Rituximab

CHOP has been the standard chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). However, indolent NHL remains largely an incurable diseases, with nearly static overall survival, and only 40% of patients with aggressive NHL are cured by CHOP. Monoclonal antibodies are an exciting advance in the treatment of lymphoma. Rituximab is a mouse/human chimeric monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal cells of the B-cell lineage, but not on primitive stem cells or mature plasma cells. Rituximab is safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. Clinical trials with rituximab indicate that the drug has broad application to NHL, although further clarification is needed to determine its optimal use in many of these clinical settings. In indolent NHL, rituximab has shown useful response rates, both as first-line therapy in relapsed disease. In aggressive lymphomas, diffuse large B-cell lymphoma is the most common form, the addition of rituximab to CHOP chemotherapy significantly lengthens disease-free and overall survival compared to CHOP alone as first line therapy, at least in elderly patients. These included combination with chemotherapy, prolonged or increased dosing regimens, and maintenance therapy, in which rituximab is administered to patients in remission to eliminate minimal residual disease and reduce the risk of relapse. Rituximab in vivo purging and maintenance is also being evaluated in autologous transplantation setting. Newer agents, including radiolabelled antibodies, Immunotoxin-linked antibodies and antibodies against novel target antigens are being tested in on-going clinical trial.     

Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression.

Rituximab is a chimeric antibody with human gamma-1 and kappa constant regions and murine variable regions. It recognizes the CD20 antigen, a pan B-cell marker. Therapeutic trials in patients with B-cell non-Hodgkin's lymphoma (NHL) have shown significant efficacy with a primary response rate of 50%, and a secondary response rate of 44% after repeat treatments in prior responders. The selection for proliferating tumor cells that no longer express CD20 may compromise repeated treatment. We have identified a patient who developed a transformed NHL that lost CD20 protein expression after two courses of therapy with rituximab. In a pretreatment lymph node biopsy, 83% of B cells (as defined by CD19 and surface immunoglobulin) expressed surface CD20. A biopsy from the recurrent tumor after two courses of rituximab revealed a diffuse large cell NHL where 0% of B cells expressed CD20 with no evidence of bound rituximab. Cytoplasmic staining showed no CD20 protein. Sequencing of immunoglobulin heavy chain cDNA identified identical variable sequences in the initial and recurrent lymphomas, confirming the association between the two tumors. Literature and database review suggests that approximately 98% of diffuse large cell lymphomas express CD20, which suggests that these tumors rarely survive without CD20. This is the first identified case of loss of CD20 expression in a lymphoma that has relapsed after rituximab therapy, although several other cases have since been identified. Considering the significant number of patients treated with anti-CD20 antibodies, this may occur only rarely and is unlikely to preclude recurrent therapy with anti-CD20 antibodies in the majority of patients. However, because many patients have relapsed after anti-CD20 antibody therapy and have not been biopsied to identify clones with down-regulated CD20 antigen, we do not currently know the true frequency of this phenomenon. When possible, patients should undergo evaluation for CD20 expression before repeated courses of anti-CD20 therapy.     

ABCs of radioisotopes used for radioimmunotherapy: alpha- and beta-emitters

Although the introduction of the monoclonal antibody rituximab 5 years ago led to a marked improvement in the treatment of non-Hodgkin's lymphoma (NHL), most patients do not experience a complete response to therapy, and many who do respond relapse. One way of improving the efficacy of monoclonal antibodies is to use them to deliver cytotoxic agents, such as radionuclides, to the tumor. Monoclonal antibodies armed with radionuclides provide a means of targeting radiation therapy specifically to tumor cells that express the antigen to which the antibody was originally raised. Subsequently, in 2002, the first radiolabeled monoclonal antibody, 90Y-ibritumomab tiuxetan was approved for the treatment of patients with relapsed or refractory low-grade follicular or transformed B-cell NHL, including patients with follicular lymphoma refractory to rituximab. Attempts to optimize the efficacy of radioimmunotherapy are ongoing, however, and there are three factors that need to be considered: choice of antibody/antigen, choice of delivery of system to be used, and choice of radionuclide. CD25 (IL-2R alpha) is an ideal choice for a target antigen as it is over-expressed by a number of tumor cells, including adult T-cell leukemia (ATL); 9 of 16 patients with ATL responded to treatment with anti-Tac (which targets the interleukin-2 receptor-alpha [IL-2R alpha]), conjugated to 90Y. The dose of radionuclide that can be delivered to a tumor can be increased dramatically by using a three-step process in which the antibody and radioactivity are delivered separately to the antigen in order to improve tumor-to-normal tissue ratios. The most commonly used radionuclides in radioimmunotherapy to date are beta-emitters. However, the pretargeting process makes the use of short-lived alpha-emitters more feasible. The results of experiments involving this pretargeting process and alpha- and beta-emitting radionuclides in leukemia and lymphoma models suggest that alpha-emitters may be more effective in the treatment of small tumors, micrometastases and isolated cells, and that beta-emitters may be more suitable for use in large tumor masses, such as lymphomas.     

Antibodies for the treatment of diffuse large cell lymphoma

The development of monoclonal antibodies has significantly affected the therapy of B-cell non-Hodgkin's lymphomas (NHLs). Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has activity in both indolent and aggressive B-cell lymphomas. Perhaps the greatest change has occurred in first-line therapy of advanced stage, diffuse large cell lymphoma (DLCL), where rituximab combined with conventional chemotherapy has improved both overall survival (OS) and progression-free survival (PFS) over combination chemotherapy alone. Further studies are needed assessing the role of rituximab in salvage therapy, as part of the conditioning regimen prior to autologous stem cell transplant, and as maintenance therapy for large cell lymphoma. Several novel monoclonal antibodies are in development and may also be active in DLCL. These agents may be most promising when combined with either chemotherapy or with rituximab. This review will summarize the use of rituximab in the therapy of diffuse large B-cell lymphoma and briefly describe antibodies in development.     

弥漫性大B细胞淋巴瘤免疫治疗进展

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）是最常见的非霍奇金淋巴瘤（NHL）亚型,其具有高度异质性和侵袭性。尽管许多患者应用R-CHOP(利妥昔单抗+环磷酰胺+阿霉素+长春新碱+泼尼松)方案一线治疗后达到完全缓解（CR）,但仍有部分患者之后发展为复发和难治性的DLBCL,而一旦发展为复发难治性的DLBCL,常规的放疗和化疗则收效甚微。近年来,免疫治疗逐渐成为研究热点,如单克隆抗体治疗、双特异性抗体治疗、抗体-药物偶连物（ADC）治疗和嵌合体抗原受体修饰T细胞（CAR-T）治疗等。本文现就弥漫性大B细胞淋巴瘤免疫治疗进展进行综述。     

Adding cytokines to monoclonal antibody therapy: does the concurrent administration of interleukin-12 add to the efficacy of rituximab in B-cell non-hodgkin lymphoma?

Interleukin-12 (IL-12) is a cytokine that facilitates cytolytic T-cell responses, enhances the lytic activity of NK cells and induces the secretion of interferon-gamma by both T and NK cells. Binding of rituximab, a chimeric murine/human monoclonal antibody, to CD20 on B-lymphocytes induces apoptosis and the Fc domain of the antibody recruits immune effector functions to mediate cell lysis. Therefore, combining IL-12 with rituximab in patients with B-cell non-Hodgkin lymphoma (NHL) may augment the immune mediated cell lysis induced by rituximab. To determine whether a synergistic effect exists when IL-12 is given in combination with rituximab, clinical trials are being done to evaluate the clinical efficacy of the combination. The two agents, when given in combination, significantly upregulate the patient's immune mechanisms. The combination upregulates gamma interferon and IP-10 expression and increases NK cell lytic activity. The combination appears to have significant clinical activity with a high clinical response rate in early phase clinical trials. However, a randomized controlled trial will be required to determine whether the addition of IL-12 adds to the efficacy of rituximab in B-cell NHL.     

