Abstract
Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.
Highlights
Tumor rejection by the immune system requires the generation and clonal expansion of tumor antigen specific, major histocompatibility complex I (MHC I) restricted, cytotoxic CD8+ T cells (CTL)
Activation, differentiation and expansion of tumor antigen specific CD8+ CTL is dependent on tumor antigen presentation by MHC I of activated dendritic cells (DC) to the T cell receptor (TCR) of cognate CD8 T cells
One efficient pathway for tumor antigen cross presentation to and activation of DC, first described by Srivastava’s group, is via protein/peptide-chaperones [2,3,4,5,6,7,8]. In this first in human study, we here describe the use of genetically modified allogeneic tumor cells secreting protein/ peptide-chaperone gp96-Ig as tumor vaccine for the treatment of advanced non-small cell lung cancer
Summary
Tumor rejection by the immune system requires the generation and clonal expansion of tumor antigen specific, major histocompatibility complex I (MHC I) restricted, cytotoxic CD8+ T cells (CTL). MHC I presentation of tumor antigens by activated DC entails antigen transfer from tumor cells to DC in a process known as “antigen cross-presentation”. One efficient pathway for tumor antigen cross presentation to and activation of DC, first described by Srivastava’s group, is via protein/peptide-chaperones [2,3,4,5,6,7,8]. In this first in human study, we here describe the use of genetically modified allogeneic tumor cells secreting protein/ peptide-chaperone gp96-Ig as tumor vaccine for the treatment of advanced non-small cell lung cancer
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