CAR T cell therapy for B-cell lymphomas

B-cell non-Hodgkin's lymphoma (NHLs)is a very heterogonous malignancy with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) as the most common subtypes. Standard treatment with anti-CD20 based chemoimmunotherapy is usually very effective for disease control. However a significant proportion of patients with high-risk features (double hit lymphoma, transformed lymphomas or early relapses) will become refractory to standard therapies and will have limited alternatives for cure. Adoptive therapy with chimeric antigen receptor (CAR) T-cells is a new paradigm for effective treatment of poor prognosis lymphomas. Here we review the biology of poor risk DLBCL and FL, the rationale for CAR T-cell therapy in malignant lymphoma and the efficacy/toxicity profile of CD19 directed CAR T cell therapy for DLBCL and FL from early single center studies to multicenter/global clinical trial with different CAR T cell constructs.     

Enabling CAR T-cell therapies for HIV-positive lymphoma patients – A call for action

People living with HIV have a higher risk of developing lymphoma. Outcomes for people living with HIV with relapsed or refractory (r/r) lymphoma remain poor. For this group of patients, chimeric antigen receptor (CAR) T-cell therapy represents a new successful treatment strategy. However, people living with HIV were not included in pivotal trials, so data are limited to case reports. We searched the PubMed and Ovid technologies databases for literature until 1 November 2022 using the terms ‘HIV and CAR-T’, ‘HIV and lymphoma’ and ‘HIV and CAR-T and lymphoma’. Six cases with sufficient information were included in the review. The mean CD4⁺ T-cell count before CAR T-cell therapy was 221 cells/μL (range 52–629). The viral load was below the limit of detection in four patients. All patients had diffuse large B-cell lymphoma (DLBCL) and were treated with gamma-retroviral-based axicabtagene ciloleucel. Four patients developed cytokine-release syndrome (CRS) grade 2 or less or immune effector-cell-associated neurotoxicity syndrome (ICANs) grade 3–4. Four of six patients responded to CAR T-cell therapy (three complete remissions, one partial remission). In summary, there are no clinical reasons to restrict the use of CAR T-cell therapy in people living with HIV with r/r DLBCL. According to the current data, CAR T-cell therapy was safe and effective. In people who meet the standard criteria for CAR T-cell therapy, this treatment approach could significantly improve the unmet need for more effective treatment options for people living with HIV with r/r lymphoma.     

CAR T in adult ALL: When and for whom?

Chimeric antigen receptor T cell therapy targeting CD19 (CART19) has shown remarkable results in patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (ALL). In patients 25 years of age or younger CART19 therapy is an accepted standard of care, while the treatment of older adults is less straight forward and possible only in the context of a clinical trial. Treatment of older patients with CAR T cells requires careful consideration of overall treatment goals, suitability of a consolidative hematopoietic stem cell transplant (HSCT), alternative treatment options, patient risk profile, and anticipated responses and toxicities of the specific CAR T cell products available. Here we use patient guided examples to inform approaches to care.     

An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patient's own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. CAR T cells are then expanded for clinical use and infused back into the patient's body to attack and destroy chemotherapy-resistant cancer. Dramatic clinical responses and high rates of complete remission have been observed in the setting of CAR T-cell therapy of B-cell malignancies. This resulted in two recent FDA approvals of CAR T cells directed against the CD19 protein for treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Thus, CAR T cells are arguably one of the first successful examples of synthetic biology and personalized cellular cancer therapy to become commercially available. In this review, we introduce the concept of using CAR T cells to break immunological tolerance to tumors, highlight several challenges in the field, discuss the utility of biomarkers in the context of predicting clinical responses, and offer prospects for developing next-generation CAR T cell-based approaches that will improve outcome.     

Clinical experience of CAR T cells for B cell acute lymphoblastic leukemia

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment for both pediatric and adult patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). Clinical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients. One product (tisagenlecleucel) is currently FDA approved for the treatment of R/R B-ALL in patients <26 y/o. Successful application of this therapy is limited by high relapse rates, potential for significant toxicity, and logistical issues surrounding collection/production. Herein, we review published data on the use of CAR T cells for B-ALL, including results from early pivotal clinical trials, relapse data, incidence of toxicity, and mechanisms to optimize CAR T cell therapy.     

Severe persistent neurotoxicity associated with CAR T therapy in children

CD19-directed chimeric antigen receptor (CAR) T-cell therapy is an important therapy for relapsed or refractory acute lymphoblastic leukaemia, but its use carries the risk of immune effector cell-associated neurotoxicity syndrome (ICANS). In children, severe ICANS is almost universally reported in association with cytokine release syndrome and is reversible. We describe two cases of severe, intractable neurotoxicity following CAR T-cell therapy in children with pre-existing central nervous system (CNS) vulnerabilities. The cases were atypical in their delayed onset and independence from cytokine release syndrome and did not respond to standard therapies.     

Potent anti‐leukemia activities of humanized CD19‐targeted Chimeric antigen receptor T (CAR‐T) cells in patients with relapsed/refractory acute lymphoblastic leukemia

Chimeric antigen receptor T (CAR‐T) cell therapy has shown promising results for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The immune response induced by murine single‐chain variable fragment (scFv) of the CAR may limit CAR‐T cell persistence and thus increases the risk of leukemia relapse. In this study, we developed a novel humanized scFv from the murine FMC63 antibody. A total of 18 R/R ALL patients with or without prior murine CD19 CAR‐T therapy were treated with humanized CD19‐targeted CAR‐T cells (hCART19s). After lymphodepletion chemotherapy with cyclophosphamide and fludarabine, the patients received a single dose (1 × 10⁶/kg) of autologous hCART19s infusion. Among the 14 patients without previous CAR‐T therapy, 13 (92.9%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, whereas 1 of the 3 patients who failed a second murine CAR‐T infusion achieved CR after hCART19s infusion. At day 180, the overall and leukemia‐free survival rates were 65.8% and 71.4%, respectively. The cumulative incidence of relapse was 22.6%, and the nonrelapse mortality rate was 7.1%. During treatment, 13 patients developed grade 1‐2 cytokine release syndrome (CRS), 4 patients developed grade 3‐5 CRS, and 1 patient experienced reversible neurotoxicity. These results indicated that hCART19s could induce remission in patients with R/R B‐ALL, especially in patients who received a reinfusion of murine CAR‐T.     

New targets for CAR T therapy in hematologic malignancies

As we expand our acumen of the intricacies of hematological malignancies at a genetic and cellular level, we have paved the way in advancing novel targeted therapeutic avenues such as chimeric antigen receptor T-cell therapies (CAR T). Engineering cells to target a specific antigen has led to dramatic remission rates in cases of relapsed/refractory non-Hodgkin lymphoma, acute lymphoblastic leukemia as well as multiple myeloma thus far with trials in place to further advance targeted therapies in other hematological malignancies. Most currently available CAR T therapies target CD19 antigen. Studies are underway exploring novel CAR T products aimed at other tumor-specific antigens with potential to improve the efficacy and reduce the toxicities. Early studies have confirmed safety and efficacy of CD22 and BCMA targeted CAR T therapies. Moreover, various other targets including CD20, CD30, CD123, kappa, and lambda light chains among others are under clinical investigation as potential avenues of targeted therapy. This review highlights the shift in the treatment paradigm in pursuing diverse antigen targets while addressing the challenges in terms of the efficacy and toxicity of current CAR T-cell therapies.     

How close are we to CAR T-cell therapy for AML?

Chimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia (AML) has thus far been elusive, in part owing to the absence of truly AML-specific surface antigens, making AML difficult to target. However, progress has been made toward the use of CAR T-cell therapy in this disease, prompting the topic of this paper. Discussion and clinical examples of potential solutions to creating a safe and effective CAR T cell for AML include: (1) Decreasing the potency or activity of CAR T cells to enhance the therapeutic window; (2) Using transient or depletable CAR T cells as part of pre-transplant conditioning; and (3) Using a gene-edited allogeneic donor hematopoietic stem cell transplant in order to allow safe and protracted anti-AML CAR T-cell function.     

Toxicities associated with adoptive cellular therapies

Chimeric antigen receptor (CAR) T cell therapy is an effective strategy for the treatment of relapsed/refractory hematologic malignancies leading to the Food and Drug Administration (FDA) approval of five CAR T cell products. Despite encouraging efficacy, the widespread utilization of CAR T cell therapy is limited by unique immune mediated toxicities, primarily cytokine release syndrome (CRS) and neurologic toxicity. Data regarding late effects and long-term toxicities of CAR T cell therapy is evolving and includes prolonged cytopenias, hypogammaglobulinemia, infections and secondary malignancies. In this review, we will describe the clinical presentation, diagnosis, mechanisms and management of short- and long-term toxicities of CAR T cell therapy.     

Phase II trial of a novel chemotherapy regimen CVEP (cyclophosphamide,vinblastine, etoposide and prednisolone) for acquired immunodeficiency syndrome (AIDS)-associated lymphomas

Management of acquired immunodeficiency syndrome (AIDS)-related diffuse large B-cell (DLBCL) and plasmablastic lymphomas (PBL) poses significant challenges. The evidence supports use of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) with or without rituximab as first-line therapy. The need for central venous access, growth factors and significant toxicities limits its use in resource-constrained settings. To address these challenges, we have developed a novel regimen, CVEP (cyclophosphamide, vinblastine, etoposide, and prednisolone) based on the pharmacodynamic principles of dose-adjusted EPOCH. This single-centre phase II study evaluated the efficacy and safety of CVEP regimen in patients with de novo systemic AIDS-related DLBCL and PBL. The primary objective was complete response (CR) rates as assessed by positron emission tomography-computed tomography. The secondary objectives were incidence of Grade 3/4 toxicities, toxicities requiring hospitalisation, and disease-free survival. From May 2011 to February 2017, 42 patients were enrolled. At the end of therapy the CR rates were 69% (29/42) in the intention-to-treat population and 80.5% (29/36) in evaluable patients. At a median follow-up of 69 months, the 5-year disease-free survival was 65.3%. Out of 217 cycles administered, febrile neutropenia occurred in 19.3% and hospitalisation was required in 18.3% of cycles. There were two treatment-related deaths. The CVEP regimen is an active and safe regimen for AIDS-related DLBCL and PBL.     

Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T-cell therapy for chronic lymphocytic leukemia

Studies of chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) have demonstrated the potential to produce deep remissions—and possibly cures—in some patients with heavily pretreated, high-risk, relapsed, and refractory disease. Unfortunately, most clinical trials of CAR T cells in CLL report complete responses only in the minority of patients, although recent studies have begun to elucidate the factors most predictive of response. These studies have suggested strategies for optimizing CAR T-cell fitness as well as the pre-existing host immune response, approaches that will likely lead to improvements in the efficacy of CAR T cells in CLL. Treating patients earlier in the course of their disease or using combination therapies with CAR T cells may further enhance efficacy. In this review, we summarize the existing literature on CAR T cell therapy in CLL, discuss mechanisms of response and resistance, and describe challenges facing the field.     

A coordinated strategy for a simple,pragmatic approach to the early identification of the ultra-high-risk patient with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma seen in clinical practice. Despite huge strides in understanding its biology, front-line therapy has remained unchanged for decades. Roughly one-third of patients have primary refractory or relapse following the end of conventional first-line therapy. The outcome of patients with primary refractory disease and those with early relapse (defined as relapse less than 1 year from the end of therapy) is markedly inferior to those with later relapse and is exemplified by dismal overall survival. In this article, the authors term patients with features that identify them as being at particularly high-risk for either primary refractory disease or early relapse, as ‘ultra-high-risk’. As new treatment options become established (e.g. bispecific T-cell engagers, chimeric antigen receptor ‘CAR’ T-cells and antibody–drug conjugates), it is likely that there will be a push to incorporate some of these agents into the first-line setting for patients identified as ultra-high-risk. In this review, the authors outline advances in positron emission tomography, widely available laboratory assays and clinical prognosticators, which can detect a high proportion of patients with ultra-high-risk disease. Since these approaches are pragmatic and able to be adopted widely, they could be incorporated into routine clinical practice.     

Monitoring clinical outcomes in aggressive B-cell lymphoma: From imaging studies to circulating tumor DNA

Recent guidelines have de-emphasized the role of routine surveillance computed tomography (CT) scans for diffuse large B-cell lymphoma (DLBCL) patients who achieve a complete response to front-line therapy. This shift in practice recommendations was prompted by retrospective studies that failed to demonstrate clear clinical utility for surveillance CT in unselected DLBCL patients. Controversy remains, however, over the role of routine surveillance CT in the highest risk patients for treatment failure who would remain candidates for aggressive salvage therapies. Novel high-throughput sequencing methods can non-invasively monitor tumor-specific DNA in the blood and offers clear advantages designed to overcome fundamental limitations of CT scans. This review will discuss the current controversies surrounding monitoring clinical outcomes in aggressive B-cell lymphomas, with a specific emphasis on DLBCL. Fundamental limitations of imaging scans will be addressed and the potential of monitoring circulating tumor DNA as an adjunct or replacement for CT scans will be discussed.     

FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform ‘UniCAR’ is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.     

Measurable residual disease after CAR T-cell therapy

Testing for measurable residual disease (MRD) provides important prognostic and predictive implications on survival and management of many hematologic diseases. Among the many clinical uses of MRD is post-therapy response assessment and risk stratification. With the integration of precision medicine in routine clinical care and the development of novel and innovative therapies resulting in deeper responses, it is necessary to refine the role of MRD, standardize available methodologies and define its role as a surrogate endpoint for relapse and time-to-next treatment in clinical studies. Chimeric Antigen Receptor (CAR) T-cell therapy is an approved treatment for various hematologic malignancies. Even though it produces high rates of remission, the durability of response is still a consideration as almost 40% to 50% of patients eventually relapse. MRD testing as a prognostic and surrogate marker is being explored in patients after CAR T-cell therapy to predict early relapse. In this chapter, we review the various tools available for MRD detection and monitoring post-CAR T-cell therapy. We later discuss disease-specific MRD assessment and its application in recent studies in the post-CAR T setting.     

Prognostic significance of tumour-infiltrating T lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: a multiparameter flow cytometry study

Tumour-infiltrating T lymphocytes (TIL-T) have been implicated in playing a role in controlling tumour growth. We evaluated TIL-T in 55 cases of de novo diffuse large B-cell lymphoma (DLBCL) using three- or four-colour flow cytometric immunophenotyping (FCI). The percentage of TIL-T varied from 3% to 72% of total viable cellular events (mean 32 +/- 20%). The CD4:CD8 ratio varied from 0.17 to 13 (mean 2.3 +/- 2.2). Cases with >/= 20% T cells and those with CD4:CD8 ratios > or = 2.0 showed a significantly better overall survival (P = 0.017 and P = 0.034 respectively). These findings were independent of clinical stage at diagnosis. The T-cell percentage and CD4:CD8 ratio were moderately correlated (Spearman correlation coefficient = 0.47, P = 0.001) and multivariate analysis revealed that the association of the two factors with prognosis was mutually dependent. The T cells in 23 cases were studied for CD45RO. The mean percentage of total T cells expressing CD45RO was 86 +/- 10%. There was a trend towards better survival for those patients with a higher percentage of CD45RO+ T cells (P = 0.06). These results suggest that TIL-T, particularly CD4+ T cells, may play a role in the control of DLBCL, and measurement of T-cell percentage and T-cell subsets using FCI may be useful in predicting the clinical behaviour of DLBCL.     

Cytolytic T-cell response to the PASD1 cancer testis antigen in patients with diffuse large B-cell lymphoma

The identification of immunogenic cancer testis antigens (CTAs) as immunotherapeutic targets represents one approach to improve treatment options for diffuse large B-cell lymphoma (DLBCL). We previously identified PASD1 [PAS (Per ARNT Sim) domain containing 1 (PASD1)], a DLBCL-associated CTA that was expressed in a range of hematopoietic malignancies. The aim of the present study was to investigate the presence of a cytotoxic T-cell (CTL) response to PASD1 in DLBCL patients. A significant γ-interferon (IFN) release was detected in 21/29 HLA-A*0201-positive DLBCL patients (18 de novo DLBCL, two transformed DLBCL and one T-cell rich B-cell lymphoma) following short-term culture of their peripheral blood mononuclear cells stimulated with five HLA-A*0201-restricted PASD1 peptides. No significant responses were detected in 21 HLA-A*0201-negative DLBCL patients (12 de novo DLBCL, seven transformed DLBCL, two T-cell rich B-cell lymphoma) or six normal subjects. CTL cell lines were able to lyse PASD1-positive tumour cells in a major histocompatibility complex-Class I dependent manner. The presence of a γ-IFN response correlated with PASD1 protein expression in the tumour cells in 12/15 cases studied. This is the first report of a CTL response to a CTA in DLBCL. Our results provide additional valuable evidence supporting PASD1 as a potential immunotherapeutic target for the treatment of DLBCL and other malignancies.     

Clinical experience of CAR T cells for multiple myeloma

Important advances in the treatment landscape of multiple myeloma (MM) had been seen over the past two decades leading to improved overall survival but despite the progress multiple myeloma is still considered incurable and the prognosis of the pentarefractory patients have been poor. The development of immunotherapy and in particular adoptive cell therapy with chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of heavily pretreated relapsed/refractory MM patients. The bulk of CAR T-cell constructs currently in clinical development target the B-cell maturation antigen (BCMA) and to date only idecabtagene vicleucel (ide-cel) is approved by the Food and Drug Administration (FDA) for commercial use in adult patients with relapsed or refractory MM based on the promising clinical responses and positive safety record shown in the pivotal KarMMa study. This review focus on the development of CAR T-cell therapy for multiple myeloma as well as a brief review of the mechanisms of resistance, toxicity and new approaches under development.     

How I manage patients with relapsed/refractory diffuse large B cell lymphoma

Despite progress in the upfront treatment of diffuse large B cell lymphoma (DLBCL), patients still experience relapses. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second‐line treatment for relapsed and refractory (R/R) DLBCL. However, half of the patients will not be eligible for transplantation due to ineffective salvage treatment, and the other half will relapse after ASCT. In randomized studies, no salvage chemotherapy regimen is superior to another. The outcomes are affected by the secondary International Prognostic Index at relapse and various biological factors. The strategy is less clear in patients who require third‐line treatment. A multicohort retros pec tive non‐Hodgkin lymphoma research (SCHOLAR‐1) study conducted in 636 patients with refractory DLBCL showed an objective response rate of 26% (complete response 7%) to the next line of therapy with a median overall survival of 6·3 months. In the case of a response followed by transplantation, long‐term survival can be achieved in DLBCL patients. There is clearly a need for new drugs that improve salvage efficacy. Encouraging results have been reported with chimeric antigen receptor ‐T cell engineering, warranting further studies in a well‐defined control group of refractory patients. The Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) was used as a handy framework to build the discussion.