Clinical implication of naive and memory T cells in locally advanced cervical cancer:A proxy for tumor biology and short-term response prediction

Background:This study was designed to investigate the feasibility of tumor-infiltrating immune cells with different phenotypic characteristics for predicting short-term clinical responses in patients with locally advanced cervical cancer(LACC).Methods:Thirty-four patients who received concurrent chemoradiotherapy and twenty-one patients who merely underwent radiotherapy were enrolled in this study.We retrospectively analyzed the T cell markers(i.e.,CD3,CD4,CD8),memory markers(i.e.,CD45,CCR7),and differentiation markers(i.e.,CD27)in the peripheral blood and tumor tissues of patients with LACC before treatment based on flow cytometry.We also analyzed the relationship of T cell subsets between peripheral blood and tumor tissues,and their correlation with complete response or partial response.Results:The percentage of central memory CD8^(+)TCM(CD8^(+)CD45RA^(−)CD27^(+)CCR7^(+))cells in LACC patients was significantly lower than that of the control group.The percentage of CD8^(+)TN in the peripheral blood of LACC patients was significantly higher than that of tumor tissues.CD8^(+)TEM in the peripheral blood was significantly lower than that of tumor tissues.The percentage of CD8^(+)TN and CD8^(+)TCM in human papillomavirus(HPV)positive samples was significantly higher than that of HPV-negative samples.Similarly,the percentage of CD8^(+)TCM in tumor tissues was significantly higher in cancer tissue samples with lymph nodes compared with those without.Conclusion:A higher proportion of CD4^(+)TCM and a lower proportion of CD8^(+)TN in the tumor microenvironment of LACC may contribute to the therapy response prediction.

Correlations between alterations of T-helper 17 cells and treatment efficacy after concurrent radiochemotherapy in locally advanced cervical cancer (stage IIB-IIIB): a 3-year prospective study

Background::Recently,T-helper 17(Th17)cells have been proved to play an important role in promoting cervical cancer.But,till now,few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments.This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer(LACC)patients before and after concurrent chemoradiotherapy(cCRT)and to analyze the correlations between the alterations in Th17 cells and treatment efficacy.Methods::A prospective study with 49 LACC(International federation of gynecology and obstetrics[FIGO]stage IIB-IIIB)patients and 23 controls was conducted.Patients received the same cCRT schedule and were followed up for 3 years.Circulating Th17 cells(CD3+CD8-interleukin[IL]-17+T cells)and related cytokines IL-17,transforming growth factor-β(TGF-β),IL-10,IL-23,IL-6,and IL-22 were detected before and after cCRT.Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed.Kaplan-Meier analysis was used for overall survival(OS)and progression-free survival(PFS).Results::We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study.The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls,and it significantly decreased after cCRT(P<0.05).After cCRT,patients were divided into two groups based on the average of the Th17 cells declined.The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times.Compared with the control patients,LACC patients had higher IL-6,IL-10,IL-22,TGF-βlevels and a lower IL-23 level(P<0.05).After cCRT,IL-6,IL-10,IL-17,IL-23 level significantly increased and TGF-βlevel significantly decreased compared with the levels before cCRT(P<0.05).Conclusion::Circulating Th17 cells in the LACC patients(FIGO stage IIB-IIIB)were higher than those in the controls,but they generally decreased after cCRT.A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.

Specific Immunotherapy in Advanced Cervical-Uterine Cancer Using Humanized Monoclonal Antibody Nimotuzumab and CIMAvax-EGF^®Therapeutic Vaccine

Cervical uterine cancer represents the fourth most common malignant neoplasm worldwide in the female sex in terms of incidence, principally from epithelial origen. The high expression of EGFR in this tumor leads to the search for therapeutic alternatives. An Expanded Access Clinical Program was carried out in parallel groups, randomized, multicenter and prospective study, to evaluate the survival of patients with advanced cervical carcinoma, without therapeutic alternative, who would be treated with the therapeutic vaccine CIMAvax-EGF®, the humanized mAb nimotuzumab or the combination of both products, which targeted EGF and EGFR respectively. The patients were included between 2008 and 2010 with a more than five years follow-up. The results show that the serious adverse events related to the experimental treatments were 0.9%;1.1% and 2.6% and a median ITT survival of 9.1, 23.5, and 16.3 months for CIMAvax-EGF®, nimotuzumab and the combination of both, respectively. Thus fulfilling the hypothesis of safety and efficacy proposed in the investigation was achieved. The three therapeutic regimens achieved overall survival rates greater than 35% at 60 months, encouraging results for advanced uterine cervical cancer. A phase III clinical trial is proposed to consolidate these results in a greater number of patients with nimotuzumab as study drug.

Concurrent chemoradiotherapy for cervical cancer： background including evidence-based data, pitfalls of the data, limitation of treatment in certain groups

Concurrent chemoradiotherapy （CCRT） is regarded as the standard treatment for locally advanced uterine cervical cancer （LACC）, including stage Ib2-IVa disease [International Federation of Gynecology and Obstetrics （FIGO） staging]. However, approximately a third of eligible patients in previous studies died of LACC despite receiving CCRT. The therapeutic significance of CCRT alone in stage Ⅲ-IVa disease has not yet been confirmed. Effective treatment of some LACC is beyond the scope of CCRT. The objective of the present review is to highlight some challenging work aimed at overcoming this seemingly intractable disease. CCRT with increased peak concentrations of cisplatin （CDDP）, surgery following CCRT, adjuvant chemotherapy （CT） following CCRT, and neoadjuvant CT followed by CCRT are strategies expected to enhance the therapeutic efficacy of CCRT. If patients with LACC were divided into those with low-risk or high-risk systemic disease or prognoses, novel strategies should be assessed in the group with high-risk disease.

Different strategies of treatment for uterine cervical carcinoma stage ⅠB2-ⅡB

Uterine cervical cancer is the second most common gynecological malignancy. It is estimated that over 35% of tumors are diagnosed at locally advanced disease, stage ⅠB2-ⅡB with an estimated 5-year overall survival of 60%. During the last decades, the initial treatment for these women has been debated and largely varies through different countries. Thus, radical concurrent chemoradiation is the standard of care in United Sated and Canada, and neoadjuvant chemotherapy followed by radical surgery is the first line of treatment in some institutions of Europe, Asia and Latin America. Until today, there is no evidence of which strategy is better over the other. This article describe the evidence as well as the advantages and disadvantages of the main strategies of treatment for women affected by uterine cervical cancer stage ⅠB2-ⅡB.