scholarly journals Spectrum of Posttransplant Lymphoproliferations in NSG Mice and Their Association With EBV Infection After Engraftment of Pediatric Solid Tumors

2020 ◽  
Vol 57 (3) ◽  
pp. 445-456 ◽  
Author(s):  
Heather Tillman ◽  
Peter Vogel ◽  
Tiffani Rogers ◽  
Walter Akers ◽  
Jerold E. Rehg
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Immune Cells ◽  
Pediatric Patients ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Diseases ◽  
Nsg Mice ◽  
Pediatric Solid Tumors ◽  
Human Immune

Pediatric patients receiving solid organ transplants may develop lymphoproliferative diseases, including graft-versus-host disease (GvHD) and posttransplant lymphoproliferative diseases (PTLDs). We characterized lesions in 11 clinically ill NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice that received pediatric-patient-derived solid tumors (PDXs) and developed immunodeficiency-associated lymphoproliferations comparable to GvHD and PTLDs over a period of 46 to 283 days after implantation. Lymphoproliferations were diffusely positive for human-specific biomarkers, including NUMA1, CD45, and CD43, but lacked immunoreactivity for murine CD45. Human immune cells were CD3-positive, with subsets having immunoreactivity for CD4 and CD8 as well as PAX5, CD79a, and IRF4, resulting from populations of human T and B cells present within the xenotransplants. Tissues and organs infiltrated included mucocutaneous zones (oral cavity and perigenital and perianal regions), haired skin, tongue, esophagus, forestomach, thyroid, salivary glands, lungs, liver, kidneys, spleen, lymph nodes, bone marrow, and brain. In 4 of 5 mice with PTLD, Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) were detected by in situ hybridization in PAX5+ human B cells associated with the PDX ( n = 1/4) or with engrafted human immune cells at other anatomic locations ( n = 4/11). One of the 4 mice had an EBV-associated human large B-cell lymphoma. NSG mice receiving xenotransplants can develop combinations of GvHD, EBV-driven PTLD, and B-cell lymphoma similar to those occurring in human pediatric patients. Therefore, pediatric xenotransplants should undergo histopathologic and immunohistochemical assessment upon collection to ensure that the specimen is not a lymphoma and does not contain lymphoma cells because these neoplasms can morphologically mimic small round blue cell pediatric solid tumors.

scholarly journals Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

2020 ◽  
Vol 14 ◽  
pp. 117955492097636
Author(s):  
Ah-Reum Jeong ◽  
Edward D Ball ◽  
Aaron Michael Goodman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Checkpoint Blockade ◽  
Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

scholarly journals Phase 1 Study of the Parp Inhibitor E7449 As a Single Agent in Patients with Advanced Solid Tumors or B-Cell Lymphoma

2014 ◽  
Vol 25 ◽  
pp. iv151 ◽  
Author(s):  
R. Plummer ◽  
D. Dua ◽  
N. Cresti ◽  
A. Suder ◽  
Y. Drew ◽  
...  
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Advanced Solid Tumors ◽  
Phase 1 Study

scholarly journals Inflammatory Cells in Diffuse Large B Cell Lymphoma

2020 ◽  
Vol 9 (8) ◽  
pp. 2418
Author(s):  
Roberto Tamma ◽  
Girolamo Ranieri ◽  
Giuseppe Ingravallo ◽  
Tiziana Annese ◽  
Angela Oranger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Antigens ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL), known as the most common non-Hodgkin lymphoma (NHL) subtype, is characterized by high clinical and biological heterogeneity. The tumor microenvironment (TME), in which the tumor cells reside, is crucial in the regulation of tumor initiation, progression, and metastasis, but it also has profound effects on therapeutic efficacy. The role of immune cells during DLBCL development is complex and involves reciprocal interactions between tumor cells, adaptive and innate immune cells, their soluble mediators and structural components present in the tumor microenvironment. Different immune cells are recruited into the tumor microenvironment and exert distinct effects on tumor progression and therapeutic outcomes. In this review, we focused on the role of macrophages, Neutrophils, T cells, natural killer cells and dendritic cells in the DLBCL microenvironment and their implication as target for DLBCL treatment. These new therapies, carried out by the induction of adaptive immunity through vaccination or passive of immunologic effectors delivery, enhance the ability of the immune system to react against the tumor antigens inducing the destruction of tumor cells.

