Abstract P2-04-05: Immunomodulation effects of metronomic oral Vinorelbine (mVRL), with or without capecitabine (CAPE), on Treg levels in advanced breast cancer (ABC) patients (pts). Preliminary results of the VICTOR-5 study
Authors: Cazzaniga ME , Baroni S , Riva F , Vigorè L , Malandrin S , Cicchiello F , Pelizzoni D , Lissoni P , Manfrida I , Brando B , Bidoli P 
Published: May 2019

BACKGROUND

In cancer patients, the accumulation of Tregs is associated with tumor progression and the suppression of anti-tumor immune response. Metronomic cyclophosphamide (mCTX) induces a profound and selective reduction of circulating Tregs, whereas no data are available regarding a possible effect on immune system. In the present analysis, we report preliminary data of Treg frequencies and function during a period of treatment of 2 months and correlations with anti-tumour T-cell response, in a group of HR+/HER2ve ABC pts.

PATIENTS AND METHODS

Following approval by the Ethical Committee, a sample of 3 ml of peripheral blood was drawn from 12 ABC pts for which mVRL 40- 50 mg thrice a week (N=10), ± mCAPE 1500 mg/day (N=2), was indicated. Median age was 66,5 years (45-86); 2/ 12 received the mCHT as 1st-line therapy, 10/12 as 2nd-line or further. Blood samples were collected at baseline (T0) and after 14 (T1), 28 (T2), 42 (T3) and 56 days (T4) of treatment. Total lymphocytes (TL) and lymphocyte subgroups were determined according to NaacK et Al guide lines. The Treg subpopulations have been identified by monoclonal antibodies CD45 V500, CD3 V450, CD4 PerCP-Cy5.5, CD25 PE, CCR4 PE-Cy7, CD 27 Alexa 647, CD45RO APC-H7, CD28 FITC, (BD Biosciences, San Jose, CA) and analyzed with BD FACS CantoTM II (Becton Dickinson, San Jose, CA), technic Lyse/Wash and software FACSDivaTM.

RESULTS

Data for the purpose of this analysis are available for 10 out of 12 enrolled pts. mVRL ± mCAPE induced a significant reduction of circulating Treg in 6/10 pts (60%) – Group A - at day 14. Median percentages of Treg among CD4+ cells were 9.4% ±1.5% SE at baseline vs 6.8% ± 4.5% SE and 7.6% ± 1.2% SE after 14 and 28 days of treatment in Group A. In patients without Treg depletion – Group B – median percentages of Treg were 8.4% ± 0.9% SE, 9.6% ± 1.3%SE and 8.2% ± 1.5%SE as measured at the same time points. The depletion of Treg is associated with a slight expansion of CD8+ cells in Group A at all times of evaluation. No increase in CD8+ population has been observed in Group B. Median percentages of Treg and CD8+ cells in the two Groups are reported in Tables 1 & 2.

Frequency of CD4+CD25+ (Treg) among total CD4+ T cells in Group A (pts with Treg depletion) and Group B (pts w/o Treg depletion)Time of evaluationMean Treg % +/- SE% - Group AMean Treg % +/- SE% - Group BT0 (baseline)9.4% +/- 1.5%8.4% +/- 0.9%T1 (+14 days)6.8% +/- 4.5%9.6% +/- 1.3%T2 (+28 days)7.6% +/- 1.2%8.2% +/- 1.5%

Frequency of CD8+ cells among total lymphocites in Group A (pts with Treg depletion) and Group B (pts w/o Treg depletion) Mean CD8+ (%) +/- SE% - Group AMean CD8+ +/- SE% - Group BT0 (baseline)20.6% +/- 1.9%30.6% +/- 3.8%T1 (+14 days)21.6% +/- 1.9%30.6% +/- 4.3%T2 (+28 days)225.5 +/- 1.9%30.8% +/- 4.7%

CONCLUSION

Our results suggest that mVRL induces different immunomodulation effects in an unselected population of ABC pts. Treg depletion seems to increase the adaptive immune response. Data obtained from a longer follow up will be presented. These findings are hypothesis-generating for future evaluation of mVRL as a priming agent to increase response to anti PDL-1 agents.

Citation Format: Cazzaniga ME, Baroni S, Riva F, Vigorè L, Malandrin S, Cicchiello F, Pelizzoni D, Lissoni P, Manfrida I, Brando B, Bidoli P. Immunomodulation effects of metronomic oral Vinorelbine (mVRL), with or without capecitabine (CAPE), on Treg levels in advanced breast cancer (ABC) patients (pts). Preliminary results of the VICTOR-5 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-05.