Dose escalation study of a personalized peptide-based neoantigen vaccine (EVX-01) in patients with metastatic melanoma.

BACKGROUND: Neoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical study NCT03715985 showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy. METHODS: Patients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study's primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates. RESULTS: Compared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score. CONCLUSION: Immunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy.

Magnetic resonance imaging-guided biopsies may improve diagnosis in biopsy-naive men with suspicion of prostate cancer.

INTRODUCTION: The purpose of this pilot study was to investigate whether a short prostate biparametric magnetic resonance imaging (bp-MRI) protocol provides a valuable diagnostic addition for biopsy guidance in biopsy-naive men with a suspicion of prostate cancer (PCa). METHODS: A total of 62 biopsy-naive patients referred to a systematic transrectal ultrasound biopsy (TRUS-bx) due to suspicion of PCa were prospectively enrolled. Bp-MRI was performed before biopsy. All lesions were scored according to the modified Prostate Imaging Reporting and Data System (PI-RADS) version 2. All patients underwent TRUS-bx followed by bp-MRI-guided biopsies (bp-MRI-bx) under MRI/TRUS image fusion from any bp-MRI suspicious lesions not obviously targeted by TRUS-bx. RESULTS: PCa was found in 42 (68%) and 32 (52%) patients by TRUS-bx and bp-MRI-bx, respectively. Bp-MRI-bx de-tected PCa in one patient who had been missed by TRUS-bx, and found the highest Gleason score (GS) in 13 (30%) patients leading to an overall GS upgrade in six (14%) patients. Bp-MRI missed nine patients with GS = 6 and two with a GS = 7 (3 + 4), all of whom were diagnosed by TRUS-bx. CONCLUSIONS: Addition of bp-MRI-bx to routine TRUS-bx seems feasible in biopsy-naive patients and may improve the detection of aggressive PCa in first-round biopsies. This pilot study thus provides an incentive for a larger investigation. FUNDING: Costs were covered by the Department of Radiology, Herlev Hospital, Denmark. TRIAL REGISTRATION: This study was registered with the Danish Data Protection Agency (HEH-2015-054, I-Suite no: 03775) and with the Committee for Health Research Ethics (no. H-15009341).

Early experience with multiparametric magnetic resonance imaging-targeted biopsies under visual transrectal ultrasound guidance in patients suspicious for prostate cancer undergoing repeated biopsy.

OBJECTIVES: The purpose of this study was to investigate the detection rate of prostate cancer (PCa) by multiparametric magnetic resonance imaging-targeted biopsies (mp-MRI-bx) in patients with prior negative transrectal ultrasound biopsy (TRUS-bx) sessions without previous experience of this. MATERIAL AND METHODS: Eighty-three patients with prior negative TRUS-bx scheduled for repeated biopsies due to persistent suspicion of PCa were prospectively enrolled. mp-MRI was performed before biopsy and all lesions were scored according to the Prostate Imaging Reporting and Data System (PI-RADS) and Likert classification. All underwent repeated TRUS-bx (10 cores) and mp-MRI-bx under visual TRUS guidance of any mp-MRI-suspicious lesion not targeted by systematic TRUS-bx. RESULTS: PCa was found in 39 out of 83 patients (47%) and mp-MRI identified at least one lesion with some degree of suspicion in all 39 patients. Both PI-RADS and Likert scoring showed a high correlation between suspicion of malignancy and biopsy results (p < 0.0001). Five patients (13%) had cancer detected only on mp-MRI-bx outside the TRUS-bx areas (p = 0.025) and another seven patients (21%) had an overall Gleason score upgrade of at least one grade based on the mp-MRI-bx. Secondary PCa lesions not visible on mp-MRI were detected by TRUS-bx in six out of 39 PCa patients. The secondary foci were all Gleason 6 (3 + 3) in 5-10% of the biopsy core. According to the Epstein criteria, 37 out of 39 cancer patients were classified as clinically significant. CONCLUSION: Using mp-MRI, even without previous experience, can improve the detection rate of significant PCa at repeated biopsy and allows more accurate Gleason grading.