Gene Expression Signature of Host Immune Response Is Predictive of Follicular Lymphoma Patient Survival in Independent Cohorts, and Correlates with Transformation to Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2951-2951
Author(s):  
Ash A Alizadeh ◽  
Andrew J Gentles ◽  
Sylvia K Plevritis ◽  
Ronald Levy
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Immune Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Independent Cohort

Abstract Abstract 2951 Poster Board II-927 Background: Expression signatures of infiltrating immune cells [1] have been shown to predict survival in follicular lymphoma (FL), but have not been cross-validated in independent patient cohorts [2,3]. These signatures may relate biologically to the frequency of infiltrating including T-cells and macrophages, or to specific transcription programs within tumor cells and/or the tumor microenvironment. We sought to evaluate the validity of this model in an independent cohort of patients with FL, assessing its relationship to outcomes including histological transformation and death. Methods: The immune response (IR) predictor score proposed by Dave et al. [1] was applied to gene expression data from an independent cohort of 88 FL patients [4] with known survival outcomes and history of transformation to diffuse large B-cell lymphoma (DLBCL). Genes (n=66) corresponding to IR1 and IR2 signatures were mapped from Affymetrix microarrays [1] to a custom cDNA array [4] via Entrez Gene ID, and the composite IR score was calculated per the scheme proposed by Dave et al. Results: The IR score was predictive of patient outcome in the 88 patient test set as a continuous variable (p=0.001, HR=2.01, 95% CI 0.50-1.30). Partitioning of patients into high and low risk groups based on the median IR score across the cohort robustly separated survival curves (Figure A). The IR score was significantly higher in FL patients known to undergo transformation to DLBCL (Figure B: mean IR score of -0.6 in non-transforming FL vs. -0.2 in transforming FL; p∼10-11, t-test). Conclusions: The IR score of Dave et al. was highly significant as a predictor of survival in the independent patient cohort [4]. Moreover, the score was significantly associated with propensity of FL to transform to DLBCL. To our knowledge, immune cell infiltration has not previously been implicated in transformation. 1. Dave SS et al. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21): 2159-2169. 2. Tibshirani R (2005) Immune signatures in follicular lymphoma. N Engl J Med 352: 1496-1497. 3. Chu G Hong WJ, Warnke R, Chu G (2005). Immune Signatures in Follicular Lymphoma (Corres). N Engl J Med. 352: 1496-1497. 4. Glas AM et al. (2005) Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 105(1): 301-307. Disclosures: No relevant conflicts of interest to declare.

Impact Of Epstein-Barr Viral Infection In The Regression Of Methotrexate-Induced Lymphoproliferative Diseases In Patients With Rheumatoid Arthritis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3006-3006 ◽  
Author(s):  
Tokuhira Michihide ◽  
Kimura Yuhta ◽  
Takahashi Yasuyuki ◽  
Tomikawa Tatsuki ◽  
Morihiko Sagawa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoproliferative Diseases ◽  
Ebv Infection ◽  
Epstein Barr

