive ipilimumab (10 mg/kg) every 3 weeks for 4 cycles (induction phase) followed by ipilimumab (10 mg/kg) every 12 weeks until progression or unacceptable toxicity (52). Thirty-eight patients (95%) did not complete the induction phase, mainly because of progression or toxicity. The OR rate was 10.3% and G≥3 AEs occurred in 50% of the patients.
Table II shows the ongoing trials of checkpoint inhibitors alone or in combination with chemotherapy in EOC.
Immune checkpoint inhibitors have demonstrated remarkable activity against hypermutated cancers, such as melanoma and lung cancer, and against tumors with mismatch repair (MRR) gene alterations, such as colon cancer, which harbor more tumor-specific neoantigens (53-56). This higher antigen load enhances the recruitment of an increased number of TILs, which is counterbalanced by PD-1 or PD-L1 overexpression. Strickland et al. (57) subdivided 245 tumor samples from patients with HGSOC in three groups: BRCA1-2 mutated (n=54), wild-type (wt)-BRCA1-2 with homologous recombination (HR) deficiency (HRD) (n=69) and wt-BRCA1-2 without HRD (HR-proficient tumors).Wt-BRCA1-2 with HRD tumors harbored mutations in several HR genes, such as Fanconi anemia, RAD50, RAD51, RAD54L, ATM and ATR, tensin homolog deleted on chromosome (PTEN) deletion, EMSY amplification or mutation and promoter hypermethylation of BRCA1 or RAD51C. Neoantigen load was higher in the BRCA1-2 mutated subset compared with HR-proficient subset (p=0.008), as well as in wt-BRCA1-2 with HRD cohort compared with HR-proficient cohort (p=0.003). Moreover, BRCA1-2 mutated tumors showed a significantly increased CD3+ and CD8+ TIL number anda significantly higher expression of PD-1 and PD-L1 compared with HR-proficient tumors. Therefore, BRCA1-2-mutated HGSOCs could represent a subset of tumors fit for treatment with immune checkpoint inhibitors alone or in combination with poly(adenosine diphosphate (ATP-ribose) polymerases (PARP) inhibitors (57-59). Moreover, Strickland et al. (60) found that 3 out of 30 (10%) CCOCs exhibited microsatellite instability (MSI) and that CCOCs with MSI had a higher number of CD3+ TILs and higher number of PD1-positive TILs compared with both microsatellite stable (MSS) CCOCs and HGSOCs. Therefore, CCOCs with MSI may represent an immunogenic subset of tumors likely to respond to anti-PD-1/PD-L1 mAbs.
Ongoing trials of checkpoint inhibitors alone or in combination with chemotherapy in epithelial ovarian cancer.
Several phase I-II studies are currently testing immune checkpoint inhibitors in combination with other biological agents, such as PARP inhibitors or anti-angiogenic agents, in patients with recurrent EOC.
The NCT02571725 trial will assess the side-effects and best dose of tremelimumab when given together with the PARP inhibitor olaparibin patients with recurrent platinum-sensitive or platinum-resistant EOC, fallopian tube cancer (FTC) or primary peritoneal cancer (PPC) and germline BRCA1 or BRCA2 mutation.
The NCT02734004 trial will evaluate the safety, tolerability, pharmacokinetics and antitumor activity of durvalumab in combination with olaparib in patients with different advanced solid tumors, including those with recurrent platinum-sensitive EOC and germline BRCA mutation.
The NCT02953457 trial will study the side-effects and best dose of olaparib when given together with durvalumab and tremelimumab, as well as the activity of this combination in treating patients with recurrent platinum-sensitive or -resistant or -refractory EOC, FTC or PPC and germline or somatic BRCA1 or BRCA2 mutation.
The NCT02484404 study will test the safety and activity of durvalumab in combination with olaparib and/or the vascular endothelial growth factor (VEGF) receptor inhibitor cediranib in patients with different advanced solid tumors, including those with recurrent platinum-sensitive, -resistant or -refractory EOC, FTC or PPC and germline BRCA1 or BRCA2 mutation.
NCT02657889 will assess the safety and efficacy of combination treatment with the PARP inhibitor niraparib and pembrolizumab in patients with triple-negative breast cancer who have received ≤3 lines of prior chemotherapy in the metastatic setting or with recurrent, platinum-resistant EOC who have received ≤4 lines of prior chemotherapy for advanced disease.
