Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy in T-cell/histiocyte-rich large B-cell lymphoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Trujillo JA
PROVIDER: S-EPMC8212512 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Primary central nervous system (PCNSL) lymphoma is an aggressive extranodal non-Hodgkin lymphoma, and most cases are classified as diffuse large B-cell lymphoma (DLBCL) by histology. T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) represents a distinct subtype of diffuse large B-cell lymphoma and is characterized by the presence of scattered large neoplastic B-cells in a background of abundant T-cells and histiocytes. This is in contrast to the dense perivascular cuffing of neoplastic B-cells in classic DLBCL. T-cell/histiocyte-rich large B-cell lymphoma should be considered in PCNSL cases in which neoplastic B-cells are sparse and scattered. Immunohistochemistry will help identify the B-cells and surrounding infiltrate rich in Tlymphocytes and histiocytes. Future studies exploring the biology of TCRLBCL and the crosstalk between the neoplastic cells and the surrounding inflammatory infiltrate may provide exciting prospects for future therapies for TCRLBCL.
| S-EPMC4703926 | biostudies-literature
Project description:T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19+ B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities.
| S-EPMC5628864 | biostudies-literature
Project description:In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis.
| S-EPMC3823948 | biostudies-literature
Project description:T-cell/histiocyte-rich large B-cell lymphoma is a rare aggressive lymphoma showing histopathological overlap with nodular lymphocyte-predominant Hodgkin lymphoma. Despite differences in tumor microenvironment and clinical behavior, the tumor cells of both entities show remarkable similarities, suggesting that both lymphomas might represent a spectrum of the same disease. To address this issue, we investigated whether these entities share mutations. Ultra-deep targeted resequencing of six typical and 11 histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma, and nine cases of T-cell/histiocyte-rich large B-cell lymphoma revealed that genes recurrently mutated in nodular lymphocyte-predominant Hodgkin lymphoma are affected by mutations at similar frequencies in T-cell/histiocyte-rich large B-cell lymphoma. The most recurrently mutated genes were JUNB, DUSP2, SGK1, SOCS1 and CREBBP, which harbored mutations more frequently in T-cell/histiocyte-rich large B-cell lymphoma and the histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma than in its typical form. Mutations in JUNB, DUSP2, SGK1 and SOCS1 were highly enriched for somatic hypermutation hotspot sites, suggesting an important role of aberrant somatic hypermutation in the generation of these somatic mutations and thus in the pathogenesis of both lymphoma entities. Mutations in JUNB are generally rarely observed in malignant lymphomas and thus are relatively specific for nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma at such high frequencies (5/17 and 5/9 cases with JUNB mutations, respectively). Taken together, the findings of the present study further support a close relationship between T-cell/histiocyte-rich large B-cell lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma by showing that they share highly recurrent genetic lesions.
| S-EPMC6355500 | biostudies-literature
Project description:BACKGROUND: Gene expression profiling has successfully identified the prognostic significance of the host response in lymphomas. The aggressive T-cell/histiocyte-rich large B-cell lymphoma and the indolent nodular lymphocyte-predominant Hodgkin's lymphoma are both characterized by a paucity of tumor cells embedded in an overwhelming background. The tumor cells of both lymphomas share several characteristics, while the cellular composition of their microenvironment is clearly different. DESIGN AND METHODS: We collected 33 cases of T-cell/histiocyte-rich large B-cell lymphoma and 56 cases of nodular lymphocyte-predominant Hodgkin's lymphoma and performed microarray gene expression profiling on ten cases of each lymphoma, to obtain a better understanding of the lymphoma host response. By quantitative reverse transcriptase polymerase chain reaction we verified that these 20 selected cases were representative of the entire population of T-cell/histiocyte-rich large B-cell and nodular lymphocyte-predominant Hodgkin's lymphomas. RESULTS: We observed that the microenvironment in nodular lymphocyte-predominant Hodgkin's lymphoma is molecularly very similar to a lymph node characterized by follicular hyperplasia, while the microenvironment in T-cell/histiocyte-rich large B-cell lymphoma is clearly different. The T-cell/histiocyte-rich large B-cell lymphoma signature is hallmarked by up-regulation of CCL8, interferon-gamma, indoleamine 2,3 dioxygenase, VSIG4 and Toll-like receptors. These features may be responsible for the recruitment and activation of T cells, macrophages and dendritic cells, characterizing the stromal component of this lymphoma, and may point towards innate immunity and a tumor tolerogenic immune response in T-cell/histiocyte-rich large B-cell lymphoma. CONCLUSIONS: The gene expression profile of T-cell/histiocyte-rich large B-cell lymphoma, in comparison with that of nodular lymphocyte-predominant Hodgkin's lymphoma, shows features suggestive of a distinct tolerogenic host immune response that may play a key role in the aggressive behavior of this lymphoma, and that may serve as a potential target for future therapy.
