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"In situ" vaccination for systemic effects in follicular lymphoma.

ABSTRACT: Therapeutic vaccines for follicular lymphoma have had limited success. A novel in situ immunotherapeutic strategy combining 3 different treatment modalities induced regression of disseminated follicular lymphoma, which correlated with systemic antitumor T-cell immunity. These results should renew interest in the development of local combined radio- and immunotherapies to achieve abscopal effects.

SUBMITTER: Kolstad A

PROVIDER: S-EPMC4485726 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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"In situ" vaccination for systemic effects in follicular lymphoma.

Kolstad Arne A Olweus Johanna J

Oncoimmunology 20150319 7

Therapeutic vaccines for follicular lymphoma have had limited success. A novel in situ immunotherapeutic strategy combining 3 different treatment modalities induced regression of disseminated follicular lymphoma, which correlated with systemic antitumor T-cell immunity. These results should renew interest in the development of local combined radio- and immunotherapies to achieve abscopal effects. ...[more]

PMID: 26140239

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Contiguous follicular lymphoma and follicular lymphoma in situ harboring N-glycosylated sites.

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Widespread in situ follicular neoplasia in patients who subsequently developed follicular lymphoma.

Project description:In situ follicular neoplasia (ISFN) is usually an occasional incidental finding in lymph nodes by BCL2 immunohistochemistry, and its true scale is unknown. We have identified six cases of follicular lymphoma (FL) with a history of solid neoplasm 4-16 years ago, from which ISFN was identified widely in the surgically cleared lymph nodes (LNs). Using clone-specific PCR and BaseScope in situ hybridisation with primers or probes specific to the VDJ or BCL2-IGHJ junction sequence, we confirmed the clonal identity among different ISFNs and overt-FL in each of the four cases successfully investigated. Mutation analyses of overt-FL by targeted next-generation sequencing identified multiple potential pathogenic changes involving CREBBP, EZH2, KMT2D, TNFRS14, and STAT6. Further investigations of these mutations in paired ISFNs using Fluidigm PCR and Illumina sequencing showed the presence of the FL-associated mutations in early lesions for two of the six cases investigated (CREBBP and KMT2D in one case and STAT6 in the other), with one case displaying stepwise accumulation of its observed mutations. Remarkably, there were considerable divergences in BCL2 variants among different ISFN-involved lymph nodes in all four cases successfully investigated, indicating ongoing intraclonal diversification by somatic hypermutation machinery. Our findings demonstrate widespread distribution of ISFN lesions, further implicating their dynamic nature with the neoplastic cells undergoing active trafficking and clonal evolution. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study.

Project description:PurposeCombining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.Patients and methodsWe treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.ResultsThis in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.ConclusionIn situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

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Active idiotypic vaccination versus control immunotherapy for follicular lymphoma.

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Project description:Follicular lymphoma (FL) is a common indolent lymphoma subtype in Western countries. FL incidence increases with age, and shows considerable variation by race/ethnicity and geography. In the United States and France, FL incidence has been stable since 2000, whereas in other Western and Asian countries it has been increasing. Five-year relative survival rates have been increasing in Western and Asian countries. Progress on identifying FL-specific risk factors has accelerated with the implementation of the InterLymph nested classification and the availability of larger epidemiologic studies and pooled analyses. Identification of risk factors for FL requires further research.

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Follicular lymphoma in situ and partial involvement by follicular lymphoma are clona lesions that carry the t(14;18) and lack genetic secondary alterations

2013-11-12 | GSE48548 | GEO

Follicular lymphoma in situ and partial involvement by follicular lymphoma are clona lesions that carry the t(14;18) and lack genetic secondary alterations

Project description:Follicular lymphoma (FL) is characterized by the t(14;18)(q32;q21), frequent numerical chromosomal alterations, and recurrent somatic mutations. However, no genetic studies are available for FL in situ (FLIS), a putative precursor lesion of FL. In this study, we analyzed cases of FLIS without manifest (m)FL, partial involvement by FL (PFL), and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrated that paired FLIS and mFL cases are always clonally related. FLIS and PFL have no or few secondary chromosomal imbalances detectable by copy number arrays and a lower level of gene methylation as compared to mFL. Additionally, EZH2 Tyr641 mutations were detected in a subset of both FLIS and PFL cases. In conclusion, this study provides evidence that FLIS represents a FL precursor lesion of long-lived clonal B-cells carrying the t(14;18) with no or few secondary genetic changes. The earliest secondary genetic alterations detected in FLIS are the EZH2 Tyr641 mutation and low levels of CNAs, as evidence of clonal evolution. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma. DNA from cases, 20 tumor samples (10 in situ Follicular lymphoma, 4 Partial infiltration folliculary lymphoma and 6 manifest FL) were analyzed with Agilent-014693 Human Genome CGH Microarray 244A platform for copy number alterations study. For cases 9-14 paired samples of in situ follicular lymphoma and manifest follicular lymphoma were analyzed. Agilent-014693 Human Genome CGH Microarray 244A arrays were performed according to the manufacturer's directions on DNA extracted from lymph nodes that were hybridized against a normal DNA (pool) of the same gender.

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