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Bevacizumab-Based Chemotherapy Triggers Immunological Effects in Responding Multi-Treated Recurrent Ovarian Cancer Patients by Favoring the Recruitment of Effector T Cell Subsets.

ABSTRACT: Increasing evidence strongly suggests that bevacizumab compound impacts the immunological signature of cancer patients and normalizes tumor vasculature. This study aims to investigate the correlation between the clinical response to bevacizumab-based chemotherapy and the improvement of immune fitness of multi-treated ovarian cancer patients. Peripheral blood mononuclear cells (PBMCs) of 20 consecutive recurrent ovarian cancer patients retrospectively selected to have received bevacizumab or non-bevacizumab-based chemotherapy (Bev group and Ctrl group, respectively) were analyzed. CD4, CD8, and regulatory T cell (Treg) subsets were monitored at the beginning (T0) and after three and six cycles of treatment, together with IL10 production. A lower activated and resting Treg subset was found in the Bev group compared with the Ctrl group until the third therapy cycle, suggesting a reduced immunosuppressive signature. Indeed, clinically responding patients in the Bev group showed a high percentage of non-suppressive Treg and a significant lower IL10 production compared with non-responding patients in the Bev group after three cycles. Furthermore, clinically responding patients showed a discrete population of effector T cell at T0 independent of the therapeutic regimen. This subset was maintained throughout the therapy in only the Bev group. This study evidences that bevacizumab could affect the clinical response of cancer patients, reducing the percentage of Treg and sustaining the circulation of the effector T cells. Results also provide a first rationale regarding the positive immunologic synergism of combining bevacizumab with immunotherapy in multi-treated ovarian cancer patients.

SUBMITTER: Napoletano C

PROVIDER: S-EPMC6462947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWe have previously shown that HCC patients and healthy subjects are equally responsive to a RNAdjuvant®, a novel TLR-7/8/RIG-I agonist based on noncoding RNA developed by CureVac, by an ex vivo evaluation. However, the immunological effect of adjuvants on immune cells from cancer patients undergoing chemotherapy remains to be demonstrated. Different adjuvants currently used in cancer vaccine clinical trials were evaluated in the present study on immune cells from cancer patients before and after chemotherapy in an ex vivo setting.MethodsPBMCs were obtained from 4 healthy volunteers and 23 patients affected by either colon (OMA) or lung cancer (OT). The effect of CpG, Poly I:C, Imiquimod and RNA-based adjuvant (RNAdjuvant®) was assessed using a multiparametric approach to analyze network dynamics of early immune responses. Evaluation of CD80, CD86 and HLA-DR expression as well as the downstream effect on CD4+ T cell phenotyping was performed by flow cytometry; cytokine and chemokine production was evaluated by Bio-Plex ProTM.ResultsTreatment with RNAdjuvant® induced the strongest response in cancer patients in terms of activation of innate and adoptive immunity. Indeed, CD80, CD86 and HLA-DR expression was found upregulated in circulating dendritic cells, which promoted a CD4+ T cell differentiation towards an effector phenotype. RNAdjuvant® was the only one to induce most of the cytokines/chemokines tested with a pronounced Th1 cytokine pattern. According to the different parameters evaluated in the study, no clear cut difference in immune response to adjuvants was observed between healthy subjects and cancer patients. Moreover, in the latter group, the chemotherapy treatment did not consistently correlate to a significant altered response in the different parameters.ConclusionsThe present study is the first analysis of immunological effects induced by adjuvants in cancer patients who undergo chemotherapy, who are enrolled in the currently ongoing cancer vaccine clinical trials. The results show that the RNAdjuvant® is a potent and Th1 driving adjuvant, compared to those tested in the present study. Most importantly, it is demonstrated that chemotherapy does not significantly impair the immune system, implying that cancer patients are likely to respond to a cancer vaccine even after a chemotherapy treatment.

Project description:BackgroundRecent studies showed inconsistent results of bevacizumab combined with chemotherapy vs single-agent therapy in terms of their safety and efficacy for the treatment of recurrent glioblastoma. Therefore, we performed a meta-analysis to explore the value of bevacizumab combined with chemotherapy and single-agent therapy in recurrent glioblastoma treatment.MethodsDatabases such as MEDLINE, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) related to the topic of bevacizumab combined with chemotherapy and single-agent therapy as treatments for recurrent glioblastoma from January 1980 to April 2018. Subsequent articles were then sorted, evaluated, and analyzed.ResultsWe pooled 1,169 patient cases from seven RCTs. Bevacizumab combined with chemotherapy showed a significantly improved progression-free survival (PFS) (HR=0.65; 95% CI 0.57-0.74; P<0.001) compared to single-agent therapy. In addition, the overall survival (OS) rate showed insignificant differences between the two groups (HR=0.96; 95% CI 0.83-1.12; P=0.622). Simultaneously, we found that bevacizumab combined with chemotherapy had a higher objective response rate (ORR) (OR=2.10; 95% CI 1.32-3.33; P=0.002), but also higher incidence of adverse events (AEs) (OR=1.85; 95% CI 1.26-2.71; P=0.002). However, in subgroup analysis, we found that AEs showed insignificant differences between the two treatment methods when bevacizumab was used as the single-agent therapy subgroup (P=0.058). In addition, in the subgroup with low corticosteroid use rate at baseline (N<50%), ORR (P=0.108) and AEs (P=0.134) showed insignificant differences between the two groups.ConclusionBevacizumab combined with chemotherapy can significantly improve PFS and ORR, but did not prolong OS in these studies, and can even lead to higher odds of AEs. In addition, bevacizumab may play a dominant role and corticosteroid may be an unfavorable factor in the combination therapy of recurrent glioblastoma.

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Bevacizumab-Based Chemotherapy Triggers Immunological Effects in Responding Multi-Treated Recurrent Ovarian Cancer Patients by Favoring the Recruitment of Effector T Cell Subsets.

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