Abstract Background Recent studies have investigated the pathogenesis of the class of conditions known as “other iatrogenic immunodeficiency-associated lymphoproliferative diseases” (OIIA-LPDs), particularly in patients with rheumatoid arthritis (RA). Methotrexate (MTX) is a potent cause of LPDs, and withdrawal of MTX can result in spontaneous regression of LPD, which suggests that this drug plays an important role in the tumorigenesis of LPDs. In addition, an impaired immunity against Epstein-Barr virus (EBV) has been obserbed in RA patients. A number of reports describe LPD regression in patients with OIIA-LPDs-RA, but its precise etiology and pathogenesis remain unclear. Furthermore, the phenomenon of relapse/regrowth of LPDs after initial regression has not been well documented. This study retrospectively analyzed the clinicopathological features of OIIA-LPDs-RA patients to determine the influence of EBV infection on regression/relapse of the disease. Methods & Results Data were collected from 35 patients with RA who developed LPD and who were treated at our institute between 1998 and 2013. All patients had received treatment with MTX. The diagnosis of RA was made according to the American College of Rheumatology criteria. Based on immunohistochemistry performed on paraffin-embedded tissue sections, diagnoses were as follows: diffuse large B cell lymphoma (DLBCL; n=14), Hodgkin lymphoma (HL; n=7), follicular lymphoma (FL; n=4), mucosal-associated lymphoid tissue (MALT; n=3), Hodgkin-like lymphoma (HL-like; n=3), T-cell lymphoma (n=3), polymorphic LPD (P-LPD; n=2) according to the 4th WHO classification. Regarding EBV infection, 16 patients (44%) were positive. Patients with FL, MALT, and T-cell lymphoma were negative for EBV, except for one patient with T-cell lymphoma. In contrast, EBV infection positivity was prevalent in patients with DLBCL, HL, HL-like and P-LPD (46%, 100%, 100%, and 50%, respectively). Although HL indicated a specific phenotype, such as positivity for CD15 and CD30 (83%, and 100%, respectively), and rarely expressed CD20, OCT2 or BOB1 (0%, 14%, 14%, respectively), the phenotypes of HL-like and P-LPD were supposedly intermediate between DLBCL and HL. The phenotypes of FL, MALT, and T-cell lymphoma were the same as those of de novo cases. LPD regression was observed in 23 (66%) of 35 patients, which is more common than that seen in previous reports. Although LPD regression was not documented in patients with T-cell lymphoma, it did occur in all patients with HL, HL-like and P-LPD. In addition, the incidence of regression among patients with DLBCL, FL and MALT was 46%, 75% and 33%, respectively. The relationship between EBV infection and LPD regression among patients with HL, DLBCL, HL-like and P-LPD was statistically significant (p=0.048, Fisher's exact test). Of 23 patients with regression, 13 patients (56%) subsequently showed relapse/regrowth, and the incidence of this phenomenon was relatively high in patients with HL, HL-like and P-LPD (100%, 67%, and 50%, respectively), whereas a lower incidence was seen in patients with DLBCL, FL, and MALT (7%, 33%, and 0%, respectively). Summary/Conclusions LPD regression was relatively common (66%) in patients with OIIA-LPDs-RA, particularly in patients with B cell phenotypes. There was a significant relationship between LPDs and EBV infection in patients with HL, DLBCL and HL-like, suggesting that underlying EBV infection might influence the immunosuppressant effect of MTX against EBV in those phenotypes. Further, LPD relapse/regrowth was common in patients with HL, HL-like and P-LPD and was unlikely in patients with DLBCL. Further studies would be of benefit to investigate the underlying molecular mechanism of regression/relapse of LPD after withdrawal of MTX. Disclosures: No relevant conflicts of interest to declare.

The Response Evaluation Criteria in Solid Tumors Can be Substituted for the International Workshop Criteria?: Comparison Using Japan Clinical Oncology Group Study JCOG0203 for Untreated Indolent B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4779-4779
Author(s):  
Kenichi Miyamoto ◽  
Takashi Watanabe ◽  
Hideaki Kitahara ◽  
Masashi Wakabayashi ◽  
Kenichi Nakamura ◽  
...  
Keyword(s):  
B Cell ◽  
Malignant Lymphoma ◽  
Solid Tumors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Kappa Coefficient ◽  
Response Evaluation

