mutant calr-peptide based vaccine in patients with mutated calr myeloproliferative neoplasm

Conditions: Myelofibrosis; Essential Thrombocythemia; MPN

Summary: the primary objective of this study is to assess the safety and tolerability of administrating mutated-calr peptide vaccine to patients with mpn. the researchers plan to enroll 10 patients over a 12 month period. maximum length of participation in 80 weeks. patients will be asked to complete questionnaires, bone marrow biopsies, research lab collection, and standard of care lab draw. this research will be taking place only at the mount sinai hospital, specifically at the ruttenberg treatment center.

current mpn treatments are geared towards symptom palliation and not on changing the natural course of the disease. mutations in calreticulin gene (calr) is the second most common driver mutation in et and mf patients (30%). all calr mutations identified to date in mpn patients result in the formation of an altered protein with an identical 36-amino acid sequence in the c-terminus. this altered protein results in a mpn-specific shared neo-antigen. the mutated calr neoantigen present in patient with mpn represents an ideal antigen for targeted immunotherapy as it is stably and specifically expressed by the malignant cells and is absent in the normal tissues. calr neoantigen is immunogenic, effector t cells are capable of recognizing this neo-antigen, and hematopoietic cells carrying the mutation can be potently killed by these specific effector t-cells in vitro. the researchers believe that a mutated-calr vaccine will enhance mutated-calr-specific t cell immunity in mpn patients carrying calr mutations, which in turn would target and eliminate calr+ malignant cells, thereby leading to improved clinical outcomes in this patient population.

Eligibility criteria:
inclusion criteria: * subjects must be ≥18 years of age at the time of signing the informed consent form. * confirmed diagnosis of chronic phase mpn: * previously treated or relapsed/refectory high risk et * low to intermediate 1 risk (dipss 0-1) pmf or et-mf * verified mutation in calr exon 9 * ps ≤ 2 * adequate organ function: * absolute neutrophil count ≥ 1000/mm3, * platelet count ≥ 50,000/mm3, * creatinine ≤ 2.5 mg/dl, * total bilirubin ≤ 2 mg/dl, (except in patients with gilbert syndrome who can have total bilirubin \< 3.0 mg/dl) * transaminases \< 3 times above the upper limits of the institutional normal. * females of childbearing potential (fcbp) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 miu/ml within 10 - 14 days prior to starting study medication and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 4 weeks prior to first dose of vaccine. fcbp must also agree to ongoing pregnancy testing. men must agree to use a condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy. * ability to understand and the willingness to sign a written informed consent. * ability to adhere to the study visit schedule and all protocol requirements. * subjects receiving cytoreductive therapy with hydroxyurea must be on a stable dose for at least 8 weeks prior to week 1. exclusion criteria: * other invasive malignancy in the past 3 years except non-melanoma skin cancer, localized cured prostate cancer and early stage breast cancer on hrt. * active autoimmune disease. * uncontrolled serious infection. * known immunodeficiency. * pregnant and breastfeeding women. * not willing to use contraception. * current use of immunosuppressive medications including steroids. * current jak inhibitor use. * current use of ifn (use of anagrelide is permitted). * treatment with other experimental drugs within 30 days of week 1. * treatment with any mpn directed therapy unless otherwise noted within 5 half-lives of week 1. * any significant psychiatric/medical condition per investigators judgment.

Keywords: calr vaccine mf et peptide