| S-EPMC2833074 | biostudies-literature
Project description:The long-term effects of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy (CD19-CARTx) for B-cell malignancies on humoral immunity are unclear. We examined antiviral humoral immunity in 39 adults with B-cell malignancies who achieved durable complete remission without additional therapy for >6 months after CD19-CARTx. Despite CD19+ B-cell aplasia in all patients, the incidence of viral infections occurring >90 days post-CD19-CARTx was low (0.91 infections per person-year). Because long-lived plasma cells are CD19- and should not be direct targets of CD19-targeted chimeric antigen receptor T cells, we tested the hypothesis that humoral immunity was preserved after CD19-CARTx based on linear mixed-effects models of changes in serum total immunoglobulin G (IgG) concentration, measles IgG concentration, and the number of viruses or viral epitopes to which serum IgG was directed (the "antivirome") using the novel VirScan assay. Samples were tested pre-CD19-CARTx and ∼1, 6, and 12 months post-CD19-CARTx. Although total IgG concentration was lower post-CD19-CARTx (mean change, -17.5%), measles IgG concentration was similar (mean change, 1.2%). Only 1 participant lost measles seroprotection post-CD19-CARTx but had undergone allogeneic hematopoietic cell transplantation before CD19-CARTx. The antivirome was also preserved, with mean absolute losses of 0.3 viruses and 6 viral epitopes detected between pre- and post-CD19-CARTx samples. Most participants gained IgG to ≥2 epitopes for ≥2 viruses, suggesting that humoral immunity to some viruses may be maintained or recover after successful CD19-CARTx. These findings may differ in children. Studies of immunoglobulin replacement and vaccination after CARTx are warranted.
| S-EPMC6880890 | biostudies-literature
Project description:Clinical trials of chimeric antigen receptors (CARs) targeting CD19 have produced impressive results in hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). However, a notable number of patients with DLBCL fail to achieve remission after CD19 CAR T-cell therapy and may therefore require a dual targeted CAR T-cell therapy. A 31-year-old man with refractory DLBCL was assessed in the present case report. The patient was treated with sequential infusion of single CD19 CAR T cells followed by dual CD19/CD22-targeted CAR T cells. The outcome was that the patient achieved partial remission after the first single CD19 CAR T-cell infusion and complete remission after the dual CD19/CD22-targeted CAR T-cell infusion. Grade 1 cytokine release syndrome (CRS) was observed after the single CD19 CAR T-cell infusion, while grade 3 CRS and hemophagocytic syndrome were observed after the dual targeted CAR T-cell infusion, but these adverse effects alleviated after the treatments. To the best of our knowledge, the present case report is the first to describe the successful application of dual CD19/CD22-targeted CAR T-cell therapy for the treatment of refractory DLBCL. The report suggests that dual CD19/CD22-targeted CAR T-cell therapy may represent a promising option for the treatment of refractory DLBCL; however, caution should be taken due to potential CRS development.
