Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow

Abstract

In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-gamma-producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow-derived memory T cells.

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…Interferon-γ (IFNγ) ELISpot assay for the detection of IFNγ secreting T cells were carried out as described previously 27,30 . Accordingly, total T cells were cultured on peptide-pulsed DCs in a 5:1 ration for 40 h. Assays were conducted in triplicates for each of the peptides tested.…”

Protection against MUC1 expressing mouse tumours by intra‐muscular injection of MUC1 cDNA requires functional CD8+ and CD4+ T cells but does not require the MUC1 tandem repeat domain

“…10 -12 Indeed, one of these peptides (LLLLTV-LTV) appears to be processed and is able to induce functional T cells found in the bone marrow of breast cancer patients. 13 Although immunisation with cDNA encoding MUC1 provided protection against tumour challenge in C57Bl/6 mice, MUC1- specific CTL were not detectable before tumour challenge in immunised mice. Tumour protection was, however, dependent upon CD4 ϩ and CD8 ϩ T cells, and MUC1-specific CTL were detectable after tumour challenge.…”

“…Moreover, T cells recognising the LLLLTVLTV peptide have been found to be present in breast cancer patients but not in healthy individuals. 13 Clearly epitopes overlapping the signal sequence will only be available for loading from endogeneously expressed, MUC1 suggesting that DNA-based formulations should be considered.We have found that intramuscular (i.m.) injection with cDNA coding for full length MUC1 can protect C57Bl/6 mice against subsequent challenge with syngeneic MUC1-expressing tumours.…”

“…Moreover, T cells recognising the LLLLTVLTV peptide have been found to be present in breast cancer patients but not in healthy individuals. 13 Clearly epitopes overlapping the signal sequence will only be available for loading from endogeneously expressed, MUC1 suggesting that DNA-based formulations should be considered.…”

Sindbis virus replicon particles encoding calreticulin linked to a tumor antigen generate long-term tumor-specific immunity

“…Antigen-specific memory T cells differ from naive cells in having less stringent requirements for activation, being less dependent on co-stimulation, and requiring lower Ag-concentrations for activation. 46,47 As a consequence, memory cells exhibit a more rapid and vigorous response to Ag-stimulation than do their naı¨ve counterparts. SINrep5 replicon particle vaccines have the potential to be developed as preventive cancer vaccines.…”