A pilot study incorporating HER2-directed dendritic cells into neoadjuvant therapy of early stage HER2+ER- breast cancer

Abstract

Type 1 dendritic cell vaccines targeting HER2 (HER2-DC1) reinvigorates antitumor immunity which correlates with neoadjuvant therapy response. A pilot trial (clinicaltrials.gov,NCT03387553,1/2/2018) using HER2-DC1 pre-neoadjuvant therapy evaluated feasibility/safety and pathologic response rates/immunogenicity. Stage II-III ER-HER2+ breast cancer patients prescribed neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) were enrolled. HER2-DC1 (2×10⁷ cells/vaccine) was given for 3 weeks prior to chemotherapy intranodal (IN) 1x/week (Arm A), IN 2x/week (Arm B), and 2x/week alternating intratumoral (IT) and IN (Arm C). HER2 ELISPOT counts (EHC) and immunofluorescence analysis of biopsies were performed. Six patients enrolled in Arms A and B, 18 patients in Arm C. Neoadjuvant HER2-DC1 demonstrated no unexpected safety signals. Pathologic complete response rates (pCR) across arms A, B, C were 42.8%, 66.6%, and 72.7%. Intranodal HER2-DC1 increased EHC, but IT + IN HER2-DC1 reduced EHC, possibly due to increased T cell tumor trafficking. Immunofluorescence showed increased T cell infiltration following IT + IN injections. Additional IT HER2-DC1 investigation is warranted.

Fig. 1

CONSORT flow diagram.

Fig. 2. HER2 ELISPOT counts across different timepoints with medians for the timepoints above each column.

A The trial schema is illustrated to clarify the timing of treatments and sampling. The figures show the ELISPOT counts for Arms A, B, and C (B, C, D, respectively). Both Arms A and B experience a statistically nonsignificant increase in median ELISPOT counts at week 4, followed by a drop during chemotherapy, and an increase over time with booster intranodal vaccination post chemotherapy particularly in arm A. Arm C differs in that there is an initial drop in circulating ELISPOT levels at week 4 followed by an increase over time during the boosters.

Fig. 3. Immunofluorescence images of baseline and on treatment biopsies for Arm C patients with markers for CD4+ helper T cells, CD8+ effector T cells, CD56 + NK/NKT cells, and CD20 + B cells.

The left most panel is a zoomed in section to better demonstrate the distribution of cell types within the stroma around tumor islands.

Fig. 4. Violin plots showing the frequency of different cell subtypes within analyzed tissue sections from baseline and week 4 biopsies from Arm C patients.

Statistically significant increases were noted in CD8+ effector T cells, interferon-gamma secreting lymphocytes, and NKT cells.

Fig. 5. Comparison of mIF samples from residual cancer patients (Non pCR) and those who eventually attained a pathology complete response (pCR).

There was a trend for pCR patients to have greater elevations in CD3 + IFNγ+ cells within their stroma after 4 weeks of DC1 vaccination compared to Non pCR patients while NKT cells appeared similar between the two groups. T cell and NKT infiltration was increased in both groups relative to baseline.