Abstract 1308: Depressed anti-HER2 CD4 Th1 responses correlate with residual disease following neoadjuvant therapy in HER2+ breast cancer patients and can be restored by dendritic cell vaccination

Abstract

Abstract BACKGROUND: We have previously demonstrated a loss of anti-HER2 CD4 T-helper type 1 responses (Th1resp) in HER2+ invasive breast cancer (IBC) pts relative to healthy donors. Compared with pathologic complete response (pCR) after neoadjuvant trastuzumab/chemotherapy (T/C), residual disease at surgery (<pCR) portends a worse prognosis. We investigated differences in anti-HER2 Th1resp between pCR and <pCR pts following neoadjuvant T/C, and impact of HER2-pulsed dendritic cell (DC) vaccination in <pCR pts. METHOD: Th1resp were generated from PBMCs pulsed with 6 HER2 class II peptides by measuring IFN-γ production via ELISPOT, and compared between HER2+ IBC groups. Th1resp metrics were anti-HER2 responsivity, no. of reactive peptides (repertoire), and cumulative response across 6 peptides (spots/10^6 cells). Th1resp of <pCR IBC pts (n = 4) receiving adjuvant HER2-pulsed type 1-polarized DC (DC1) vaccination were analyzed pre-/post-immunization. RESULTS: The study comprised 85 pts. The diminished anti-HER2 Th1resp in treatment-naïve HER2+ IBC pts (n = 21) - assessed by responsivity, repertoire, or cumulative response - did not improve globally in T/C-treated IBC pts (n = 64). Within this T/C-treated cohort, neoadjuvant T/C receipt (60.9%) was associated with higher repertoire (1.5 vs 0.7; p = 0.04), but not responsivity or cumulative response, compared with adjuvant T/C. <pCR (n = 23) and pCR (n = 16) cohorts did not differ by age, menopausal status, race, BMI, comorbidity, or stage at diagnosis; however, pCR pts were more likely to have ER- tumors (69% vs 30%, p = 0.03). <pCR pts demonstrated dramatically lower anti-HER2 responsivity (30% vs 94%, p<0.001), repertoire (0.3 vs 3.3 peptides, p<0.001), and cumulative response (24.6 vs 148.2, p<0.001) compared with pCR pts. This disparity was not attributable to <pCR pts’ immune incompetence or increase in suppressive (Treg/MDSC) populations, but associated with shifts in IFNγ:IL10-producing Th phenotypes. Four pts in the residual disease cohort were recruited to our adjuvant HER2-pulsed DC1 vaccination trial, receiving 6 weekly injections followed by booster doses. Evaluable anti-HER2 Th1resp at 3 month post-vaccination (prior to 1st booster dose) indicated significantly restored repertoire (3.0 post vs 0.5 pre, p = 0.003) and cumulative response (152.5 vs 33.7; p = 0.03). CONCLUSION: Beyond the known association between ER status and pathologic response following neoadjuvant T/C in HER2+ breast cancer, we identify a novel correlation between <pCR and depressed anti-HER2 CD4 Th1resp. Even in these heavily pre-treated pts, this Th1 deficit is not “fixed” and can be restored by HER2-pulsed DC1 vaccination. Given the worse prognosis in <pCR pts, combinations of existing HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may decrease the risk of recurrence. Note: This abstract was not presented at the meeting. Citation Format: Jashodeep Datta, Erik Berk, Shuwen Xu, Elizabeth Fitzpatrick, Lea Lowenfeld, Noah Goodman, David Lewis, Robert E. Roses, Angela DeMichele, Brian J. Czerniecki. Depressed anti-HER2 CD4 Th1 responses correlate with residual disease following neoadjuvant therapy in HER2+ breast cancer patients and can be restored by dendritic cell vaccination. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1308. doi:10.1158/1538-7445.AM2015-1308