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Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV.

ABSTRACT: Chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain (IgHV) are at risk of early disease progression compared to patients with mutated IgHV. As a preventive strategy, we treated 19 previously untreated CLL patients with unmutated IgHV in a phase 1/2 trial (clinicaltrials.gov, NCT03939234) exploring the efficacy and toxicity of a therapeutic cancer vaccine containing peptides derived from programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2), hoping to restore immunological control of the disease. According to the International Workshop on Chronic lymphocytic Leukemia (iwCLL) response criteria, no patients obtained a response; however, during follow-up, one patient had complete normalization of the peripheral lymphocyte count and remained in biochemical remission after a follow-up time of 15 months. At the end of treatment, one patient had progressed, and 17 patients had stable disease. During follow-up with a median time of 23.5 months since inclusion, seven patients had progressed, and eight patients had stable disease. The median time to first treatment (TTFT) from diagnosis was 90.3 months with a median follow-up time of 50.1 months. This apparent favorable outcome in TTFT needs to be investigated in a randomized setting, as our population may have been biased. More than 80% of patients obtained vaccine-specific immune responses, confirming the immunogenicity of the vaccine. The vaccine was generally well tolerated with only grade I-II adverse events. Although there were some signs of clinical effects, the vaccine seems to be insufficient as monotherapy in CLL, possibly due to a high tumor burden. The efficacy of the vaccine should preferably be tested in combination with novel targeted therapies or as a consolidating treatment.

SUBMITTER: Klausen U

PROVIDER: S-EPMC9723164 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV.

Klausen Uffe U Grauslund Jacob Handlos JH Jørgensen Nicolai Grønne Dahlager NGD Ahmad Shamaila Munir SM Jonassen Merete M Weis-Banke Stine Emilie SE Martinenaite Evelina E Pedersen Lone Bredo LB Lisle Thomas Landkildehus TL Gang Anne Ortved AO Enggaard Lisbeth L Hansen Morten M Holmström Morten Orebo MO Met Özcan Ö Met Özcan Ö Svane Inge Marie IM Niemann Carsten Utoft CU Pedersen Lars Møller LM Andersen Mads Hald MH

Frontiers in oncology 20221122

Chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain (IgHV) are at risk of early disease progression compared to patients with mutated IgHV. As a preventive strategy, we treated 19 previously untreated CLL patients with unmutated IgHV in a phase 1/2 trial (clinicaltrials.gov, NCT03939234) exploring the efficacy and toxicity of a therapeutic cancer vaccine containing peptides derived from programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2), hoping to restore im ...[more]

PMID: 36483037

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Project description:Genetic and epigenetic changes have provided essential insights into the biology and clinical behavior of chronic lymphocytic leukemia (CLL). Overall, increasing number of chromosomal aberrations are related to disease evolution. Complex karyotype (CK) is defined as presence of at least 3 numerical and/or structural aberrations detected by chromosome banding analysis. CK frequently occur in the context of CLLs with unmutated IGHV (U-CLL) and are associated with mutations in ATM or TP53. In this context, the relationship of karyotype complexity and DNA methylation aberrations in CLL remains largely unexplored. In the present study, we selected a highly curated cohort of 52 U-CLL cases with known karyotypes and ATM and TP53 aberration status. An unsupervised Principal Component Analysis using all the CLL samples showed that there is no specific clustering according to karyotype complexity. Although CK was not a major driver of epigenetic variability, a differential methylation (DM) analysis between CK vs non-CK samples led to a small signature of 59 CpGs, suggesting only a subtle relationship between karyotypic complexity and DNA methylation. We noticed that cases with deletions in ATM and TP53 tend to cluster differently in the first two principal components independently of karyotype complexity. A consensus clustering analysis using the 5,000 most variable CpGs confirmed the two clusters, which were enriched in ATMdel (U-CLL C1, P=0.015) and TP53del/mut (U-CLL C2, P=0.004), respectively. U-CLL C1 was also enriched in ATM mutations (P=0.017) and del(13q) (P=0.007), while U-CLL C2 was also related to trisomy 12 (tri12) (P=0.004). Both clusters showed a similarly unfavorable clinical behavior, both in terms of time to first treatment and overall survival. A DM analysis between them resulted in 4,333 differential CpGs. Surprisingly, despite the fact that all the cases are U-CLLs, and therefore germinal center-inexperienced, 2,150 CpGs were modulated in normal B-cell differentiation. Remarkably, 87% of those CpGs showed that cases in the U-CLL C1 cluster are associated with a DNA methylome of less mature B cells (more similar to NBC) whereas cases in the U-CLL C2 were related to more mature B cells (more similar to MBC). A phylogenetic analysis using previously reported CpGs significant for normal B-cell differentiation confirmed this observation. The remaining DM CpGs between the two clusters were largely related to a de novo DNA hypomethylation signature (n=1,679 CpGs) in the U-CLL C2 cluster. In summary, despite not finding a major relationship between complex karyotype and DNA methylation, we discovered the presence of two epitypes in the U-CLL dataset with distinct genetic profiles and methylation signatures related to different levels of epigenetic imprinting, a finding reinforcing the perception that CLL rises from a continuum of B-cell maturation stages.

Project description:Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined.We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS).Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL.PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.

Dataset Information

Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV.

Publications

Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV.

Similar Datasets

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