Potential and perspectives for cancer immune therapy in the Philadelphia chromosome negative chronic myeloproliferative neoplasia

​PhD student: Morten Orebo Holmström, MD

The Philapdelphia chromosome negative chronic myeloproliferative neoplasia (MPN) encompass the diseases essential thrombocytemia, polycythemia vera and myelofibrosis, which are incurable neoplasms of the hematopoietic cells in the bone marrow. Patients with MPN have an elevated risk of thrombosis and hemorrhage as well as an elevated risk of progression to acute myeloid leukemia. The MPNs are characterized by very specific mutations, as more than 50 % of the patients harbor the JAK2 V617F mutation and approximately75 % of the patients with essential thrombocytemia and myelofibrosis which do not have the JAK2 V617F mutation harbor a mutation in the CALR-gene. The mainstay treatment for the MPNs is either chemotherapy or the immunostimulatory drug interferon-alpha, the latter being able to induce regression of the malignant cells in a subset of the patients. However a large fraction of the patients have to stop treatment with interferon-alpha due to intolerable side effects. Hence we still have an unmet need for new treatment modalities in the MPN.

The JAK2- and CALR-mutations give rise to proteins that are different from normal JAK2 and CALR proteins and these abnormal proteins should in theory become recognized and targeted by the immune system. It is believed that interferon-alpha might work by stimulating the immune system to attack the cells that produce the mutated CALR and JAK2 proteins – the cancer cells. As such there is a potential for the employment of cancer immune therapy such as vaccination or adoptive cell therapy for these diseases by targeting the MPN specific mutations. Furthermore there might be a potential for targeting immune check points such as PD1 and PDL1 which is already done with great success in several solid tumors.

In this project we will clarify, if there might be a spontaneous immune response against the mutated CALR- and JAK2-proteins If so, we will, by employing modern immunological techniques such as flow cytometry and cloning, elucidate how we might attenuate this immune response and hereby potentiate the immune system to target and kill the cancer cells.

The outlined study will have the potential to revolutionize the treatment of MPN by introducing a completely new treatment modality for the MPNs, thus paving the way for a potential cure for these chronic cancer diseases. ​