The Overall Goal of this proposal is to characterize human immune responses to MHC-associated phosphopeptides, a new category of cancer antigens (Ag) that are selectively overexpressed in cancer cells and linked to processes that underlie malignancy. We have discovered over 600 phosphopeptides are presented by MHC-I and MHC-II molecules on different cancer cells. Most of these phosphopeptides come from proteins that have been linked to cellular growth control and signaling processes, many of which are disregulated in cancer cells. Very few are displayed on normal cells. These phosphopeptides represent a novel and unique collection of cancer Ags to be understood and exploited for cancer immunotherapy. We have also recently discovered that immune responses to some phosphopeptides in healthy individuals are surprisingly strong and are due to CD8 T cells that already show a memory phenotype. This pre-existing memory immunity is not generally observed to other kinds of cancer Ags in normal individuals, but is only evident in cancer patients, and often only after vaccination. Importantly, strong immunity to many phosphopeptides was diminished or absent in patients with chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). It could be restored in AML patients by bone marrow transplantation from an allogeneic donor. Overall, these results suggest the hypothesis that prior exposure to phosphopeptides, in the absence of discernible cancer and potentially as an aspect of immune surveillance, leads to the development of phosphopeptide-specific T cell memory. Furthermore, cancer progression is associated with failure to develop this type of immunity, or its loss over time. However, much additional work is needed to establish the existence of pre-existing memory immunity in normal individuals to a larger cohort of phosphopeptides associated with leukemias and solid tumor malignancies, and to understand the basis for its development. In addition, it is important to understand whether lack of phosphopeptide-specific immunity is evident in patients with other forms of cancer. Finally, it is important to determine whether resuscitation or amplification of this immunity is possible in cancer patients. Accordingly, the Specific Aims are: 1) To determine whether the development of pre-existing memory in normal individuals is based on responses to phosphopeptides associated with EBV transformation;2) To determine the status of immunity to MHC-associated phosphopeptides selectively expressed on leukemias and solid tumor malignancies in patients with these cancers;3) To longitudinally evaluate immunity to phosphopeptides in myelodysplastic syndrome (MDS) patients, and its association with the eventual development of AML;4) To evaluate the ability of therapeutic interventions in cancer patients to resuscitate or augment immune responses to phosphopeptides. This work will set the stage for clinical trials targeting cancer-associated phosphopeptides through vaccination or adoptive transfer approaches, potentially combined with other immunotherapeutic or chemotherapeutic modalities.
In this proposal, we will characterize immunity to a new type of antigen that can focus the immune system specifically on the cancer cell. These antigens come from proteins that may regulate processes involved in malignancy. Successful completion of the work will set the stage for clinical trials of these antigens in cancer patients.
|Zarling, Angela L; Obeng, Rebecca C; Desch, A Nicole et al. (2014) MHC-restricted phosphopeptides from insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer. Cancer Res 74:6784-95|