Abstract OT1-01-02: Pilot trial of a type I polarized autologous dendritic cell vaccine incorporating tumor blood vessel antigen-derived peptides in patients with metastatic breast cancer
Authors: Baar J , Storkus W , Finke J , Butterfield L , Lazarus H , Reese J , Brufsky A , Downes K , Budd GT , Fu P 
Published: May 2016

Abstract
BACKGROUND. Cancer vaccines based on tumor-associated antigens are rarely curative in advanced cancer. This limitation relates to the heterogeneity of cancer due to defects in antigen presentation and altered immunophenotypes. Therefore, another method to promote anti-tumor immunity is to prime T cells against tumor-associated stromal cells. We have reported that IL-12 gene-therapy of established HLA-A2neg B16 melanomas in HLA-A2 transgenic (Tg) mice resulted in CD8+ T cell-mediated immunity against the host HLA-A2+ stromal cells within the tumor microenvironment (TME). We have also shown that vaccines based on a subset of tumor blood vessel antigen (TBVA)-derived peptides (DLK1310-318, EphA2883-891, HBB31-39, NRP1433-441, RGS55-13 and TEM1691-700) prevented HLA-A2neg MC38 tumor establishment and promoted the regression of melanomas in HLA-A2 Tg mice by CD8+ T cell targeting of HLA-A2+ pericytes and vascular endothelial cells in the TME.
TRIAL DESIGN. Based on this pre-clinical data, we are undertaking a Susan G. Komen-funded (IIR13261822; IND 15722) IRB-approved clinical trial of chemo-immunotherapy using the immunomodulatory drug gemcitabine (GEM) to suppress tumor infiltrating suppressor cells such as myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs) with a dendritic cell (DC) vaccine pulsed with the above six HLA-A2-presented TBVA-derived peptides (DC-TBVA) in 30 HLA-A2+ patients with metastatic breast cancer (MBC). Eligible patients will first undergo leukapheresis for the generation of the DC-TBVA vaccine. Patients will then receive 3 cycles of GEM, 1000 mg/m2 IV on days 1 and 8 of a 21-day cycle for 3 cycles. Patients will then receive the DC-TBVA vaccine administered twice intradermally 7 days apart.
ELIGIBILITY CRITERIA. Patients must be HLA-A2+ and have radiologically measurable MBC, an ECOG performance status of 0-1 and not have any active immune disorders. Prior GEM therapy is acceptable as long as the last dose was ≥ 3 months from registration on this study. Patients may not be on steroids.
SPECIFIC AIMS. The 4 specific aims are to 1) assess the safety of GEM + αDC1-TBVA vaccination, 2) assess the clinical response of MBC to GEM + αDC1-TBVA vaccination, 3) determine the clinical efficacy of GEM + αDC1-TBVA vaccination in generating Tc1 immunity, and 4) correlate changes in MDSC and Tregs with the generation of anti-TBVA Tc1-cell immunity
STATISTICAL METHODS. Clinical response: if the response rate is less than 10%, then there is probability 0.05 or less of accepting the vaccine therapy; if the response rate is bigger than 32%, then the probability of rejecting the combination is less than 0.2. While the secondary goals of the study are exploratory, there is sufficient statistical power to identify moderate to large effects (i.e., there will be statistical power &gt;.80 to detect changes from baseline in the different immune function parameters that are &gt;0.6 standard deviations of the parameter.)
TARGET ACCRUAL. We will enroll 30 patients over 3 years, with the first patient expected to be enrolled in July 2015.
CONTACT INFORMATION. Joseph Baar, MD, PhD. Seidman Cancer Center. E-mail: joseph.baar@uhhospitals.org.
Citation Format: Baar J, Storkus W, Finke J, Butterfield L, Lazarus H, Reese J, Brufsky A, Downes K, Budd GT, Fu P. Pilot trial of a type I polarized autologous dendritic cell vaccine incorporating tumor blood vessel antigen-derived peptides in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-02.