Chimeric Antigen Receptor T-cell Therapy Research Articles

Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective.

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products.

Recent Advances in Cancer Immunotherapy: Clinical Implications and Future Directions

Cancer immunotherapy has transformed cancer treatment by harnessing the immune system to recognize and eliminate cancer cells. Recent years have witnessed significant advancements in this field, including the development of immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, cancer vaccines, and adoptive cell therapy. These approaches have shown promising results in clinical trials, leading to improved outcomes for cancer patients. This paper provides an in-depth overview of recent advances in cancer immunotherapy, their clinical implications, challenges, and future directions.

An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy’s efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.

Case report: Rapid resolution of grade IV ICANS after first line intrathecal chemotherapy with methotrexate, cytarabine and dexamethasone

Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse overall survival (OS) and progression-free survival (PFS) after chimeric antigen receptor T-cell (CAR-T cell) therapy. Many options are being investigated for prophylaxis and management. Accumulating evidence supports the use of intrathecal (IT) chemotherapy for the management of high-grade ICANS. Here, we describe a case of a patient with stage IV Primary mediastinal B-cell lymphoma (PMBCL) successfully treated with IT methotrexate, cytarabine, and dexamethasone as first-line therapy for CD19 CAR-T cell-associated grade IV ICANS. The stable and rapid resolution of ICANS to grade 0 allowed us to discontinue systemic corticosteroid use, avoiding CAR-T cells ablation and ensuring preservation of CAR-T cell function. The described patient achieved a complete radiologic and clinical response to CD19 CAR-T cell therapy and remains disease-free after 9 months. This case demonstrates a promising example of how IT chemotherapy could be used as first-line treatment for the management of high-grade ICANS.

HER2-targeting CAR-T cells show highly efficient anti-tumor activity against glioblastoma both in vitro and in vivo.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options for GBM include surgical resection, radiation, and chemotherapy, which predominantly slow cancer growth and reduce symptoms, resulting in a 5-year survival rate of no more than 10%. Chimeric antigen receptor (CAR) T-cell therapy is a new class of cellular immunotherapy that has made great progress in treating malignant tumors. Human epidermal growth factor receptor 2 (HER2) is overexpressed in GBM and may provide a potential therapeutic target for GBM treatment. In this study, we constructed third-generation CAR-T cells targeting the HER2 antigen in GBM. HER2-CAR-T cells showed effective anti-tumor activity both in vitro and in vivo. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting abilities against GBM cells in vitro. Anti-HER2 CAR-T cells also exhibited increased cytotoxicity with increasing effector-to-target ratios. Anti-HER2 CAR-T cells delivered via peritumoral injection successfully stunted tumor progression in vivo. Moreover, peritumoral intravenous administration of anti-HER2 CAR-T cells resulted in therapeutic improvement against GBM cells compared with intravenous administration. In conclusion, our study shows that HER2 CAR-T cells represent an emerging immunotherapy for treating GBM.

Comparison of CAR T-cell vs. bispecific antibody as third- or later-line large B-cell lymphoma therapy: A Meta-analysis.

This meta-analysis evaluates the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We searched MEDLINE, Embase, and Cochrane databases until July 2023 for trials assessing CAR T-cell therapies and CD20×CD3 bispecific antibodies as third- or subsequent-line in R/R DLBCL. Random effects models estimated the complete response (CR) rate and secondary outcomes, with meta-regressions adjusting for relevant covariates. Sixteen studies comprising 1,347 patients were included in the pooled analysis. The pooled CR rate for bispecific antibodies was 0.36 (95% CI, 0.29 to 0.43), compared to 0.51 (0.46 to 0.56) for CAR T-cell therapy (p<0.01). This superiority persisted when comparing the CAR-T naïve patients within the bispecific antibody group, CR rate of 0.37 (0.32 to 0.43). Multivariable meta-regression also revealed better efficacy of CAR-T with adjustment for the proportion of double-hit lymphoma. The pooled one-year progression-free survival rate mirrored these findings (0.32 [0.26 to 0.38] vs 0.44 [0.41 to 0.48], p<0.01). For adverse events of ≥ grade 3, the bispecific antibody had incidences of 0.02 (0.01 to 0.04) for cytokine release syndrome, 0.01 (0.00 to 0.01) for neurotoxicity, and 0.10 (0.03 to 0.16) for infections. The CAR-T cell had rates of 0.08 (0.03 to 0.12), 0.11 (0.06 to 0.17), and 0.17 (0.11 to 0.22), respectively, with significant differences observed in the first two categories. In summary, CAR-T cell therapy outperformed bispecific antibody in achieving higher CR rates, though with an increase in severe adverse events.

Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

What Is the Issue? Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) T-cell therapy. The US FDA and Health Canada approved tocilizumab, an anti-interleukin-6 receptor antagonist, for the management of severe or life-threatening cases of CRS. Corticosteroids also play an important role in CRS management and are the mainstay of ICANS management. Decision-makers are interested in understanding the use of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and/or corticosteroids in the management of CRS and ICANS following T-cell engager or CAR T-cell therapy. What Did We Do? We identified and summarized the literature comparing the clinical effectiveness and safety of anticytokine therapy and/or corticosteroids with alternative care or treatment as usual for treating and preventing of CRS and ICANS. We also searched for evidence-based recommendations for the use of anticytokine therapy and/or corticosteroids to treat and prevent CRS and ICANS. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and February 26, 2024 for CRS; and between January 1, 2019 and March 4, 2024 for ICANS. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? This report presents evidence-based findings on 3 retrospective chart review studies, 2 prospective cohort studies, and 4 consensus guidelines. Limited and low-quality clinical evidence from studies with a high risk of bias suggested that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of a high-grade CRS without a negative impact on neurotoxicity or immunotherapy treatment outcomes. The included guidelines recommend the use of tocilizumab for treatment of higher-grade CRS, or for treatment of grade 1 CRS if symptoms persist for 3 days or more. Corticosteroids could be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy. For the management of ICANS in the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS, while corticosteroids are recommended for the management of grade 2 to 4 ICANS. In the presence of concurrent CRS, guidelines recommend tocilizumab therapy as per management of CRS, and corticosteroids should be continued until improvement to grade 1. We did not identify any clinical evidence regarding the clinical efficacy and safety of anticytokine therapy and/or corticosteroids for treatment of CRS and ICANS compared with alternative treatment or treatment as usual. We also did not identify any guidelines for the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS. What Does This Mean? Despite limited and low-quality evidence, the findings suggest some potential benefits of prophylactic or early use of anticytokine therapy and corticosteroids for the management of immunotherapy-related toxicities. Guidelines offer guidance on the management of CRS, ICANS and other less common toxicities related to immunotherapy based on the available low-quality evidence. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality. To improve the certainty of findings, there is a need for more robust prospective clinical trials with larger sample sizes, and lower risk of bias.

Economic evaluation of anti-CD19 CAR T-cell pathway for large B-cell lymphomas in the real-life setting: the experience of an Italian hub center in the first three years of activity.

Poor literature report actual and detailed costs of chimeric antigen receptor (CAR) T-cell pathway in a real-life setting. We retrospectively collect data for all patients with relapsed/refractory aggressive large B-cell lymphoma who underwent leukapheresis between August 2019 and August 2022. All costs and medical resource consumption accountability were calculated on an intention-to-treat (ITT) basis, starting from leukapheresis to the time when the patient (infused or not) exited the CAR T-cell pathway for any reason. Eighty patients were addressed to leukapheresis and 59 were finally infused. After excluding CAR-T product cost, the main driver of higher costs were hospitalizations followed by the examinations/procedures and other drugs, respectively 43.9%, 26.3% and 25.4% of the total. Regarding costs of drugs and medications other than CAR T products, the most expensive items are those referred to AEs, both infective and extra-infective within 30days from infusion, that account for 63% of the total. Density plot of cost analyses did not show any statistically significant difference with respect to the years of leukapheresis or infusion. To achieve finally 59/80 infused patients the per capita patients without CAR-T products results 74,000 euros. This analysis covers a growing concern on health systems, the burden of expenses related to CAR T-cell therapy, which appears to provide significant clinical benefit despite its high cost, thus making economic evaluations highly relevant. The relevance of this study should be also viewed in light of continuously evolving indications for this therapy.

