HER-2/neu vaccine-primed autologous T-cell infusions for the treatment of advanced stage HER-2/neu expressing cancers

Abstract

This Phase I study evaluated the feasibility of expanding HER-2/neu (HER2) vaccine-primed peripheral blood T-cells ex vivo and assessed the safety of T-cell infusions. Eight patients with HER2 + treatment refractory metastatic cancers were enrolled. T-cells could be expanded to predefined parameters in 7 patients (88%). Ninety-two percent of adverse events were grades 1 or 2. Three of 7 patients developed infusion related inflammatory reactions at their disease sites. HER2 specific T-cells significantly increased in vivo compared to pre-infusion levels (p=0.010) and persisted in 4/6 patients (66%) over 70 days after the first infusion. Partial clinical responses were observed in 43% of patients. Levels of T-regulatory cells in peripheral blood prior to infusion (p<0.001), the level of HER2 specific T-cells in vivo (p=0.030), and development of diverse clonal T-cell populations (p<0.001) were associated with response. The generation of HER2 vaccine primed autologous T-cells for therapeutic infusion is feasible and well tolerated. This approach provides a foundation for the application of T-cell therapy to additional solid tumor types.

Functional T cells targeting tumor-associated antigens are predictive for recurrence-free survival of patients with radically operated non-small cell lung cancer

“…This is in accordance with more recent efforts to treat cancer with a multimodal approach incorporating surgery, immune checkpoint blockade, cytotoxic therapy, targeted therapy and therapeutic vaccination for optimal immune-mediated tumor control. 36,37 Taken together, our data suggest that the TAAs, Aurora kinase A, HER2/ neu, NY-ESO-1, and p53, all of which have been examined in clinical trials, [38][39][40][41] are candidate target antigens for future immunotherapies. To our knowledge, this comprehensive analysis of spontaneous TAA-specific T cells in operable NSCLC is the first of its kind.…”

Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach?

“…In this study 63 , improved clinical outcomes were associated with less clonotype loss and maintenance of high-frequency clonotypes during treatment 63 ; perhaps these features could act as surrogates for clinically-relevant antitumour responses. In fact, these changes in T-cell clonality have been associated with increased overall survival in clinical trials with cohorts of patients with prostate 64 or breast 65 cancer. These, along with other immunological tests, should be used to supplement standard examination criteria in order to more accurately determine the extent of disease response 66 .…”

CD8+cytotoxic T cell responses to dominant tumor-associated antigens are profoundly weakened by aging yet subdominant responses retain functionality and expand in response to chemotherapy

“…These T cell responses were associated with partial clinical responses in 43% of patients. 40 The involvement of lower avidity T cells may enhance the persistence and function of T cells in vivo as higher avidity T-cells are more likely to be tolerized and lose function in the tumor environment. 41,42 Importantly, others have shown in metastatic melanoma that recognition of multiple epitopes, particularly those with lower binding affinity to HLA molecules, is associated with tumor regression after adoptive T cell transfer.…”