Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study

Abstract

PurposeThe PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment.Patients and methodsPatients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays.Results66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected.ConclusionsThe PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose.Trial registration numberNCT01149343, Results.

Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma

“…This CTA has been recently exploited as immunotarget in several vaccination trials, as full-length protein/peptides either alone or in combination with a different tumor antigen. In particular, PRAME-based immunotherapy had an acceptable safety profile and induced anti-PRAME-specific humoral and cellular immune responses in melanoma (44,45), as well as in non-small cell lung cancer, (46) prostate carcinoma and renal clear cell carcinoma. (45) The vaccination approaches using PRAME as target, however, clearly showed the difficulty of in vivo reactivating PRAME-specific CD8+ T cells, even after several consecutive rounds of administration of the immunogenic protein/peptides.…”

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

“…Several groups have demonstrated the ability to generate ALY/HLA-A2-specific CD8 cytotoxic T lymphocytes (CTLs) that can specifically lyse PRAME + HLA-A2 + tumors and are reactive against primary leukemia (16)(17)(18), providing proof that this epitope is presented and can be targeted by immunotherapy. Clinical trials have also demonstrated that patients vaccinated against PRAME can develop PRAME-specific CTLs (19) and helper T cells (20). There are several major constraints to cellular and vaccine-based strategies.…”

Immune reconstitution and remission in CML

“…A number of consequences have been associated in patients with mutations in FH, including atypical hemolytic uremic syndrome (aHUS). [4][5][6] Although hemolytic uremic syndrome is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure, aHUS has the added characteristic of not being associated with infection of Escherichia coli commonly found with HUS. aHUS results in damage to the microvasculature and endothelium because of rare genetic defects in FH.…”

“…More elegantly, and specifically, might be to treat these patients with a more selective agent that would further direct the immune system to leukemia antigens PR1 or stem cell antigens such as WT1 or PRAME. This treatment might be a vaccine [2][3][4][5] or a T-cell receptor mimic antibody [6][7][8] or an engineered T cell.…”