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Current Problems in Cancer Feb 2022Chimeric antigen receptor-modified (CAR) T-cell therapy targeting CD19 has revolutionized the treatment of relapsed or refractory B-cell lymphomas. Based on... (Review)
Review
Chimeric antigen receptor-modified (CAR) T-cell therapy targeting CD19 has revolutionized the treatment of relapsed or refractory B-cell lymphomas. Based on unprecedented response rates and durability of response in high risk B-cell lymphoma patients, anti-CD19 CAR T-cell therapy was rapidly approved by the FDA for a variety of lymphoma subtypes. Anti-CD19 CAR T-cell therapy is now considered standard of care for patients with relapsed or refractory (R/R) aggressive non-Hodgkin's Lymphoma (NHL) after 2 or more lines of therapy. Three second-generation anti-CD19 CAR T-cell products have been FDA approved for R/R aggressive B-cell lymphoma and FDA approval has been obtained for Mantle Cell Lymphoma and Follicular lymphoma as well. This has ensured broad access to CAR T-cell therapy for patients with NHL and new real-world trials have helped confirm feasibility of CAR T-cell therapy for a broad patient population. The emergence of CAR T-cell therapy will likely provide a new patient population who is status post anti-CD19 CAR T-cell therapy. Investigation of mechanisms of failure of CAR T-cell therapy and clinical trials to study strategies to address this are thus required. Here we provide a thorough review on the use of the FDA approved anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel in patients with indolent or aggressive B-cell lymphoma, and touch on mechanisms of failure of CAR T-cell therapy and potential approaches which are currently under investigation to address this.
Topics: Adult; Antigens, CD19; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasm Recurrence, Local
PubMed: 35012754
DOI: 10.1016/j.currproblcancer.2021.100826 -
Cancer Cell Apr 2020The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical...
The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials.
Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Precision Medicine; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 32289277
DOI: 10.1016/j.ccell.2020.03.015 -
Archives of Pathology & Laboratory... Sep 2022Intravascular large B-cell lymphoma (IVLBCL) is a rare hematopathologic entity, posing both a clinical and histologic challenge for diagnosis. Numerous pitfalls can... (Review)
Review
CONTEXT.—
Intravascular large B-cell lymphoma (IVLBCL) is a rare hematopathologic entity, posing both a clinical and histologic challenge for diagnosis. Numerous pitfalls can hinder making the diagnosis.
OBJECTIVE.—
To summarize recent developments in literature pertaining to IVLBCL and point out key pitfalls pathologists should be prepared to encounter.
DATA SOURCES.—
Literature review via PubMed search and hospital (Darnall Medical Library) resources.
CONCLUSIONS.—
The 3 primary pitfalls of IVLBCL include masking of IVLBCL, mimicry by IVLBCL, and mimicry of IVLBCL. These scenarios illustrate the importance of histologic pattern recognition and subsequent usage of immunohistochemistry, especially in context of a clinical history that may be noncharacteristic.
Topics: Humans; Immunohistochemistry; Lymphoma, Large B-Cell, Diffuse
PubMed: 34979566
DOI: 10.5858/arpa.2021-0165-RA -
Advances in Clinical and Experimental... Aug 2019Although gastrointestinal (GI) tract is the most common extranodal site involved in non-Hodgkin lymphoma (NHL), primary gastrointestinal NHL (gNHL) is a rare problem... (Review)
Review
Although gastrointestinal (GI) tract is the most common extranodal site involved in non-Hodgkin lymphoma (NHL), primary gastrointestinal NHL (gNHL) is a rare problem which concerns about 10-15% of NHL patients and 30-40% of extranodal NHL patients. Lymphoid neoplasms may consist of mature B, T and (less commonly) extranodal NK/T cells. The most common diagnoses are diffuse large B-cell lymphoma and marginal zone lymphoma (MALT), but many other lymphomas may be found in the GI tract. There are a few well-known risk factors of gNHL and some of them affect treatment. The most frequent sites of occurrence are the stomach followed by small intestine and ileocecal region. In the last 2 decades, there has been a rapid development in the diagnosis, staging and management of GI lymphoma, but still some of such lymphomas, especially T-cell ones, are a therapeutic challenge. In this review, we present clinical and pathological features of GI lymphomas. We also describe the current status in diagnosis and treatment.
Topics: Gastrointestinal Neoplasms; Humans; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse
PubMed: 31414733
DOI: 10.17219/acem/94068 -
Nature Reviews. Clinical Oncology Jun 2019The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B... (Review)
Review
The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.
