Abstract
BackgroundMembrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated NK cells. A phase I clinical trial has shown that repeated re-infusions of ex vivo TKD/IL-2-activated, autologous leukapheresis product is safe. This study investigated the maintenance of the cytolytic activity of NK cells against K562 cells and autologous tumor after 6 plus 3 infusions of TKD/IL-2-activated effector cells.MethodsA stable tumor cell line was generated from the resected anastomotic relapse of a patient with colon carcinoma (pT3, N2, M0, G2). Two months after surgery, the patient received the first monthly i.v. infusion of his ex vivo TKD/IL-2-activated peripheral blood mononuclear cells (PBMNC). After 6 infusions and a pause of 3 months, the patient received another 3 cell infusions. The phenotypic characteristics and activation status of tumor and effector cells were determined immediately before and at times after each infusion.ResultsThe NK cell ligands Hsp70, MICA/B, and ULBP-1,2,3 were expressed on the patient's anastomotic relapse. An increased density of activatory NK cell receptors following ex vivo stimulation correlated with an enhanced anti-tumoricidal activity. After 4 re-infusion cycles, the intrinsic cytolytic activity of non-stimulated PBMNC was significantly elevated and this heightened responsiveness persisted for up to 3 months after the last infusion. Another 2 re-stimulations with TKD/IL-2 restored the cytolytic activity after the therapeutic pause.ConclusionIn a patient with colon carcinoma, repeated infusions of ex vivo TKD/IL-2-activated PBMNC initiate an intrinsic NK cell-mediated cytolytic activity against autologous tumor cells.
Highlights
Membrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated natural killer (NK) cells
Patient characteristics and study setting A 65 year-old male came to our attention in 03/05 at the time of an anastomotic relapse of a colon carcinoma which was initially diagnosed as being in stage IIIc (pT3, pN2 (5/17), M0, G2) using the recently revised American Joint Committee on Cancer (AJCC) Sixth Edition Cancer Staging System [16,17]
A comparative H&E immunohistochemistry staining of the primary tumor biopsy (Figure 2B) and the anastomotic relapse (Figure 2C) revealed that the cytosolic Hsp70 content is elevated in the anastomotic relapse, indicating that Hsp70 levels might be associated with a more aggressive tumor stage
Summary
Membrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated NK cells. This study investigated the maintenance of the cytolytic activity of NK cells against K562 cells and autologous tumor after 6 plus 3 infusions of TKD/IL-2activated effector cells. In contrast to normal tissues, tumors frequently express the stress protein heat shock protein 70 (Hsp70) on their plasma membrane, and this membraneassociated form of the Hsp molecule acts as a tumorspecific recognition structure for Hsp70-peptide activated natural killer (NK) cells expressing CD94 [2,3]. Four repeated re-infusions of purified TKD/IL-2-activated NK cells have been shown to eradicate the primary tumor and prevent metastasis in a xenograft tumor mouse model of human pancreatic cancer [10]. In the presence of other lymphocytes and antigen presenting cells (APC), the cytotoxic response against Hsp membrane-positive tumors has been found to be selectively mediated by NK cells (unpublished observations)
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