Endometrial Cancer
The dualistic model for endometrial cancer (EC) subdivides this malignancy in two main categories: type-I estrogen-dependent endometrioid carcinomas and type-II estrogen-independent non-endometrioid carcinomas (61-63). Major molecular alterations of type-I carcinomas include PTEN silencing, PIK3CA mutations, MMR defects, MSI and K-RAS or β-catenin (CTNNB) mutations, whereas type II-carcinomas often show p53 mutations, p16 inactivation, low E-cadherin expression, Her-2/neu overexpression, STK15 amplification and loss of heterozygosity (LOH) on several chromosomes (62-67).
The loss of PTEN function with consequent activation of PIK3CA/AKT/mTOR pathway is an early and common event in the pathogenesis of endometrioid carcinomas, occurring approximately up to 80% of these malignancies and 55% of endometrial hyperplasias (68, 69). Beta-catenin mutations with nuclear protein accumulation, MSI, and K-RAS mutations have been detected in 25% to 38%, 25% to 35% and 10% to 30% of endometrioid carcinomas, respectively (62, 63, 68-70). Whereas MSI, PTEN alterations or K-RAS mutations may coexist in many cases, these molecular abnormalities are not usually associated with β-catenin mutations. However, this dualistic model does not take into account the molecular, biological and pathological heterogeneity among each category and recently a novel classification system has been proposed by The Cancer Genome Atlas Research Network (TCGA) (71, 72). The integrated genomic, transcriptomic and proteomic characterization of 373 ECs using array- and sequencing-based technologies has suggested to classify these malignancies into four categories: polymerase ε (POLE) ultramutated, MSI hypermutated, copy number low (endometrioid) and copy number high (serous-like).
POLE is a catalytic subunit of DNA polymerase involved in DNA replication, DNA repair and cell cycle control (73). POLE ultramutated tumors display very high mutation rates (232×10−6 mutations/Mb) and are characterized by hotspot mutations in the exonuclease domain of POLE, high frequency of base substitutions and large excess of cytosine → adenine transversions, elevated incidence of PTEN, PIK3CA, FBXW7 and K-RAS mutations, strong association with endometrioid histology and MSS (71, 72, 74). Although p53 mutations can be detected in approximately one third of the cases, it is important not to misclassify these tumors as serous carcinomas (75). Tumor grade ranges from 1 to 3 but more frequently is 3, with prognosis beingexcellent also in cases with high histological grade (75-79). POLE mutations were detected in 6.1% of 788 ECs enrolled in PORTEC-1 and-2 randomized trials. Women with POLE-mutant ECs had fewer relapses (6.2% versus 14.1%) and tumor-related deaths (2.3% versus 9.7%) (76). It is noteworthy that among the 109 grade 3 tumors, disease relapsed in none of 15 POLE-mutant carcinomas versus 30.9% of 94 POLE wild-type carcinomas. Meng et al. (77) identified POLE mutations in 15% of 53 grade 3 endometrioid carcinomas compared with 0% of 25 serous carcinomas, 0% of 16 clear cell carcinomas and 0% of 5 de-differentiated carcinomas. None of the patients with POLE mutated tumors in this study (77), as well as in the study of Hussein et al. (75), developed recurrent disease. McCornery et al. (79) detected POLE mutations in 9.6% of 406 ECs. POLE-mutated women were younger and frequently had stage I disease (92%), tumor grade 3 (62%), endometrioid histology (82%) and lymphovascular space involvement (LVSI) (49%). POLE mutation was an independent favorable prognostic variable for PFS (HR=0.34, 95%CI=0.15-0.73) and disease-specific survival (DSS) (HR=0.35, 95%CI=0.13-0.92).
MSI hypermutated ECs show high mutation rates (18×10−6 mutations/Mb), recurrent RPL22 frameshift deletions, frequent PTEN and K-RAS mutations, as well asendometriod histology (71, 72). Tumor grade ranges from 1 to 3, with prognosis beingusually good but less favorable than that of POLE ultramutated EC (intermediate prognosis). Alterations of MMR genes are involved in the pathogenesis of the hypermutated tumors.
Copy number low ECs include MSS grade 1-2 endometrioid tumors with low mutation rates (2.9×10−6 mutations/Mb), frequent PTEN, PI3KCA and β-catenin (CTNNB) mutations and intermediate prognosis, whereas copy number high (serous-like) ECs show extensive copy number aberrations, low mutation rates (2.3×10−6 mutations/Mb), very frequent p53 mutations and MSS (71, 72). Histological type can be serous, grade 3 endometrioid, as well asmixed, serous and endometrioid, with poor prognosis.
