Abstract
Women with stage IV metastatic breast cancer (mBrCa) have limited treatment options since toxicities from chemotherapy and radiotherapy become limiting. Non-toxic immunotherapy approaches to improve targeting and cytotoxicity directed at breast cancer are needed. Our earlier study showed that anti-CD3 activated T cells (ATC) could be expanded in culture and then armed with anti-CD3 × anti-Her2/neu bispecific antibody (HER2Bi). The armed ATC mediate enhanced specific cytotoxicity, proliferate, and induce cytokine/chemokine secretion (
J Hematotherapy & Stem Cell Res 10:247, 2001
). In a Phase I trial using ATC armed with Her2Bi, 18 Stage IV BrCa patients (pts) were treated with 8 infusions (twice/week) for 4 weeks totaling 40 (6 pts), 80 (2 pts), 160 (7 pts), and 320(1 pt) billion ATC armed with Her2Bi without dose-limiting toxicities. The most frequent side-effects were chills, fever, and hypotension that were easily controlled with medications. Two stage IV mBrCa patients had minor responses with decreases in CEA (35.2 to 4.1 ng/ml) or CA 27-29 (57.7 to 35.6 U/ml) and one pt had partial response with a decreased liver metastatic lesion. None of the pts developed human anti-mouse antibodies levels above10 ng/ml. Immunoaffinity-depletion of BiAb-armed ATC from PBMC of a high risk IV mBrCa pt at post-treatment time points showed an increase in anti-BrCa tumor cell activity exhibited by endogenous immune cells that persisted up to 4 months after treatment. Increasing proportions and absolute numbers of CD25+ cells in CD4+ and CD8+ subsets were observed as a function of treatment with nearly all CD4+ and CD8+ cells being CD25+ by 1 week post-final infusion. Significant treatment-associated elevations (several log increases over baseline) of circulating IFNγ, TNFα, IL-2, IL-5, IL-10, IL-12p70, and IL-13 were detected in serum of nearly all of the patients beginning 1–2 weeks after initiation of infusions. Particularly remarkable was the 3 log increase of mean (n=9) serum IL-12p70 from 0 to 1200 pg/ml. There was a Th1 shift that persisted during therapy. To date, results from the phase I clinical trial suggest that Her2Bi-armed ATC activate the endogeneous immune system to generate an adaptive immune responses despite the presence of high tumor burdens. The figure shows the overall survival for 18 women (All) treated on the phase I protocol with the median survival not yet defined for the HER2/neu 3+ group and the entire study group. The median survival for the 9 pts with Her2/neu negative disease was 21.5 months. Together these data are encouraging and strongly suggest infusions of armed targeted T cells may immunized the patient against their own tumor antigens leading to immunoreactivity manifested as the development of a persistent CTL response that may lead to improved overall survival.
Figure
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal