p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy
| Autor: | Don J. Diamond, Joshua D. I. Ellenhorn, Mihaela C. Cristea, Lucille Leong, Julie Kilpatrick, Raechelle Tinsley, Sharon P. Wilczynski, Melissa Eng, Christopher Ruel, Nicola Hardwick, Ferdynand Kos, Robert J. Morgan, Weimin Tsai, Vincent Chung, Paul Frankel, Teodora Kaltcheva |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology Adult Cancer Research Modified vaccinia Ankara medicine.medical_specialty medicine.medical_treatment T-Lymphocytes Carcinoma Ovarian Epithelial Cancer Vaccines Deoxycytidine Article 03 medical and health sciences 0302 clinical medicine Immunophenotyping Internal medicine medicine Humans Neoplasm Metastasis Adverse effect Aged Neoplasm Staging Platinum Chemotherapy business.industry Cancer Middle Aged medicine.disease Combined Modality Therapy Gemcitabine 030104 developmental biology Treatment Outcome Drug Resistance Neoplasm 030220 oncology & carcinogenesis Toxicity Female Tumor Suppressor Protein p53 Ovarian cancer business medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 24(6) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response. Toxicity: there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315–25. ©2018 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|