The immune system plays an important role both in the physiological changes of endometrium and inendometrial carcinogenesis (80, 81). de Jong et al. (82) assessed CD8+ TILs and T-reg cells on paraffin-embedded tissue specimens from 368 patients with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I-IV EC. A high number of CD8+ T cells and/or a high CD8+ T cell /T-reg cell ratio correlated with early stage, low histologic grade, superficial myometrial invasion, lack of LVSI, negative lymph nodes and absence of distant metastases at the time of diagnosis. A high number of CD8+ T cells was an independent favorable prognostic variable for OS in the entire cohort (HR=0.48, 95%CI.=0.26-0.89) and in type II ECs (HR=0.17, 95% CI=0.08-0.36), whereas a high CD8+ T cell/T-reg cell ratio was an independent good prognostic factor for OS in type I ECs (HR=0.44, 95%CI=0.23-0.84). The analysis of paraffin-embedded specimens from 53 women with EC revealed thatT-reg cell count and T-reg cell/CD8+ T cell ratios were significantly higher in patients with advanced, poorly differentiated carcinomas and with LVSI than in those with early, well-differentiated carcinomas and without LVSI (83). Disease-free survival (DFS) of patients with high T-reg cell count and high T-reg cell/CD8+ T cell ratio was significantly worse than that of patients with low T-reg cell count and low T-reg cell/CD8+ T cell ratio.
PD-1 and PD-L1 have been detected in EC tissues (84, 85). The immunohistochemical analysis of tumor samples from 301 ECs showed positive immunostaining for PD-1 and PD-L1 in 77.9% and 39.7%, respectively, of endometrioid carcinomas, 68.2% and 10.2% of serous carcinomas, 69.2% and 23.1% of clear cell carcinomas and 80.0% and 22.2% of carcinosarcomas (84).
Howitt et al. (86), who assessed tumor specimens from 63 patients with EC, found that median neoantigen load per sample was 8,342 (range=628-20,440) in POLE ultramutated tumors, 541 (range=146-8,063, p<0.001) in MSI hypermutated tumors and 70.5 (range=7-1,877, p<0.001) in MSS tumors. Similarly, POLE ultramutated and MSI hypermutated ECs had significantly higher numbers of CD3+ TILs and CD8+ TILs compared with MSS ECs; this high immunogenicity could be an explanation of their favorable prognosis. Moreover, PD-1 was overexpressed in TILs and peritumoral lymphocytes of POLE and MSI tumors, whereas PD-L1 expression was infrequent in tumor cells but common in intraepithelial immune cells, especially in POLE and MSI tumors. Therefore, POLE ultramutated and MSI hypermutated ECs show high neoantigen load and high number of TILs, counterbalanced by PD-1 and PD-L1 overexpression. Such features could represent a strong rationale for testing immune checkpoint inhibitors in these cancer subgroups (86-88).
Santin et al. (89) reported a remarkable clinical response to nivolumab intwo patients with recurrent, heavily pretreated ultramutated or hypermutated endometrial cancer.
The ongoing trials of checkpoint inhibitors in EC are shown in the Table III. In the NCT02630823 trial, the mechanism of action of pembrolizumab on tumor environment will be investigated by examining both pre-treatment endometrial biopsy and the definite surgical specimen after two cycles of pembrolizumab.
Ongoing trials of checkpoint inhibitors in endometrial cancer and cervical cancer.
Cervical Cancer
The goal of treatment of women with recurrent, persistent or metastatic cervical cancer (CC) not amenable to surgery or radiotherapy is palliation of symptoms and prolongation of survival and the combination of paclitaxel (TAX) + cisplatin (CDDP) has been long considered as the standard of care (90). The Gynecologic Oncology Group (GOG) 240 phase III trials randomized 452 patients with stage IVB, recurrent or persistent CC to receive combination chemotherapy with TAX + CDDP (every 3 weeks) or topotecan + TAX (every 3) weeks with or without bevacizumab (BEV) (15 mg/kg every 3 weeks) (91). Topotecan + TAX showed a significantly higher risk of progression and a trend to a higher risk of death when compared with CDDP + TAX either with or without BEV. With the data for the two regimens combined together, the addition of BEV significantly improved median PFS (8.2 versus 5.9 months; HR=0.67, 95% CI=0.54-0.82) and median OS (17.0 versus 13.3 months; HR=0.71, 95% CI=0.54-0.95) compared with chemotherapy alone.