Current treatment of follicular non-Hodgkin's lymphoma

56200 new cases of NHL are expected to be diagnosed in the United States (US) per year. For reasons that are not fully understood, the number of new cases per year has nearly doubled in the past three decades. Most patients with follicular lymphoma are over 50 years of age and present with widespread disease at diagnosis. Nodal involvement is very common, often accompanied by splenic and bone marrow disease. Despite the advanced stage, the median survival ranges from 8 to 12 years. The vast majority of patients with advanced stage follicular lymphoma are not cured using the current therapeutic options. The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses (CRs) to treatment. Therapeutic options in follicular NHL include watchful waiting, oral alkylating agents, purine nucleoside analogues, combination chemotherapy, interferon and monoclonal antibodies. Radiolabelled monoclonal antibodies, autologous or allogeneic bone marrow or peripheral stem cell transplantation are under current clinical evaluation. The approval of rituximab, an unconjugated chimeric antibody against the CD20 antigen for the treatment of relapsed follicular B-cell NHL marked a milestone in the development of antibody treatment. In addition, newer approaches like radioimmunoconjugates with myeloablative activity induced response rates of 80-100% in heavily pretreated patients. Various clinical trials combining monoclonal antibodies with conventional therapies are currently ongoing to determine whether these new biological agents will alter the natural history of follicular lymphoma.     

Recent progress in rituximab therapy and its resistance--how do we overcome?

With the introduction of rituximab to chemotherapy in lymphoma, CHOP changed to R-CHOP in elderly, intermediate risk DLBCL (diffuse large B-cell lymphoma) patients. Although the treatment is not yet standard, due to insufficient evidence, in clinical practice it is an R-containing regimen, for example, in mantle cell lymphoma, such as HyperCVAD/MA to R-HyperCVAD/MA. Recently, another group and ours reported the presence of rituximab resistance during R-containing chemotherapy. If the lymphoma is bulky,the overexpression of CD 55 (complement regulatory molecule) leads to resistance to rituximab. When the patients evidenced the loss of CD 20 antigen in refractory/relapsed lymphoma after R-containing therapy, some patients showed the presence of CD 20 point mutation. In the cases of refractory/relapsed cases, radioimmunotherapy or other monoclonal antibodies are prepared, including Zevalin and CD 22, CD 40, CD 74, and HLA-DR targeting antibodies. Not only monoclonal antibodies but also HDACI or bortezomib (NF-kappaB) and other signal inhibitors (for Akt, ERK/MAPK) have been developed. In Japan, we must consider the higher speed of infusion rituximab and we must prepare standard therapy for lymphoma because of recruiting phase I/II clinical trials after use of rituximab for easy entry.     

Epratuzumab in the therapy of oncological and immunological diseases

B cells play an important role in the pathogenesis of certain lymphomas and leukemias, as well as many autoimmune diseases. Antagonistic B-cell antibodies are thus gaining an increasing role in the management of these diseases. The first antibody target in this regard was CD20, with the development and introduction of rituximab in the management of B-cell malignancies, as well as rheumatoid arthritis. A second candidate target is CD22. The first antagonistic antibody to this B-cell marker, epratuzumab, appears to function, in contrast to CD20 antibodies, more by modulation of B cells rather than by their high depletion in circulation. Originally developed for the treatment of non-Hodgkin’s lymphoma, epratuzumab has now been found to be effective, with a very good safety profile, in two prototype autoimmune diseases: systemic lupus erythematosus and primary Sjögren’s syndrome. Recent studies have demonstrated the activity and safety of epratuzumab in non-Hodgkin’s lymphoma patients who have relapsed or are refractive to conventional therapy, including rituximab, and has also shown good activity in follicular and diffuse large B-cell lymphoma in combination with rituximab. As such, this new investigative antibody may have a significant market potential owing to the multitude of diseases and patients who may benefit from a CD22, B-cell antibody immunotherapy that is complementary to the known effects and role of CD20 antibodies, but can usually be administered within 1 h and depletes approximately 50% of circulating B cells.     

New developments in immunotherapy for non-Hodgkin’s lymphoma

The clinical development of immunotherapy with rituximab (chimeric anti-CD20 monoclonal antibody) has markedly affected the treatment approach for patients with B-cell non-Hodgkin’s lymphoma (NHL). Rituximab was initially evaluated in relapsed indolent lymphoma and has substantial activity in this setting both alone and in combination with chemotherapy. Ongoing efforts in indolent NHL are seeking to optimize the dose and schedule of rituximab through ‘maintenance’ strategies exploring chemotherapyrituximab combinations and the use of other biologic agents or antibodies that may enhance activity when employed together with rituximab. Other studies in indolent NHL suggest that radiolabeled anti-CD20 antibodies (such as I-131 tositumomab and Y-90 ibritumomab tiuxetan) may be useful in relapsed and refractory disease and have potential utility as part of initial treatment as well. In diffuse large B-cell lymphoma, the addition of rituximab to CHOP chemotherapy can improve survival, though benefits are more limited in mantle cell lymphoma. Further studies of unlabeled and radiolabeled immunotherapies are ongoing in order to optimize their use for maximal clinical benefit.     

Rituximab Therapy of B-Cell Neoplasms

The development of rituximab, an anti-CD20 monoclonal antibody, represents a revolutionary advance in the therapy of hematological malignancies. Rituximab was approved in 1997 by the Food and Drug Administration for the treatment of relapsed or refractory, CD20+, B-cell, low-grade or follicular non-Hodgkin's lymphoma (NHL). Recent studies have documented activity of rituximab in other CD20- expressing hematological malignancies including mantle cell lymphoma, small lymphocytic lymphoma, aggressive NHL, chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia. When used in combination with cytotoxic chemotherapy, rituximab achieves response rates of 90%–95% in low-grade follicular and aggressive NHL patients. Currently, rituximab is undergoing intensive investigation in several large phase II and III trials, both as a single agent and in combination with chemotherapy. Clinical research will help define the ultimate role of this agent and its potential impact on survival of patients with B-cell neoplasms. This article describes current clinical trials with rituximab and discusses their significance.     

Epratuzumab in the therapy of oncological and immunological diseases

B cells play an important role in the pathogenesis of certain lymphomas and leukemias, as well as many autoimmune diseases. Antagonistic B-cell antibodies are thus gaining an increasing role in the management of these diseases. The first antibody target in this regard was CD20, with the development and introduction of rituximab in the management of B-cell malignancies, as well as rheumatoid arthritis. A second candidate target is CD22. The first antagonistic antibody to this B-cell marker, epratuzumab, appears to function, in contrast to CD20 antibodies, more by modulation of B cells rather than by their high depletion in circulation. Originally developed for the treatment of non-Hodgkin's lymphoma, epratuzumab has now been found to be effective, with a very good safety profile, in two prototype autoimmune diseases: systemic lupus erythematosus and primary Sj?gren's syndrome. Recent studies have demonstrated the activity and safety of epratuzumab in non-Hodgkin's lymphoma patients who have relapsed or are refractive to conventional therapy, including rituximab, and has also shown good activity in follicular and diffuse large B-cell lymphoma in combination with rituximab. As such, this new investigative antibody may have a significant market potential owing to the multitude of diseases and patients who may benefit from a CD22, B-cell antibody immunotherapy that is complementary to the known effects and role of CD20 antibodies, but can usually be administered within 1 h and depletes approximately 50% of circulating B cells.     

Factors associated with toxicity and response to yttrium 90-labeled ibritumomab tiuxetan in patients with indolent non-Hodgkin's lymphoma

Treatment of patients with indolent non-Hodgkin's lymphoma (NHL) is evolving. These patients usually present with advanced-stage disease. Treatment options for patients who experience relapse are limited, and no treatment has been shown to be superior to others in improving overall survival of this group of patients, with the possible exception of allogeneic stem cell transplantation. Therefore, new approaches are needed to improve outcomes in patients with relapsed or refractory disease. The anti-CD20 monoclonal antibody, rituximab, was the first monoclonal antibody approved for the treatment of indolent B-cell NHL. As a single agent in the treatment of relapsed or refractory indolent lymphoma, response rates as high as 56% have been observed. This promising new therapy was followed by development of radioimmunotherapy, a novel treatment approach that combines the targeting capability of monoclonal antibodies with the additional cytotoxic effects of radiation. Yttrium 90-labeled ibritumomab tiuxetan (Zevalin) is a radiolabeled monoclonal antibody that has been shown to produce clinically significant responses in up to 80% of patients with indolent NHL and is the first radiolabeled monoclonal antibody approved for therapeutic use in the treatment of lymphoma. This article reviews some of the safety and efficacy data for this agent in addition to examining factors that could aid in predicting response and toxicity in patients with low-grade relapsed or refractory NHL treated with 90Y ibritumomab tiuxetan.     

An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab.

The chimeric anti-CD20 monoclonal antibody rituximab has become part of the standard therapy for patients with non-Hodgkin's lymphoma (NHL). To date, more than 300 000 patients have been treated with rituximab worldwide, including patients with indolent and aggressive NHL, Hodgkin's disease and other B-cell malignancies. Combination of rituximab with cytotoxic agents or cytokines has been explored in a number of different studies. Rituximab is now also approved for patients with diffuse large B-cell lymphoma when combined with standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone). The monoclonal antibody is generally well tolerated. Most adverse events are infusion-associated, including chills, fever and rigor related to the release of cytokines.     

Immunotherapy for non-Hodgkin's lymphoma

The first attempt at using monoclonal antibodies in lymphoma therapy, reported in 1980, was unsuccessful. Since that time, several immunotherapeutic approaches to treating non-Hodgkin's lymphoma have been developed, with varying degrees of success. These approaches are largely based on the fact that each lymphoma is a clone of identical cells with a unique immunoglobulin on its surface. This unique portion of the immunoglobulin--the idiotype--is an ideal target for therapy. Clinical trials with antibodies have mostly targeted CD20, which is present on 95% of all B-cell lymphomas, as well as CD19 and CD22. This concept of using the idiotype to broaden the antilymphoma effect and to use it as a vaccine model has recently been evaluated. This approach would theoretically produce an active immunization with induction of humoral and cellular responses that would be longer acting than passive antibodies alone. The response is heterogeneous and polyclonal, which may be an advantage. Studies of these approaches will be outlined in this article.     

Beyond rituximab: The future of monoclonal antibodies in B-cell non-Hodgkin lymphoma

The treatment of non-Hodgkin lymphoma (NHL) has changed dramatically since the introduction of rituximab, a monoclonal antibody that binds to the B-cell transmembrane protein CD20 and causes lysis of the lymphoma cells. Since then, a number of additional antibodies have been tested against other B-cell targets, resulting in variable efficacies. The goal of these newer agents is to achieve similar or better response rates as seen with rituximab and perhaps demonstrate activity in rituximab-refractory disease. Several of the antibodies have been investigated in combination with each other as well as with conventional chemotherapeutic regimens. Approval of such antibodies by regulatory committees and their eventual integration into clinical practice will likely depend on positive results from randomized trials.     

Beyond rituximab: The future of monoclonal antibodies in B-cell non-Hodgkin lymphoma

The treatment of non-Hodgkin lymphoma (NHL) has changed dramatically since the introduction of rituximab, a monoclonal antibody that binds to the B-cell transmembrane protein CD20 and causes lysis of the lymphoma cells. Since then, a number of additional antibodies have been tested against other B-cell targets, resulting in variable efficacies. The goal of these newer agents is to achieve similar or better response rates as seen with rituximab, and perhaps demonstrate activity in rituximab-refractory disease. Several of the antibodies have been investigated in combination with each other as well as with conventional chemotherapeutic regimens. Approval of such antibodies by regulatory committees and their eventual integration into clinical practice will likely depend on positive results from randomized trials.     

Radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for patients with relapsed CD20+ B-cell non-Hodgkin's lymphoma

The clinical development and US Food and Drug Administration approval in 1997 of the monoclonal anti-CD20 antibody rituximab have been major treatment advances for patients with B-cell non-Hodgkin's lymphoma (NHL). Rituximab produces responses in approximately 50% of cases of relapsed, low grade NHL. Most of these responses are partial remissions; cure remains elusive. One way to enhance the effectiveness of monoclonal antibodies is to chelate radionuclides such as yttrium-90 ((90)Y) to the antibody. ( 90)Y is a high-energy, beta-emitting radioisotope that delivers most of its radiation over a path length of 2 to 5 mm. Therefore, the antibody delivers, or targets, the radiation only to CD20+ cells, sparing normal cells from the radiation. Ibritumomab is the murine anti-CD20 antibody that was engineered to develop the human chimeric antibody rituximab. Tiuxetan is a linker/chelator that is attached to the antibody to form ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA). Zevalin can be reacted with (111)indium ((111)In) for imaging and (90)Y for therapy. Phase I studies of Zevalin have determined that patients with a baseline platelet count greater than 150,000 10(6)/L receive 0.4 mCi/kg. Patients with a platelet count of 100 to 149,000 10(6)/L should receive 0.3 mCi/kg. Zevalin has a higher overall response rate (ORR) than its cold antibody counterpart rituximab, as demonstrated in two separate clinical trials. The first trial (IDEC 106-04) randomized 143 rituximab-na?ve patients with relapsed NHL to receive rituximab or Zevalin. The ORR for Zevalin was 80% compared with 56% for rituximab (P = 0.002). The second trial (IDEC 106-06) tested the efficacy of Zevalin in patients who were rituxan-refractory; the ORR was 74%. The main toxicity of Zevalin was reversible myelosuppression. These studies indicate that radiolabeled anti-CD20 antibodies can produce a higher ORR than rituximab. Single-dose Zevalin is another treatment alternative for patients with relapsed low grade NHL. It is well-tolerated even by older adults. The exact role of Zevalin in the therapy of NHL is undetermined. New studies are underway to explore whether patients can safely receive a second dose of Zevalin and to combine Zevalin with high-dose chemotherapy and stem cell rescue. The outcome of these studies will be helpful in deciding how best to integrate this new modality into the treatment paradigm of NHL.     

Phase I trial of a novel intradermal idiotype vaccine in patients with advanced B-cell lymphoma: specific immune responses despite profound immunosuppression

The immunoglobulin receptor of B-cell lymphomas constitutes a specific tumor antigen (idiotype) and a target for active immunotherapy. Encouraging results have been reported in phase II trials after s.c. vaccination of follicular lymphoma patients during clinical remission with idiotype produced from eukaryotic cell lines and coupled to an immunogenic carrier macromolecule. We have developed a good manufacturing protocol for rapid expression of idiotype vaccines as recombinant Fab fragments in Escherichia coli. The objectives of this trial were to show safety and feasibility of intradermal immunization with this vaccine and to investigate whether immune responses were induced by this immunization route. Patients (n = 18) with advanced B-cell malignancies received repetitive intradermal vaccinations with 0.5 to 1.65 mg recombinant idiotype Fab fragment mixed with lipid-based adjuvant in combination with 150 mug granulocyte macrophage colony-stimulating factor s.c. at the same location. The patients' immune status was assessed by flow cytometry of peripheral blood lymphocytes and concomitant hepatitis B vaccination. Cellular and humoral immune responses to the vaccine were assessed by enzyme-linked immunospot and ELISA. Side effects of a total of 65 vaccinations were mild and did not affect the immunization schedule. No patient developed hepatitis B surface antibodies (anti-HBs) after two hepatitis B immunizations. Of 17 evaluable patients, five developed specific anti-vaccine antibodies, and eight developed anti-Fab T-cell responses. T-cell reactivity was independent of the cellular immune status and was idiotype specific as shown by statistical regression analysis (P = 0.0024) and epitope mapping studies. Intradermal administration of uncoupled recombinant idiotype with appropriate adjuvants may overcome profound clinical immunosuppression and induce specific immune responses.     

CAR T-cell therapy for B-cell lymphoma

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.