Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms

Abstract

BackgroundThe calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR-mutant MPN.MethodsThe safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALRmut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446).ResultsPatients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines.ConclusionTherapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response.

The immune landscape in BCR‐ABL negative myeloproliferative neoplasms: inflammation, infections and opportunities for immunotherapy

“…Although a decline in platelet count was observed in the initial 100‐day period after vaccination, unfortunately none of the patients had either a clinical or molecular response. In this study, IFNγ enzyme‐linked immunospot (ELISPOT) responses were observed in four of 10 patients before vaccination, and in four additional patients after vaccination, confirming an increase in in vitro anti‐cancer immune activity and a potential role for therapeutic vaccines combined with other modalities to enhance the efficacy of anti‐tumour T‐cell activity 88 …”

“…The safety and efficacy of vaccination with a peptide derived from the CALR exon 9 mutation was recently tested in a phase I clinical trial in 10 patients with mut CALR MPN 88 . Although a decline in platelet count was observed in the initial 100‐day period after vaccination, unfortunately none of the patients had either a clinical or molecular response.…”

PD-1 inhibition in advanced myeloproliferative neoplasms

“… 17,30 Similarly, in a recent phase 1 study that evaluated the safety and efficacy of vaccination against mutated CALR in patients with MPNs, vaccine-induced T-cell responses were significantly greater in patients with essential thrombocythemia than in those with MF. 31 Of note, although this study demonstrated safety and tolerability, the mutated CALR vaccine had no clinical efficacy. 31 Taken together, these findings underscore the multifactorial causes of immune tolerance in MPNs.…”

“… 31 Of note, although this study demonstrated safety and tolerability, the mutated CALR vaccine had no clinical efficacy. 31 Taken together, these findings underscore the multifactorial causes of immune tolerance in MPNs. These observations also suggest that as disease progresses, a coordinated dysregulation of the immune milieu may contribute to antitumor T-cell suppression.…”

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

“…Therapeutic cancer vaccination against mutated CALR was suggested as a new treatment modality in CALR-mutated MPN. Although many patients displayed T cell responses, unfortunately, no clinical responses have been observed so far [ 97 ].…”