Abstract Introduction: The International Workshop Criteria (IWC) has been used for response evaluation in malignant lymphoma since 1999. In contrast, the Response Evaluation Criteria in Solid Tumors (RECIST) has been used for most solid tumors since 2000. The IWC is more complicated than RECIST, partly because it requires calculating the sum of the product of bidimensional diameters of the target lesions, whereas RECIST is based on unidimensional assessment of target lesions. If RECIST can be demonstrated to be more valid and precise than the IWC for malignant lymphoma, RECIST would be the substitute for IWC even for malignant lymphoma. The objective of this study was to evaluate whether RECIST could be substituted for the IWC using data from the JCOG0203 trial, a phase II/III study of R-CHOP-21 versus R-CHOP-14 in untreated, advanced-stage indolent B-cell lymphoma where the superiority of R-CHOP-14 in progression-free survival (PFS) was not shown (hazard ratio [HR], 0.92; 95% CI, 0.68-1.25; one-sided log-rank p = 0.30) (J Clin Oncol 2011;29:3990-8). Methods: Three hundred patients aged 20-69 with stage III or IV indolent B-cell NHL were enrolled in the JCOG0203 trial between 2002 and 2007. Patients ineligible after the central pathological review (CPR) or patients with no target lesions for RECIST were excluded from this analysis. We calculated the kappa coefficient to evaluate the degree of agreement between IWC and RECIST. RECIST would be considered better in cases of a kappa coefficient of ≥0.7 because this indicates that both are in good agreement and RECIST is less complicated. If the kappa coefficient is <0.7, RECIST would be considered discordant with IWC. We evaluated which criteria were more predictive for PFS. In particular, criteria that can show a good separation of PFS, namely, the lower point estimate of the hazard ratio (HR) of a complete response (CR, including complete response and unconfirmed CR [CRu]) vs. a non-CR, is defined as more useful criteria. The landmark-time analysis was applied to PFS counted from day 168, when response status (CR vs. non-CR) for all patients was fixed. Results: Overall, 269 patients were included in this analysis, 14 patients were ineligible by the CPR and 17 patients without target lesions for RECIST were excluded.The median age was 54 years, and 46.8% of the patients were men. Two-hundred fifty-six (95.2%) were diagnosed as having follicular lymphoma and 8 (3.0%) with extranodal marginal zone B-cell lymphoma. According to the Follicular Lymphoma International Prognostic Index, 85 (31.6%), 112 (41.6%), and 72 (26.8%) patients were classified as being at low, intermediate, and high risk, respectively.Based on the IWC, 207 patients (77.0%) had a CR/CRu, 54 (20.1%) a partial response (PR), 3 (1.1%) had stable disease (SD), 4 (1.5%) had progressive disease (PD), and 1 (0.4%) was not evaluable (NE). Based on RECIST, 120 (44.6%) had a CR, 137 (50.9%) had a PR, 6 (2.2%) SD, 4 (1.5%) had PD, and 2 (0.7%) were NE. The kappa coefficient between IWC and RECIST was 0.342 (95% CI, 0.261-0.424), indicating poor agreement. Subsequently, we calculated the HR (CR vs. non-CR) of PFS for each criterion with 264 patients in the landmark analysis. The HR of the IWC (0.473: 95% CI, 0.330-0.677, log-rank test p < 0.001) was lower than that of RECIST (0.635: 95% CI, 0.454-0.888, p = 0.0075). In terms of overall survival, the HR (CR vs. non-CR) was 0.500 (95% CI, 0.223-1.119, p = 0.0856) and 0.471 (95% CI, 0.197-1.130, p = 0.0843) according to IWC and RECIST, respectively. Conclusion: RECIST cannot be substituted for the IWC in untreated, advanced-stage indolent B-cell NHL. Although fluorodeoxyglucose-positron emission tomography should be included in the standard response criteria currently used, introduction of unidimensional assessment is not recommended. Disclosures Maruyama: Takeda: Honoraria; Janssen: Honoraria. Tobinai:Chugai Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Eisai: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Celgene: Research Funding; HUYA Bioscience: Honoraria; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; Zenyaku Kogyo: Honoraria; GlaxoSmithKline: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

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