| S-EPMC7405542 | biostudies-literature
Project description:Background: The therapeutic efficacy of chimeric antigen receptor (CAR) T-cells targeting CD19 has been illustrated in the treatment of diffuse large B-cell lymphoma (DLBCL). However, there is a 21-35% relapse rate after anti-CD19 CAR T-cell induced remission. In addition, CAR T-cell therapy has severe adverse reactions, such as cytokine release syndrome (CRS) and CART-related encephalopathy syndrome (CRES). Because of the potential mortality associated with severe CRES, patients with primary central nervous system lymphoma (PCNSL) are usually excluded from clinical trials involving CAR T-cell therapy. Here, we report a case of refractory and relapsed primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). Case Presentation: The patient is a 67-year-old male who was diagnosed with PCNSL in 2011. He achieved complete remission (CR) after receiving 6 cycles of temozolomide and high-dose methotrexate. In December 2016, he experienced his first relapse and was treated with surgery and multicourse chemotherapy. He achieved CR again after the treatment. However, he experienced a second relapse in August 2017. MRI revealed a residual mass of 26 mm*35 mm*30 mm on the right side of the post-operative cavity and stale hemorrhage in the left basal ganglia. After confirming the expression of CD19 and CD70 in his tumor samples, the patient was given lymphodepletion chemotherapy followed by infusion of 4th generation CD19-CAR T-cells (4SCART19) and 4th generation CD70-CAR T-cells (4SCART70). One month later, the patient had symptomatic improvement, and brain MRI showed CR. Both CART19 and CART70 cells were detected in the 10th month after CAR T-cell infusion. Notably, neither CRS nor CRES occurred during treatment and follow-up. To date, the patient has maintained disease-free survival with more than 17 months of follow-up. Conclusions: The results of this study indicate that combination of CD19- and CD70-specific CAR T-cells may effectively target PCNSL and maintain disease-free survival without inducing CRS or CRES. Therefore, central nervous system lymphoma is not an absolute contraindication for dual-target CAR T-cell therapy.
| S-EPMC6904344 | biostudies-literature
Project description:ImportanceAxicabtagene ciloleucel, an anti-CD19-CD28-CD3ζ chimeric antigen receptor T-cell therapy, was the first US Food and Drug Administration-approved, genetically engineered T-cell therapy for adults with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. There has not been a US Food and Drug Administration-approved product for these cancers in more than 4 decades.ObservationsUnlike traditional anticancer therapies, axicabtagene ciloleucel is a patient-specific, live-cell product that has unique requirements for manufacturing, shipping, and storage, as well as for its administration and management of its adverse events. In addition, axicabtagene ciloleucel has demonstrated efficacy in patients with refractory LBCL. This review presents a timeline of the rapid clinical development of axicabtagene ciloleucel from bench to bedside, highlights how axicabtagene ciloleucel satisfies an unmet medical need for treatment of refractory LBCL, outlines the logistics of the production process and administration of axicabtagene ciloleucel, describes its mechanism of action, and summarizes the results of the pivotal study. This review also provides a survey of adverse events, with attention to the kinetics of their clinical presentation; discusses the management of adverse events; and offers suggestions for appropriate patient selection for safe administration of axicabtagene ciloleucel.Conclusions and relevanceThe integration of axicabtagene ciloleucel therapy into standard-of-care practice for relapsed/refractory LBCL is the beginning of a paradigm shift in the treatment of patients with LBCL and is likely to lead to improvements in their survival and curability. Timely referral to centers offering the therapy is necessary for optimal patient outcomes.
| S-EPMC7859915 | biostudies-literature
Project description:B-cell non-Hodgkin lymphoma (B-NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti-CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B-NHL. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B-cell leukemia and lymphoma. Recently, several clinical trials have shown remarkable efficacy of anti-CD19 CAR T-cell therapy, not only in B-acute lymphoblastic leukemia but also in B-NHL. Nonetheless, there are several challenges to overcome before introduction into clinical practice, such as: (i) further refinement of the manufacturing process, (ii) further improvement of efficacy, (iii) finding the optimal infusion cell dose, (iv) optimization of lymphocyte-depleting chemotherapy, (v) identification of the best CAR structure, and (vi) optimization of toxicity management including cytokine release syndrome, neurologic toxicity, and on-target off-tumor toxicity. Several ways to solve these problems are currently under study. In this review, we describe the updated clinical data regarding anti-CD19 CAR T-cell therapy, with a focus on B-NHL, and discuss the clinical implications and perspectives of CAR T-cell therapy.
| S-EPMC5480083 | biostudies-literature