NorthWest Biotherapeutics Inc (NWBO)

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Late Effects of Radiation Therapy AND Vaccination
We have conducted clinical trials of an LPS (TLR4 agonist)-primed, HER-2/neu peptide-pulsed DC vaccine for patients with HER-2/neu overexpressing ductal carcinoma in situ (DCIS) of the breast (83). The vaccines consisted of HER2 peptide-pulsed autologous DC activated with IFN-? and clinical-grade TLR agonist LPS, resulting in high-level IL-12 and Th1 chemokine secretion (DC1). The results suggested consistent immune sensitization and frequent clinical response. Vaccination induced infiltration of CD4+ helper T cells, CD8+ CTLs and CD20+ B cells around DCIS lesions. Marked reduction of HER2 expression in lesions was frequently observed. In HLA-A2.1+ subjects, post-vaccination CD8+ T cells routinely recognized HER2-positive breast cancer cell lines (but not HER2-negative lines) and specifically secreted IFN-? in vitro. Moreover, the immunity generated by this vaccination regimen proved to be long-lived. All evaluated subjects had long-term CD4 T-cell immunity to vaccine peptides demonstrated by ELISPOT (83).

We recently compared clinical and immune responses post-vaccination in estrogen-dependent and estrogen-independent patients (ER+ and ER-, respectively). Interestingly, complete tumor regression was significantly more common in patients with ER-independent DCIS (40% of patients) compared to ER-dependent DCIS (4% of patients). Moreover, those patients who had received radiotherapy to the ipsilateral breast for a previous breast cancer event derived particular benefit compared to patients with ER-dependent disease and those who had received prior irradiation to the contralateral breast (Fig. 2) (84). These results suggest that radiation may have a sustained local effect that enhances subsequent vaccine efficacy. Observations such as these highlight limitations in our current understanding of the interactions between radiation therapy and DC-based immunotherapy. Determining the durability of radiation-induced changes in the tumor microenvironment and the optimal timing and sequencing of combined therapies will be important areas for further investigation.

www.ncbi.nlm.nih.gov/pmc/articles/PMC4143901/