First-in-human clinical trial of personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE243545 | GEO | 2023/09/20
REPOSITORIES: GEO
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Project description:First-in-human clinical trial of personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma
| PRJNA1018898 | ENA
Project description:Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
| S-EPMC11317512 | biostudies-literature
Project description:Cancer vaccines have encountered their ideal personalized partner along with evidence for great breakthroughs in the identification and synthesis of neoantigens. Individual cancer neoantigen vaccines are capable of eliciting robust T-cell responses and have been demonstrated to achieve striking clinical efficacy due to their high immunogenicity and central thymic tolerance escape of neoantigens. Two recent phase I clinical trials have provided support for the hypothesis and have heralded a nascent era of personalized vaccines in the field of immunotherapy. This review aims to address the identification of neoepitopes and describes advances made in personalized vaccines. In addition, this review discusses the challenges related to the exploitation of vaccine therapy, and provides potential thoughts for the improvement of vaccine design and applications.
| S-EPMC6096398 | biostudies-literature
Project description:Immunotherapy treatments harnessing the immune system herald a new era of personalized medicine, offering considerable benefits for cancer patients. Over the past years, tumor neoantigens emerged as a rising star in immunotherapy. Neoantigens are tumor-specific antigens arising from somatic mutations, which are proceeded and presented by the major histocompatibility complex on the cell surface. With the advancement of sequencing technology and bioinformatics engineering, the recognition of neoantigens has accelerated and is expected to be incorporated into the clinical routine. Currently, tumor vaccines against neoantigens mainly encompass peptides, DNA, RNA, and dendritic cells, which are extremely specific to individual patients. Due to the high immunogenicity of neoantigens, tumor vaccines could activate and expand antigen-specific CD4+ and CD8+ T cells to intensify anti-tumor immunity. Herein, we introduce the origin and prediction of neoantigens and compare the advantages and disadvantages of multiple types of neoantigen vaccines. Besides, we review the immunizations and the current clinical research status in neoantigen vaccines, and outline strategies for enhancing the efficacy of neoantigen vaccines. Finally, we present the challenges facing the application of neoantigens.
| S-EPMC9576504 | biostudies-literature
Project description:Lymphoplasmacytic lymphomas and marginal zone lymphomas of nodal, extra-nodal and splenic types account for 10% of non-Hodgkin lymphomas. They are similar at the cell differentiation level, sometimes making difficult to distinguish them from other indolent non-Hodgkin lymphomas. To better characterize their genetic basis, we performed array-based comparative genomic hybridization in 101 marginal zone lymphomas (46 MALT, 35 splenic and 20 nodal marginal zone lymphomas) and 13 lymphoplasmacytic lymphomas. Overall, 90.1% exhibited copy-number abnormalities. Lymphoplasmacytic lymphomas demonstrated the most complex karyotype (median=7 copy-number abnormalities), followed by MALT (4), nodal (3.5) and splenic marginal zone lymphomas (3). A comparative analysis exposed a group of copy-number abnormalities shared by several or all the entities with few disease-specific abnormalities. Gain of chromosomes 3, 12 and 18 and loss of 6q23-q24 (TNFAIP3) were identified in all entities. Losses of 13q14.3 (MIRN15A-MIRN16-1) and 17p13.3-p12 (TP53) were found in lymphoplasmacytic and splenic marginal zone lymphomas; loss of 11q21-q22 (ATM) in nodal, splenic marginal zone and lymphoplasmacytic lymphomas; loss of 7q32.1-q33 in MALT, splenic and lymphoplasmacytic lymphomas. Abnormalities affecting the NF-kB pathway were observed in 70% of MALT and lymphoplasmacytic lymphomas and 30% of splenic and nodal marginal zone lymphomas, suggesting distinct roles of this pathway in the pathogenesis/progression of these subtypes. Elucidation of the genetic alterations contributing to the pathogenesis of these lymphomas may guide to design specific therapeutic approaches.
2012-01-24 | GSE35278 | GEO
Project description:Lymphoplasmacytic lymphomas and marginal zone lymphomas of nodal, extra-nodal and splenic types account for 10% of non-Hodgkin lymphomas. They are similar at the cell differentiation level, sometimes making difficult to distinguish them from other indolent non-Hodgkin lymphomas. To better characterize their genetic basis, we performed array-based comparative genomic hybridization in 101 marginal zone lymphomas (46 MALT, 35 splenic and 20 nodal marginal zone lymphomas) and 13 lymphoplasmacytic lymphomas. Overall, 90.1% exhibited copy-number abnormalities. Lymphoplasmacytic lymphomas demonstrated the most complex karyotype (median=7 copy-number abnormalities), followed by MALT (4), nodal (3.5) and splenic marginal zone lymphomas (3). A comparative analysis exposed a group of copy-number abnormalities shared by several or all the entities with few disease-specific abnormalities. Gain of chromosomes 3, 12 and 18 and loss of 6q23-q24 (TNFAIP3) were identified in all entities. Losses of 13q14.3 (MIRN15A-MIRN16-1) and 17p13.3-p12 (TP53) were found in lymphoplasmacytic and splenic marginal zone lymphomas; loss of 11q21-q22 (ATM) in nodal, splenic marginal zone and lymphoplasmacytic lymphomas; loss of 7q32.1-q33 in MALT, splenic and lymphoplasmacytic lymphomas. Abnormalities affecting the NF-kB pathway were observed in 70% of MALT and lymphoplasmacytic lymphomas and 30% of splenic and nodal marginal zone lymphomas, suggesting distinct roles of this pathway in the pathogenesis/progression of these subtypes. Elucidation of the genetic alterations contributing to the pathogenesis of these lymphomas may guide to design specific therapeutic approaches. One hundred fourteen patients were included in this study: 46 MALT lymphomas (22 pulmonary, 11 salivary glands, 7 lacrimal glands and 6 gastrointestinal), 35 splenic marginal zone lymphomas, 20 nodal marginal zone lymphomas and 13 non-Waldenström’s Macroglobulinemia lymphoplasmacytic lymphomas. All cases were reviewed prior to study on paraffin sections with immunohistochemistry. Sections of each frozen tissue used for study were also reviewed by histological examination and immunohistochemistry before was submitted for the study.
2012-01-24 | E-GEOD-35278 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.
| S-EPMC10171177 | biostudies-literature
Project description:Analyse of gene expression profiling in nasal mucosa of dogs affected by sino-nasal aspergillosis or lymphoplasmacytic rhinitis.
2012-01-01 | E-MEXP-3166 | biostudies-arrayexpress
Project description:Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour-specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers. Herein, we provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses. In addition, we discuss the current status of clinical studies testing personalized neoantigen vaccines in patients with cancer and considerations for future clinical investigation of this novel, individualized approach to immunotherapy.
| S-EPMC7816749 | biostudies-literature
Project description:Normal-cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B-lymphocytes prior to lymphoma remains uncertain. We sequenced multiple stages of the B-lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of high-prevalence of mutated MYD88. We observed similar accumulation of random mutations in B-lineages from both cohorts and, unexpectedly, found MYD88L265P in normal precursor and mature B-lymphocytes from lymphoma patients. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B-cell precursors and BCL2 overexpression. Thus, MYD88L265P is a pre-neoplastic event, which challenges current understanding of lymphomagenesis and may have implications for early detection of B-cell lymphomas.
2021-11-04 | GSE185156 | GEO