Peter Vuylsteke (Namur, Belgium)
Clinique Sainte-ElisabethAuthor Of 2 Presentations
43P - Dynamic alterations of immunosenescence-related genes in older women with breast cancer receiving chemotherapy (ID 61)
- Qi Wu (Leuven, Belgium)
- Barbara Brouwers (Brugge, Belgium)
- Bruna S. Dalmasso (Genova, Italy)
- Cindy Kenis (Leuven, Belgium)
- Lissandra Dal Lago (Brussels, Belgium)
- Patrick Neven (Leuven, Belgium)
- Peter Vuylsteke (Namur, Belgium)
- Guy Debrock (Genk, Belgium)
- Heidi F. Van den Bulck (Bonheiden, Belgium)
- Ann Smeets (Leuven, Belgium)
- Annouschka Laenen (Leuven, Belgium)
- Hans Wildiers (Leuven, Belgium)
- Sigrid Hatse (Leuven, Belgium)
Abstract
Background
The exact impact of chemotherapy on the immune system of older patients with breast cancer is not well known. This longitudinal study was performed investigating the evolution of the blood immune profile during and after chemotherapy in this population.
Methods
The study included 39 patients receiving adjuvant chemotherapy (chemotherapy group, CTG, median age, 73 years) and 32 patients receiving only hormone therapy (control group, CG, median age, 76 years). A 10-gene panel associated with immunosenescence was measured in peripheral blood mononuclear cells (PBMC) before (T1), at 3 months (T2) and at 12 months (T3) after initiation of adjuvant therapy. Nutrition status was assessed by using a mini nutritional assessment scale (≥12 normal; <12 abnormal). Longitudinal mixed model analyses were performed for trajectory evolution, with or without adjusting for age, tumor stage, breast cancer phenotype, and/or corresponding baseline gene levels.
Results
Six genes relating to T cell activation (CD28, CD27, CD86, LCK, GRAP, LRRN3 ), and two genes relating to oxidative stress (PRDX6, HMOX1) exhibited a significant group-by-time effect, even after adjusting covariates (p≤ 0.01). In CTG, the T cell activation genes substantially declined from T1 to T2 and bounced back to a level higher than baseline at T3 (p<0.03), which was not observed in CG (p>0.26). Patients with malnutrition detected at T1 experienced more pronounced perturbation regarding CD27, LCK, CD69, VAMP5, and LRRN3 (p<0.05).
Conclusions
Chemotherapy leads to transient perturbation of immune-related gene expression and potentially stimulates immunity in the long term. Well-nourished patients experience less impact of chemotherapy on immune-related gene expression profiles.
Clinical trial identification
This is a sub-study of NCT00849758.
Legal entity responsible for the study
The authors.
Funding
Fonds voor Wetenschappelijk Onderzoek – Vlaanderen.
Disclosure
All authors have declared no conflicts of interest.
171P - Biomarker and multivariate analyses results from AIPAC: A phase IIb study comparing eftilagimod alpha (a soluble LAG-3 protein) vs. placebo in combination with weekly paclitaxel in HR+ HER2- metastatic breast cancer (ID 179)
- Frederik Marmé (Mannheim, Germany)
- Hans Wildiers (Leuven, Belgium)
- Luc Dirix (Antwerp, Belgium)
- Anne Armstrong (Manchester, United Kingdom)
- Eveline De Cuypere (Brugge, Belgium)
- Florence Dalenc (Toulouse, France)
- Carolina Pia Schröder (Groningen, Netherlands)
- Peter Vuylsteke (Namur, Belgium)
- Etienne Brain (Saint-Claud, France)
- Sherko Kuemmel (Essen, Germany)
- Zsuzsanna Pápai (Budapest, Hungary)
- Christian Mueller (Berlin, Germany)
- Chrystelle Brignone (Orsay, France)
- Frederic Triebel (Orsay, France)
Abstract
Background
Eftilagimod alpha (EF) is a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules and mediates activation of antigen-presenting cells followed by T-cells. AIPAC investigated EF + paclitaxel (PA). We hereby report exploratory biomarker and multivariate analyses.
Methods
This double-blinded, 1:1 randomized phase IIb trial enrolled pts with HR+ HER2- MBC. Pts received PA (80 mg/m2 IV on D1, D8, D15) + EF (30 mg) or placebo (PL) on D2, D16 per cycle (28 days) for 24 wks + EF/PL for 52 wks. Exploratory EPs were potential biomarkers and their correlation to efficacy. Multivariate analysis used backward selection p>0.15 (univariate cox model). Blood cell subsets (CD4; CD8, PBMCs, monocytes) & Th1 biomarker CXCL-10 were measured centrally. Comparison was done using 2-sided Wilcoxon test.