Topics: Antigens, CD19; Clinical Trials as Topic; Disease Progression; Drug Resistance, Neoplasm; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Secondary Prevention
PubMed: 30837712
DOI: 10.1038/s41571-019-0184-6 -
Journal of Hematology & Oncology Aug 2021B-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex... (Review)
Review
B-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex interaction between tumor cells and the tumor microenvironment (TME), which is composed of stromal cells and extracellular matrix. Although the roles of the TME have not been fully elucidated, accumulating evidence implies that TME is closely relevant to the origination, invasion and metastasis of B-cell lymphoma. Explorations of the TME provide distinctive insights for cancer therapy. Here, we epitomize the recent advances of TME in B-cell lymphoma and discuss its function in tumor progression and immune escape. In addition, the potential clinical value of targeting TME in B-cell lymphoma is highlighted, which is expected to pave the way for novel therapeutic strategies.
Topics: Animals; Antineoplastic Agents; B-Lymphocytes; Drug Discovery; Humans; Immunotherapy; Lymphoma, B-Cell; Molecular Targeted Therapy; Tumor Escape; Tumor Microenvironment
PubMed: 34404434
DOI: 10.1186/s13045-021-01134-x -
Nature Medicine Feb 2020Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients...
Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trial of T cells expressing the new anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (P = 0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detected in blood from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.
Topics: Adolescent; Adult; Aged; Antigens, CD19; Cytokines; Feasibility Studies; Female; Humans; Immunotherapy, Adoptive; K562 Cells; Lymphoma, B-Cell; Male; Middle Aged; Phenotype; Protein Domains; Receptors, Chimeric Antigen; Remission Induction; Young Adult
PubMed: 31959992
DOI: 10.1038/s41591-019-0737-3 -
British Journal of Haematology Jun 2020Aggressive B-cell non-Hodgkin lymphoma (B-NHL) accounts for ≈60% of NHL in children/adolescents. In newly diagnosed Burkitt lymphoma and diffuse large B-cell lymphoma,... (Review)
Review
Aggressive B-cell non-Hodgkin lymphoma (B-NHL) accounts for ≈60% of NHL in children/adolescents. In newly diagnosed Burkitt lymphoma and diffuse large B-cell lymphoma, short intensive multiagent chemotherapy is associated with a five-year event-free survival of around 90%. Very few children/adolescents with aggressive B-NHL show a relapsed/refractory (r/r) disease. The outcome is poor, with cure rates <30%, and there is no standard of care. Rituximab-containing salvage regimens may provide a complete/partial response in 60-70% of cases. However, long-term survival is <10% for non-transplanted patients. Autologous or allogeneic haematopoietic stem cell transplant is, nowadays, the best option for responding patients, with survival rates around 50%. The benefit of autologous versus allogeneic HSCT is not clear. Numerous novel therapies for r/r B-NHL are currently being tested in adults, including next-generation monoclonal antibodies, novel cellular therapy strategies and therapies directed against new targets. Some are under investigation also in children/adolescents, with promising preliminary results.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Combined Modality Therapy; Cranial Irradiation; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Kaplan-Meier Estimate; Lymphoma, B-Cell; Male; Mediastinal Neoplasms; Prognosis; Recurrence; Risk Factors; Salvage Therapy; Therapies, Investigational; Treatment Outcome; Young Adult
PubMed: 32141616
DOI: 10.1111/bjh.16461 -
Nature Medicine Jun 2019Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application....
Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 10-4 × 10 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.
Topics: Adult; Aged; Antigens, CD19; Cytokines; Female; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Receptors, Chimeric Antigen; Remission Induction; T-Lymphocytes; Treatment Outcome; Young Adult
PubMed: 31011207
DOI: 10.1038/s41591-019-0421-7 -
International Journal of Biological... 2022As the most common subtype of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL) is characterized by a huge degree of clinical and prognostic heterogeneity.... (Review)
Review
As the most common subtype of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL) is characterized by a huge degree of clinical and prognostic heterogeneity. Currently, there is an urgent need for highly specific and sensitive biomarkers to predict the therapeutic response of DLBCL and assess which patients can benefit from systemic chemotherapy to help develop more precise therapeutic regimens for DLBCL. Systems biology (holistic study of diseases) is more comprehensive in quantifying and identifying biomarkers, helps addressing major biological problems, and possesses high accuracy and sensitivity. In this article, we provide an overview of research advances in DLBCL prognostic biomarkers made using the multi-omics approach of genomics, transcriptomics, epigenetics, proteomics, metabonomics, radiomics, and the currently developing single-cell technologies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biomarkers, Tumor; Humans; Lymphoma, Large B-Cell, Diffuse; Prognosis
PubMed: 35280688
DOI: 10.7150/ijbs.67892