Charting new paradigms for CAR-T cell therapy beyond current Achilles heels

Charting new paradigms for CAR-T cell therapy beyond current Achilles heels

Advantages of high cell concentration prior to cryopreservation of initial leukapheresis in CAR-T cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy is increasingly used in patients affected by B-cell lymphoma and acute lymphoblastic leukemia. For logistical reasons, initial apheresis products may be cryopreserved for shipment to manufacturing centers. Due to the characteristics of these patients, cells are often collected in large volumes, meaning more bags must be cryopreserved. This requires increased storage, time and monetary costs. In this context, we aimed to evaluate a high cell concentration cryopreservation protocol by centrifugation to standardize the initial CAR-T manufacturing procedure. Sixty-eight processes of leukapheresis of 57 patients affected by refractory/relapsed B cell lymphoma and 9 patients affected by acute lymphoblastic leukemia who were eligible for anti-CD19 CAR-T cell treatment performed between June 2019 and October 2022 were analyzed. Whole blood count, percentage and number of T cells were assessed on the apheresis final product. The apheresis product, which was alternatively stored overnight at 4°C, was centrifuged, adjusting the volume to approximately 40 mL. The product was immediately cryopreserved to achieve a final cell concentration of 50-200×106 cells/ml for cryopreservation. Leukapheresis volume was reduced by almost fivefold (median: 185 to 40 mL), resulting in a higher product concentration in one bag. In addition, the number of non-target cells (monocytes, platelets and erythrocytes) was also reduced during the development of CAR-T cell therapy, thereby maintaining T lymphocyte levels and providing a purer starting material. The advantages of the protocol include reducing economic costs, saving storage space, simplifying the manufacturing process, and facilitating shipping logistics. In conclusion, we present a validated, simple, and cost-effective cell enrichment processing protocol that provides high-quality cryopreserved products as starting material for the CAR-T cell manufacturing process.

FDG-PET in Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy Toxicity: A Systematic Review

The utilization of chimeric antigen receptor (CAR) T-cell therapy to target cluster of differentiation (CD)19 in cancer immunotherapy has been a recent and significant advancement. Although this approach is highly specific and selective, it is not without complications. Therefore, a systematic review was conducted to assess the current state of positron emission tomography (PET) in evaluating the adverse effects induced by CAR T-cell therapy. A thorough search of relevant articles was performed in databases such as PubMed, Scopus, and Web of Science up until March 2024. Two reviewers independently selected articles and extracted data, which was then organized and categorized using Microsoft Excel. The risk of bias and methodological quality was assessed. In total, 18 articles were examined, involving a total of 753 patients, in this study. A wide range of utilities were analyzed, including predictive, correlative, and diagnostic utilities. While positive outcomes were observed in all the mentioned areas, quantitative analysis of the included studies was hindered by their heterogeneity and use of varying PET-derived parameters. This study offers a pioneering exploration of this promising field, with the goal of encouraging further and more focused research in upcoming clinical trials.

Evolving Evidence-Based Value Assessment of One-Time Therapies: Tisagenlecleucel as a Case Study.

Economic evaluation of one-time therapies during reimbursement decision-making is challenging due to uncertain long-term outcomes. The availability of 5-year outcome data from the ELIANA trial and real-world evidence of tisagenlecleucel, the first chimeric antigen receptor T-cell (CAR-T) therapy, presents an opportunity to re-evaluate the predictions of prior cost-effectiveness analyses (CEAs). To conduct a systematic literature review (SLR) of prior CEAs of tisagenlecleucel for pediatric/young adult relapsed or refractory acute lymphoblastic leukemia (r/r ALL) and evaluate the impact of recently available 5-year efficacy data from ELIANA and advances in CAR-T manufacturing in an updated CEA model. OVID MEDLINE/Embase and health technology assessment (HTA) databases were searched for full-text economic evaluations in English reporting cost-effectiveness results for tisagenlecleucel for r/r ALL. Evaluations with publicly reported incremental cost-effectiveness ratios (ICERs) were included in the SLR. Study screening and data abstraction were conducted following PRISMA guidelines. Data extracted included the country/currency, perspective, clinical trial evidence, model structures, long-term efficacy extrapolation approaches (i.e., overall survival [OS]), time horizon, discount rates, and outcomes (i.e., life years [LY], quality-adjusted LY [QALY], and ICERs). The CEA model reported in Wakase et al. was updated using 5-year OS data from ELIANA and the CAR-T infusion rate informed by real-world practice. Sixteen records corresponding to 15 unique studies were included in the SLR (11 publications and 5 HTA reports); all were conducted from the health care system perspective of the respective countries. Most studies found tisagenlecleucel to be cost effective, but all studies' projected 3- and 5-year OS rates for tisagenlecleucel were lower than the observed 3- and 5-year rates, respectively, derived from 5-year ELIANA data. When applying updated OS projections from the most recent ELIANA data cut and higher infusion rates of 92.5% (per the real-world infusion rate)-96.0% (per the manufacturer success rate) to theCEA of Wakase et al., the associated QALYs for tisagenlecleucel increased from 11.6 to 14.6-15.0, andLYs increased from 13.3 to 17.0-17.5. Accordingly, the ICERs for tisagenlecleucel decreased from ¥2,035,071 to ¥1,787,988-¥1,789,048 versus blinatumomab and from ¥2,644,702 to ¥2,257,837-¥2,275,181 versus clofarabine combination therapy in the updated CEA model. Projections at launch of the likely cost effectiveness of tisagenlecleucel appear to have underestimated its ultimate economic value given more recent trial and real-world data. To balance uncertainty in initial valuation with the need to provide access to novel oncology therapies, payers can consider flexible reimbursement policies alongside ongoing assessments as new data emerge.

