Icahn School of Medicine at Mount Sinai
Project Term: July 1, 2018 - June 30, 2021
The objective of this study is to develop a vaccine platform targeting neoantigens resulting from calreticulin (CALR) mutations in patients with MPN. We demonstrated that mutated CALR is an immunogenic target and we propose to evaluate the efficacy of such vaccine in eliminating MPN hematopoietic cells. This preclinical research will inform the design of a clinical trial investigating the first-in-man immunotherapy for the treatment of MPN patients harboring CALR mutations.
Myeloproliferative neoplasms (MPN) are a heterogeneous group of chronic blood cancers in which the bone marrow produces abnormal blood cells. While the exact causes that trigger MPN are not known, several mutations have been discovered in genes which encode for proteins responsible for normal blood cells growth and function. These mutations cause the production of abnormal proteins which in turn, drive the malignant process in these disorders. One of such mutated genes encodes for a protein called calreticulin (CALR) which, among its many functions, is involved in cancer cell death mediated by the immune system. Mutations in CALR gene are the second most common mutations in two types of MPN, essential thrombocytemia and myelofibrosis. We and others showed that the abnormal CALR protein resulting from these mutations can be recognized by the immune cells which then become activated and have the potential to recognize and kill the cancer cells carrying the abnormal protein. In this study, we propose to characterize in detail the ability of the mutated CALR to induce immune cell responses. These studies will then allow us to develop a CALR mutation-specific vaccine and to test this new vaccine for its ability to trigger immune responses to eradicate MPN cancer cells. However, in some patients the immune cells are suppressed and may not adequately recognize and attack the cancer cells carrying the mutated CALR. Therefore, we propose to test in the laboratory if the MPN cancer cells can be killed by a combination treatment consisting of mutated CALR vaccine and drugs that were shown to restore the immune response in other types of cancer. The results of these studies will represent the basis for a clinical study utilizing the CALR vaccine for the treatment of patients with MPN.