Advanced Pancreatic Cancer: Adjuvant Anti-Tolerogenic Immunomodulation Improves Chemoimmunotherapy
| Autor: | J.C. Dau, F. Galmarini, J. Vazquez, P. Goldschmidt, T. Carlevaro, Eduardo Lasalvia-Prisco, E.E. Lasalvia-Galante |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Chemotherapy Pathology education.field_of_study Myeloid Cyclophosphamide business.industry medicine.medical_treatment Population Hematology Gastroenterology Gemcitabine medicine.anatomical_structure Oncology Internal medicine Toxicity medicine IL-2 receptor Lymph business education medicine.drug |
| Zdroj: | Annals of Oncology. 25:iv367 |
| ISSN: | 0923-7534 |
| DOI: | 10.1093/annonc/mdu342.18 |
| Popis: | Aim: In advanced pancreatic cancer (APC), tumor antigens evidenced in circulating blood were used as immunogens by transference to the lymph system through vaccination sites in skin. The reported antitumor activity of such Autologous Hemoderivative Cancer Vaccine (AHCV) improved when chemotherapy (CH) was associated to enhance antigen cross-presentation. Development of AHCV + CH requires switching of malignancy-induced immunologic tolerance. Translational research identified an immunomodulatory drug set (IDS) that induces such switching by targeting (tg) an immune-committed cell population with each drug of this set: Cimetidine (Cm) tg Dendritic cells; Cyclophosphamide (Cp) tg T-Regulatory (T-Reg) cells; Celecoxib (Cx) tg Myeloid Derived Suppressor cells (MDSC); Metformin (Mf) tg Memory Cells (MC). The aim of this study is to explore APC survival adding the IDS-induced switching to AHCV + CH. Methods: 24 patients (Pts). Inclusion/exclusion criteria: APC, exocrine adenocarcinoma, M1, PS ≤ 2, no M1 Brain, no surgery, chemo or radiotherapy, no comorbility, 4-month treated, 2-arm randomized Arm 1 / Arm 2 (12 Pts each), 1-yr follow-up. Treatment: Arm 1, four 28-day cycles, AHCV (as previously published) day (d) 28 + Gemcitabine 1000 mg/d 1, 8, 15; Arm 2, like Arm 1 + IDS (Cp 50 mg/d) (Cm 400 mg, Cx 400 mg, Mf 500 mg)/12 h, d 1 to 112. Assessment: PBMC, immunochemistry flow cytometry, IDS-targeted cell population count. Survival (% 1-yr and median). Toxicity (Tx) by NCI Common Tx Criteria v 2.0. Statistics: Arm 2 vs Arm 1, Mean comparisons by Student-T test, and survival by Kaplan-Meier/log rank test. Significance: p Results: Conclusions: In advanced pancreatic cancer, antitolerogenic conditioning of immunity by IDS improves survival obtained with AHCV + CH, safely. Future development is warranted. Arm 1 (Mean ± SE) Arm 2 (Mean ± SE) Day 1 Day 112 Day 1 Day 112 DC x ml Lymphoid DR+ lin-CD11- 8200 ± 2710 9100 ± 2800 8018 ± 2562 *12670 ± 2080 Myeloid DR+ lin-CD11 + 5430 ± 1810 5480 ± 1945 5588 ± 1954 *6810 ± 1670 T-Reg %CD4 + CD4 + CD25 hiFoxP3 + 8.1 ± 2.6 7.2 ± 2.1 7.9 ± 2.2 *4.3 ± 1.9 CD4 + CD25 + 20.4 ± 3.3 18.6 ± 3.4 19.8 ± 2.9 *12.6 ± 2.0 MDSC % PBMC Granulocytic Lin-HLA-DR-D33 + CD11b + CD15 + 8.8 ± 3.4 7.1 ± 3.5 9.1 ± 3.5 *5.4 ± 2.7 Monocytic Lin-HLA-DR-D33 + CD11b + CD14 + 0.9 ± 0.1 0.7 ± 0.2 0.8 ± 0.2 *0.4 ± 0.1 MC % CD8 + /CD4 + Effectors CD8 + CD45RO + 42.3 ± 7.1 50.0 ± 6.1 41.6 ± 5.7 *51.6 ± 4.8 Helper CD4 + CD45RO + 55.5 ± 5.0 57.2 ± 5.9 56.1 ± 4.8 *66.9 ± 3.6 TOXICITY (Event Grade 3/4) 2 1 SURVIVAL Arm 1 Arm 2 Months (Median ± 95%CI) 5.6 (95% CI, 5.0-6.2) *7.1 (95% CI, 6.2-8.1) 1-Yr (%) 16.7 *41.7 * Arm 2 vs Arm 1: p Disclosure: All authors have declared no conflicts of interest. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|