The treatment after platinum failure is a big challenge and the currently available single-agents, such as topotecan (92), vinorelbine (93), gemcitabine (94), pemetrexed (95), capecitabine (96), docetaxel (97) and nab-paclitaxel (98), have shown unsatisfactory activity. Therefore, the assessment of novel drugs, such as immunecheckpointinhibitors, is strongly warranted in this clinical setting (99-102).
Both PD-1 and PD-L1 have been detected in CC tissues (101, 103-106). Heeren et al. (106) assessed PD-L1 expression in tumor specimens from two cohorts of CC patients: primary tumor samples from cohort I (squamous cell carcinoma (SCC), n=156 and adenocarcinoma (AD), n=49) and primary and paired metastatic tumor samples from cohort II (SCC, n=96 and AD, n=31). PD-L1 positivity was observed in >5% of the tumor cells in 54% of SCCs and in 14% of ADs (p<0.001), PD-L1-positive TAMs were present in 53% of the former and 12% of the latter (p<0.001) displaying an M2-like phenotype characterized by pro-tumorigenic properties (107). DFS and DSS were significantly poorer in SCC patients with diffuse PD-L1 expression than in those with marginal PD-L1 expression in primary tumors (p=0.022 and p=0.046, respectively). Moreover, DSS was worse in AD patients with PD-L1-positive TAMs than in those without PD-L1-positive TAMs (p=0.014).
More dense cordons of PD-L1-positive immune cells were found surrounding the metastases compared with the paired primary tumors in both SCC and AD. These findings appear to provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway in CC.
Several phase I-II trials are currently testing immune checkpoint inhibitors in CC but no results have been releasedyet (Table III).
In the NCT02257528 trial,immune infiltration-related biomarkers (i.e., CD4+T, CD8+ T, T-reg) in tumor specimens and PD-1 and PD-L1 expression in TILs and CC cells will be related to OR, PFS and OS of patients with persistent, recurrent or metastatic CC treated with nivolumab.
NCT02488759 is a phase 1-2 study investigating the safety and efficacy of nivolumab alone andin combination with ipilimumab or BMS-986016 anti- lymphocyte activation gene-3 (LAG-3) mAb or daratumumab (anti-CD38 mAb) in patients with different tumors, including squamous cell carcinoma of the cervix, vagina, or vulva.
Longoria and Tewari (100) have proposed a clinical trial of combined anti-angiogenic therapy and immunotherapy in metastatic, recurrent or persistent CC. Patients with evidence of response and no unacceptable toxicity after combination chemotherapy (CDDP+TAX or carboplatin+TAX or topotecan+ TAX) plus BEV (15 mg/kg every 3 weeks) for 7 cycles will be randomly allocated to receive either chemotherapy +BEV + nivolumab (3 mg/kg) every 3 weeks or chemotherapy + BEV + placebo every 3 weeks until progression or unacceptable toxicity.
Conclusion
Very limited data are currently available about the activity of immune checkpoint inhibitors in gynecological cancers; however, immune checkpoint inhibitors, and especially anti-PD-1 and anti-PD-L1 mAbs, could represent a novel pharmacological tool for the management of gynecological malignancies, although is yet to be defined which patients could draw a greater clinical benefit from these agents and when immunecheckpointinhibitors should be incorporated into the therapeutic strategy (37, 108, 109). Moreover, reliable biomarkers predictive of response have not been identified yet.
BRCA1-2-mutated HGSOC and CCOC with MSI could have an elevated probability of response to these agents because these tumors show increased neoantigen load, increased CD3+ and CD8+ TIL number, as well as PD-1 and PD-L1 overexpression. Immune checkpoint inhibitors in combination with PARP inhibitors are currently investigated in patients with recurrent EOC and mutated BRCA1-2.
As far as EC is concerned, POLE ultramutated tumors have a median number of neo-antigensalmost 15-fold higher than MSI hypermutated tumors,with the latter having a median number of neo-antigens 7-fold higher than MSS tumors. POLE ultramutated and MSI hypermutated ECs exhibit a high number of TILs counter balanced by PD-1 and PD-L1 overexpression and, therefore, they are likely to be sensitive to PD-1/PD-L1 pathway blockade. Immune check-point inhibitors could have a role as maintenance treatment in patients with persistent, recurrent or metastatic CC in response after chemotherapy.
Footnotes
This article is freely accessible online.
- Received May 8, 2017.
- Revision received May 23, 2017.
- Accepted June 2, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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