Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine
| Autor: | Belinda Akpeng, Shiwen Peng, Sofia Lyford-Pike, Annie A. Wu, T-C Wu, John R. Saunders, Chien Fu Hung, Drew Hannaman, Sara I. Pai |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Cyclophosphamide medicine.medical_treatment Immunology Population Antineoplastic Agents Pharmacology CD8-Positive T-Lymphocytes Cancer Vaccines Article DNA vaccination Mice Immune system Vaccines DNA Immunology and Allergy Medicine Cytotoxic T cell Animals Papillomavirus Vaccines education education.field_of_study business.industry Immunotherapy Neoplasms Experimental Flow Cytometry Combined Modality Therapy Vaccination Mice Inbred C57BL Oncology business CD8 medicine.drug |
| Popis: | Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8(+) T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8(+) T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8(+) T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8(+) T cells, which led to higher ratios of CD8(+)/Treg and CD8(+)/CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8(+) T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. |
| Databáze: | OpenAIRE |
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