Autologous dendritic cell vaccine directed at wild type p53 in patients with high-risk breast cancer treated with adjuvant chemotherapy.

Abstract #2152

Background: The tumor suppressor gene p53 is over-expressed in many human tumors, resulting in presentation of p53 epitopes in the MHC class I and II groove. This elicits antibodies to mutant and wt p53 and primes p53-specific T-cell responses to many p53 epitopes. Vaccination with dendritic cells (DCs) transduced with wt p53 using an adenovirus vector (Ad-p53) induces T-cell responses against wt p53 which can kill tumor cells that over-express wt or mutant p53. This vaccine in pts with extensive small cell lung cancer also appeared to enhance response to subsequent chemotherapy. Methods: Pts with breast cancers 4 cms or larger and/or involved 4 or more nodes and that stained > 5% for p53 by immunohistochemistry were eligible. Pts were randomized to p53 DCs immunization (IMZ) during (early) or following (late) chemotherapy. Mononuclear cells collected with one apheresis, were divided and cryopreserved. Cells were thawed, matured into DCs and transduced with Ad-p53. The adjuvant therapy was dose-dense doxorubicin, cyclophosphamide (AC) followed by paclitaxel (P), then 33 doses of radiation (R). Early p53 DC IMZ was scheduled for 1 week post AC and 1, 15 and 21 weeks post P. Late p53 DC IMZ was scheduled 15,17,19 and 21 weeks post P. Each dose had approximately 5X10⁷ DCs. Antigen specific immune assays included anti-p53 and anti-Ad antibodies and p53-specific T-cell response assays by interferon gamma ELISPOT in addition to flow cytometric analysis of cellular phenotypes were done on blood drawn before AC, each IMZ and 3, 6, and 12 mos after the last IMZ. Safety and immune responses were the primary endpoints. Results: Twenty-three pts (10 early, 13 late) have received a total of 88 IMZs of p53 DCs. The pts have been followed a median of 29 mos (range 5.5-50.5mos) from study entry. The only toxicity attributed to IMZ was grade 1 redness and itching at the IMZ site. One IMZ was held in a pt who had pre-IMZ thrombocytopenia that persisted. Two pts relapsed 8 and 23 months after diagnosis. T-cell CD-4 numbers declined following AC from an average of 4.9+0.5 x10⁵/ml to 1.7+0.3x10⁵/ml, but increased to an average of 2.7+ 0.3 x 10⁵/ml, 21 weeks after P or 12 weeks after R. Antibody to adenovirus or p53 was not detected. In 14 pts evaluated at least 6 mos from last IMZ, T-cell response to p-53 was measured in all 7 early arm pts and 4 of 7 late arm pts. The median baseline response was 0.7 (range, 0-2) and median peak was 8.54 (range, 0.09-32.5). Post-IMZ responses in 2, 6 and 4 pts peaked at 3, 6 and 12 mos, respectively. Conclusions: The p53 DC IMZ is safe with CD-4 cells recovering 12 weeks after R. Although most IMZs were given when CD-4 cells were low, p53-specific T-cell responses were induced, appeared to peak at 6 mos and could persist 12 mos after the last IMZ. These studies suggest that IMZ strategies may be used with adjuvant chemotherapy and R.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2152.