Managing Infection Complications in the Setting of Chimeric Antigen Receptor T cell (CAR-T) Therapy

Chimeric antigen receptor T-cell (CAR T-cell) therapy has changed the paradigm of management of non-Hodgkin’s lymphoma (NHL) and Multiple Myeloma. Infection complications have emerged as a concern that can arise in the setting of therapy and lead to morbidity and mortality. In this review, we classified infection complications into three categories, pre-infusion phase from the time pre- lymphodepletion (LD) up to day zero, early phase from day of infusion to day 30 post-infusion, and late phase after day 30 onwards. Infections arising in the pre-infusion phase are closely related to previous chemotherapy and bridging therapy. Infections arising in the early phase are more likely related to LD chemo and the expected brief period of grade 3-4 neutropenia. Infections arising in the late phase are particularly worrisome because they are associated with adverse risk features including prolonged neutropenia, dysregulation of humoral and adaptive immunity with lymphopenia, hypogammaglobinemia, and B cell aplasia. Bacterial, respiratory and other viral infections, protozoal and fungal infections can occur during this time . We recommend enhanced supportive care including prompt recognition and treatment of neutropenia with growth factor support, surveillance testing for specific viruses in the appropriate instance, management of hypogammaglobulinemia with repletion as appropriate and extended antimicrobial prophylaxis in those at higher risk (e.g. high dose steroid use and prolonged cytopenia). Finally, we recommend re-immunizing patients post CAR-T based on CDC and transplant guidelines.

Patients with aggressive B-cell lymphoma receiving CAR T-cell therapy have a low rate of severe infections despite lack of universal antibacterial and antifungal prophylaxis.

Our aim was to describe the frequency and severity of infectious complications after chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL). We retrospectively reviewed clinical records of LBCL patients treated with CD19-targeted CAR T-cell therapy from July/2018 to December/2021 at our institution, and identified all infectious episodes from CAR T-cell infusion until disease progression, death or last follow-up. Overall, 137 patients were included. Thirty six percent had received ≥3 previous lines of therapy and 26% an autologous hematopoietic cell transplantation (auto-HCT). Cytokine release syndrome occurred in 87 (64%) patients. Antibacterial prophylaxis was not used in any patient; only 38% received antifungal prophylaxis. Sixty three infectious events were observed in 41 (30%) patients. Fifty two (83%) of the infectious events had at least one pathogen identified (bacteria [n = 38], virus [n = 11], and fungi [n = 3]). Most of the infectious events occurred during hospitalization for CAR-T treatment. Infection-related mortality was observed in two patients. Independent risk factors for infection included male gender, previous auto-HCT, ≥3 lines of treatment and pre-lymphodepletion neutropenia. Infections after CAR T-cell therapy in patients with lymphoma are frequent but generally not severe. A conservative and tailored antimicrobial prophylaxis seems to be a safe approach.

CAR T-cell therapy: a potential treatment strategy for pediatric midline gliomas.

Pediatric brain tumors are the primary cause of death in children with cancer. Diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG) are frequently unresectable due to their difficult access location, and 5-year survival remains less than 20%. Despite significant advances in tumor biology and genetics, treatment options remain limited and ineffective. Immunotherapy using T cells with a chimeric antigen receptor (CAR) that has been genetically engineered is quickly emerging as a new treatment option for these patients. High levels of expression were detected for both disialoganglioside (GD2) and B7-H3 in pediatric DMG/DIPG. Numerous studies have been conducted in recent years employing various generations of GD2-CAR T cells. The two most prevalent adverse effects found with this therapy are cytokine release syndrome, which varies in severity from mild constitutional symptoms to a high-grade disease associated with potentially fatal multi-organ failure, and neurotoxicity, known as CAR T-cell-related encephalopathy syndrome. During the acute phase of anticancer action, peri-tumoral neuro-inflammation might cause deadly hydrocephalus. The initial results of clinical trials show that the outcomes are not highly encouraging as B cell malignancies and myelomas. In vivo research on CAR T-cell therapy for DIPG has yielded encouraging results, but in human trials, the early results have shown potentially fatal side effects and very modest, but fleeting improvements. Solid tumors present a hindrance to CAR T-cell therapy because of the antigenic dilemma and the strong immune-suppressing tumor microenvironment.