Results
226 pts [efti n=114; placebo n=112] were included. Pts were endocrine resistant (84%), pre-treated with CDK4/6 inhibitors (44.2%). Post-study treatment was similar. Safety/efficacy were reported at SABCS 2020 #132; SITC 2021 #948 In the multivariate predictive model 4 groups (high Neutrophil/Lymphocyte Ratio [NLR]; no prior taxanes; low monocytes and <5 yrs since diagnosis) were significant for OS (Table) On treatment mean fold-changes of monocytes (5.81 vs. 2.29; p=0.025), PBMCs (2.00 vs. 1.41; p=0.041), T cells (2.28 vs. 1.48; p=0.086), & CXCL10 (2.78 vs. 1.56; p=0.06) were significantly higher (EF vs PL) and linked to higher OS. Post baseline CD4 (median 896/μl vs. 736 μl; p=0.038) & CD8 (median 377/μl vs. 223 μl; p=0.005) T cell count increased significantly in pts with higher OS EF vs. PL. OS for subgroups significant p<0.15 in the multivariate model
Subgroup Treatment group OS Median [95% CI] Absolute gain; Hazard ratio (HR) [95% CI]; p-value (univariate analysis) High (>3.65) NLR at baseline Efti 21.85 [13.6-29.0] +6.9 months; HR 0.61 [0.39-0.94]; p=0.012 Placebo 14.95 [8.9-17.6] No prior taxanes Efti 22.3 [17.3-33.0] +4.8 months; HR 0.74 [0.49-1.12]; p=0.076 Placebo 17.5 [12.3-23.5] Low (<0.25/nL) monocytes at baseline Efti 32.5 [18.2--] +19.6 months; HR 0.44 [0.22-0.88]; p=0.008 Placebo 12.9 [7.5-20.4] <5 yrs since diagnosis Efti 22.31 [11.93-33.0] +4.8 months; HR 0.62 [0.38-1.00]; p=0.025 Placebo 13.25 [9.0-17.6]
Conclusions
EF + PA elicits significant effects on different immune cells which is significantly associated with higher OS. Multivariate analysis identified potential target populations for phase III.
Clinical trial identification
The AIPAC trial protocol has been published, please see Dirix, L. & Triebel, F. Future Oncol. 2019 Jun;15(17):1963-1973. The trial identifiers are IMP321-P011 (code for sponsor), 2015-002541-63 (EudraCT) and NCT02614833.321-P011 (code for sponsor), 2015-002541-63 (EudraCT) and NCT02614833.
Legal entity responsible for the study
Immutep S.A.
Funding
Immutep S.A.
Disclosure
F. Marmé: Financial Interests, Personal, Other: Roche,AstraZeneca,Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, Eisai, Celegene, Clovis, Janssen-Cilag, Gilead/Immunomedics, GSK, MSD, Seagen, Myriad, Pierre Fabre. H. Wildiers: Financial Interests, Institutional, Research Grant: Roche & Novartis; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Roche, Pfizer; Other, Personal, Other, Consulting or Advisory Role: Roche, Lilly, Pfizer, AstraZeneca, AbbVie, Daiichi Sankyo, KCE, PSI Cro AG, MSD, AstraZeneca Pharmaceuticals Ireland & Immutep Pty; Other, Personal, Speaker’s Bureau: EISAI, MSD & AstraZeneca. A. Armstrong: Other, Personal, Other, Stock Or Otherownership: spousal shares in AstraZeneca; Other, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Conference fees: MSD, Gilead; Other, Institutional, Other, Ad Board Partication: MSD, Gilead. E. De Cuypere: Other, Personal, Other, Travel, Accomodations, Expenses: PharmaMar, MSD. F. Dalenc: Other, Personal, Other, Travel, Accomodations, Expenses: Pfizer, Roche. P. Vuylsteke: Other, Personal, Other, Consulting or Advisory role: Roche, MSD, BMS, Lily, Novartis; Other, Personal, Invited Speaker, Travel,Accomodations, expenses: Roche, Pfizer, Lily, BMS; Other, Personal, Invited Speaker, Speakers Bureau: Roche, Novartis. E. Brain: Other, Personal, Other, Honoraria: Eli Lilly, Pfizer, Seagen; Other, Personal, Other, Consulting or Advisory Role: Bristol Myers Squibb, Pfizer, G1 Therapeutics, Sandoz; Other, Personal, Other, Travel, Accomodations, Expenses: Pierre Fabre, Pfizer, AstraZeneca, Novartis, Roche, Sandoz. S. Kuemmel: Other, Personal, Other, Consulting Fees: Roche, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, MSD, Pfizer, PFM Medical, Lilly, Sonoscape, Seagen, Gilead; Other, Personal and Institutional, Other, Contracted Research: Somatex – Research Grant /Funding Institution; Other, Personal, Other, Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds): WSG – Westdeutsche Studiengruppe- Co-Director; Other, Personal, Other, Travel/Accommodation/Expenses: Roche/ Daiichi Sankyo/Sonoscape. C. Mueller: Other, Personal, Other, Employment: Immutep; Financial Interests, Personal, Financial Interests, Stock and Other Ownership Interests: Immutep. C. Brignone: Other, Personal, Other: Immutep SAS; Other, Personal, Other, Stock and Other ownership: Immutep Ltd.; Other, Personal, Other, Patents, Royalties, Other Intellectual Property: Immutep. F. Triebel: Other, Personal, Other, Employment: Immutep SAS; Other, Personal, Other, Stock and Other Ownership Interests: Immutep Ltd.; Other, Personal, Other, Patents, Royalties, Other Intellectual Property: Being an inventor on patents on LAG-3 owned by Immutep SAS. All other authors have declared no conflicts of interest.