Camelia Iancu-Rubin, PhD and Nina Bhardwaj, MD, PhD - Icahn School of Medicine at Mount Sinai

Camelia Iancu-Rubin, PhD and Nina Bhardwaj, MD, PhD - Icahn School of Medicine at Mount Sinai

Camelia Iancu RubinProject title: 

Defining the immunomodulatory properties of mutated calreticulin in MPN

Focus area(s):

Application of Immunotherapy Approaches to MPNs

Question / Issue:

There is some evidence that patients with the CALR mutation have better overall survival than those with the JAK2, MPL or triple negative patients. These researchers feel that the CALR protein is capable of producing an immune response.

Project Description:

These researchers want to accurately define this response. Once they do, they will be able to develop a CALR based vaccine and a chimeric antigen receptor T cell that will be a new immunotherapy for patients.

Project Abstract:

Calreticulin (CALR) is a multi-functional protein that determines immunogenic cancer cell death. CALR mutations are found in the majority of patients with MPN who are negative for JAK2 or MPL mutations. With the exception of hematopoietic stem cell transplantation, curative treatments for these patients do not exist. CALR mutations result in a unique epitope (mut-CALR) which is shared by all MPN patients carrying the mutations. Our preliminary data indicate that CALR levels are elevated in MPN and mut-CALR peptide can bind human MHC class I molecules with high affinity, suggesting that mut-CALR epitope could be immunogenic in vivo. Moreover, MPN patients with mut-CALR have better overall survival than mut-JAK2, mut-MPL or triple-negative patients. We hypothesize that mut-CALR has immunogenic functions which may contribute, at least in part, to the superior survival observed in these patients. Thus, we plan to accurately define the immunogenicity of the mut-CALR peptide (Aim 1) and the immunomodulatory effects of mut- CALR expressed by patient-derived MPN hematopoietic cells (Aim 2). The results will establish the mut-CALR as the first MPN-specific neoantigen and provide us with a strong rationale for developing personalized mut-CALR-based vaccines and, potentially chimeric antigen receptor T cells as novel immunotherapies for patients with MPN.

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