InsT-ALLing CD7 chimeric antigen receptors before transplantation.

In their paper, the authors present their experience with the use of chimeric antigen receptor T cells targeting CD7 as a bridge to allogeneic haematopoietic cell transplantation in patients with relapsed/refractory T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma. Commentary on: Cao etal. A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19445.

Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis

BackgroundPatients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear.MethodsWe tested a novel “all-in-one” strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored.ResultsAfter CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease–negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100).ConclusionsOur findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.)

Sequencing of anti-CD19 therapies in the management of diffuse large B-cell lymphoma.

Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant are directed against the B-cell antigen CD19. The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and cellular phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA-cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. While CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression-which may not be detectable with current routine methodologies-have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies with CD19-directed therapy has been hampered by the exclusion of patients with prior CD19-directed therapies from major clinical trials. Antigen escape, attributed to mechanisms including epitope loss and defective cell-surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy and retrospective analyses indicate that some patients with disease that relapses after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T is restricted to small case series. Prospective studies and detailed analyses to understand how pre- and post-treatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy are needed to fully maximize treatment strategies.

Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia

Chimeric antigen receptor T-cell (CAR-T) therapy is effective in the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL); however, patients who receive CAR-T therapy are predisposed to infections, with considerable detrimental effects on long-term survival rates and the quality of life of patients. This study retrospectively analyzed infectious complications in 79 pediatric patients with R/R B-ALL treated with CAR-T cells at our institution. Overall, 53 patients developed 88 infections. Nine patients experienced nine infections during lymphodepletion chemotherapy, 35 experienced 41 infections during the early phase (days 0–+ 30 after infusion), and 29 experienced 38 infections during the late phase (day + 31–+ 90 after infusion). Pathogens were identified in 31 infections, including 23 bacteria, seven viruses, and one fungus. Four patients were admitted to the intensive care unit for infection and one died. In a univariate analysis, there were ten factors associated with infection, including tumor load, lymphodepleting chemotherapy, neutrophil deficiency and lymphocyte reduction, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), etc. In a multivariate analysis, CRS ≥ grade 3 was identified as a risk factor for infection (hazard ratio = 2.41, 95% confidence interval: 1.08–5.36, P = 0.031). Therefore, actively reducing the CRS grade may decrease the risk of infection and improve the long-term quality of life of these patients.

Rituximab potentially improves clinical outcomes of CAR-T therapy for r/r B-ALL via sensitizing leukemia cells to CAR-T-mediated cytotoxicity and reducing CAR-T exhaustion.

Despite chimeric antigen receptor (CAR) T-cell therapy has achieved great advances in recent year, approximately 50% of relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) patients treated with CAR-T experience relapse 6 months post CAR-T treatment. CD20 express on 30 to 50% of B-ALL, which makes CD20 Monoclonal Antibody as one of the potential therapy strategies to decrease the tumor burden and improve the efficacy of CAR-T therapy. Adding Rituximab to chemotherapy protocol had been demonstrated to improve the outcome for CD20-positive ALL. However, rare study explored the influence of Rituximab combined with CAR-T therapy. We retrospectively analyzed 20 r/r B-ALL patients who received CAR-T therapy, all of whom had failed multiple lines of therapy. Before CAR-T infusion, we administered Rituximab to 10 patients with high CD20 expression at a dose of 375mg/m2 for 1 day. Meanwhile, we selected 10 patients with the comparable features who underwent CAR-T treatment without Rituximab in the same period as the control group. In vitro, the surface molecule expression and killing of CAR-T post Rituximab-treated B-ALL cells co-incubated with CAR-T cells were detected by flow cytometry. The median follow-up of Rituximab and Control groups were 29.27 and 9.83 months. We found that adding Rituximab may confer a favorable prognosis compared with Control group. The 2-year overall survival (OS) and leukemia-free survival (LFS) rates both were longer in the Rituximab group (90% vs. 26.7%, p=0.0342; 41.7% vs. 25%, p=0.308). In vitro, we observed that Rituximab-treated tumour cells are more sensitive to CAR-T killing and a broad range of cytokines and chemokines were produced when Rituximab-treated Nalm-6 cells co-cultured with 19-22CAR-T cells, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). To investigate whether Rituximab has an effect on CAR-T persistence, we stimulated CAR-T cells repeatedly in vitro with Rituximab-treated Nalm-6 to evaluate the changes in CAR-T surface exhaustion molecules at different times. We found that the expression of exhaustion molecules (LAG-3, PD-1, TIM-3) on CAR-T cells were significantly lower in the Rituximab group than in the Control group. Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion.