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REPORT DATE / /2010 2. REPORT TYPE Final 3. DATES COVERED 1 Apr 2007-31 Mar 2010
TITLE AND SUBTITLEA direct synergistic effect of immunotherapy and chemotherapy
5a. CONTRACT NUMBERW81XWH-07-1-0315as a new paradigm in treatment of breast cancer 5b. GRANT NUMBER
BC061707 (IDEA)5c. PROGRAM ELEMENT NUMBER
AUTHOR(S)Dmitry Gabrilovich 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER
PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER
Mofftt Cancer CenterTampa, FL,
SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)
U.S. Army Medical Research and ateriel Fort Detrick, Maryland
SPONSOR/MONITOR'S REPORT
21702-5012
NUMBER(S)
DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited
SUPPLEMENTARY NOTES
ABSTRACTTreatment of patients with advanced stages of breast cancer remains an unresolved clinical problem. The main objectives of this study are to determine whether immunotherapy sensitizes tumor to chemotherapy and to identify some of the main mechanisms of this effect. We investigated the possibility of a direct synergy between immunotherapy and chemotherapy in vitro. We found that pre-treatment of tumor target cells with doxorubicin or paclitaxel significantly increased cytotoxic effect of T-lymphocytes. Importantly, that effect was antigen-specific, since it was observed only in tumor cells loaded with specific but not a control peptide. In contrast, pre-treatment of splenocytes did not result in enhancement of target cell killing. In parallel experiments we have determined that both drugs increased the expression of p53 in tumor cells. However, that increase observed only after 48 hr of treatment and therefore could not contribute to observed sensitization of tumor cells to CTLs. To determine the effect of the combined treatment in vivo, mammary carcinoma TUBO was established s.c. in BALB/c mice. Dendritic cell vaccine alone slowed down tumor growth, which was consistent with previous results obtained by many laboratories. Paclitaxel had similar effect. However, in both cases tumor growth resumed in about a week...