Safety Of CAR-T Cell Therapy Research Articles

Editorial: Efficacy and safety of CAR-T cell therapy in hematologic malignancies

Editorial: Efficacy and safety of CAR-T cell therapy in hematologic malignancies

The underlying mechanism of chimeric antigen receptor (CAR)-T cell therapy triggering secondary T-cell cancers: Mystery of the Sphinx?

The U.S. Food and Drug Administration (FDA) has reported cases of T-cell malignancies, including CAR-positive lymphomas, in patients receiving B cell maturation antigen (BCMA)- or CD19-targeted autologous CAR-T cell immunotherapy. These reports were derived from clinical trials and/or post-marketing adverse event data. This finding has attracted widespread attention. Therefore, it is essential to explore the potential mechanisms by which chimeric antigen receptor (CAR)-T cell therapy triggers secondary T-cell cancers to further guarantee the safety of CAR-T cell therapy.

Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis

Background Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. Methods The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. Conclusion Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.

Risk of T-cell malignancy after CAR T-cell therapy in children, adolescents, and young adults

Our global survey reveals no cases of insertional mutagenesis following CAR T-cells in pediatric patients challenging concerns of secondary malignancy risk in this population. This underscores the safety of CAR T-cell therapy in this population, but ongoing surveillance required.

Safety of CAR T-Cell Therapy in Patients with Active Autoimmune Diseases: A Case Report (P3-14.003)

Safety of CAR T-Cell Therapy in Patients with Active Autoimmune Diseases: A Case Report (P3-14.003)

Efficacy and Safety of CAR T-Cell Therapy in Patients ≥ 70 Years Old

Introduction Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of multiple myeloma(MM) and No Hodgkin Lymphoma (NHL) in patients with relapsed or refractory disease without other treatment options. Both MM and NHL incidence increases with age. At the time of diagnosis, the average age of patients with multiple myeloma is 69 years old, and 65 years old for patients with large cell lymphomas . Elderly patients tend to have more comorbidities and greater treatment-related toxicity, requiring stricter monitoring. However, data regarding efficacy and toxicity CAR T -cell therapy in the elderly, geriatric population are insufficient. Objective : to describe the efficacy and safety of CAR T-cell therapy in the elderly. Materials and methods Single-center, retrospective, case series study. Patients ≥70 years old with a diagnosis of MM or NHL who received commercial CAR T-cell therapy between September 2018 and June 2023 were included. Patients were followed up from the infusion date until death or loss to follow-up. Outcomes Efficacy: Global response (RG) and complete response (CR), 1-year overall survival (OS), 1-year progression-free survival (PFS) Safety: Cytokine release syndrome (CRS) of any grade, ≥ grade 2 and ≥ grade 3. Immune Effector Cell Associated Neurotoxicity (ICANS) of any grade, ≥ grade 2 and ≥ grade 3. Cytopenias grade ≥3, Neutrophil recovery at day 90, Platelet recovery at day 90. Result A total of 28 patients were included, with a median of 76 years old (range 70 to 84 years), 71% were male (n=20). Ten patients (36%) were diagnosed with MM and 18 (65%) with NHL (16 Diffuse Large B-cell Lymphomas, and three Mantle Lymphomas). 21% (n=6) of patients had a comorbidity score (HCT-CI) ≥4 and 29% (n=7) had a Karnofsky Index ≤70%. CAR T-cell therapy was Kymriah (n=8), Breyanzi (n=4), Tecartus (n=3), Yescarta (n=3), Abecma (n=7), and Carvykti (n=3). The median follow-up was 239 days (range 30 to 1468). The most frequent complication was CRS, present in 75% of the patients (n=21). CRS was grade 2-3 in 11 patients (40%) and ≥3 in 1 patient (4%). The proportion of patients with ICANS was 42% (n=12); with a grade ≥ 2 in 7 patients (58%) and ≥3 in 3 patients (25%). The median time for CRS was 3 days (range 1 to 14 days) and for ICANS 5 days (range 3 to 8 days). 58% (n=12) of patients with CRS developed ICANS, but all the patients with ICANS also developed CRS. CRS preceded ICANS in 66% of patients (n=8) and occurred simultaneously in 40% of cases (n=4). Half of the patients who presented grade 2-3 ICANS presented grade 2-3 CRS (n= 3). Tocilizumab was used in 16 patients and dexametasona in 16 patients. No patient died from complications. 22 patients (79%) developed grade ≥3 cytopenias. Neutropenia was the most frequent (n=22) followed by thrombocytopenia (n=15). The GR was 89% (n=25), the CR 60% (n=25), and the PR 29% (n=25). During follow up, seven patients (25%) relapsed or progressed, with a median of 132 days. An identical relapse rate was observed between MM and NHL patients, 29% and 28% respectively. Eight patients died (29%), 3 due to relapse. Half of the dead patients had an HCT-CI ≥3 and a Karnofsky ≤70%. Only 1 patient died during admission. The 1y-OS was 71% and the 1y-RFS was 62%. Conclusion The outcomes of CAR T-cell therapy in our population are comparable to the ones reported in literature for geriatric and younger patients, indicating that age per se should not automatically exclude older patients from consideration for CAR T-cell therapy. The use of CAR T-cell therapy in patients older than 70 years without frailty, presented an adequate response and an acceptable safety profile, CAR T-cell therapy toxicity was manageable in most cases with early and timely treatment. Keywords: A case-control study, CAR T-cell therapy, Multiple myeloma, Non-Hodgkin lymphoma.

CAR-T Cell Therapy Vs. Standard of Care for B-Cell Lymphoma: A Systematic Review and Meta- Analysis of Updated Results of Clinical Trials

Background: For many years, platinum based immunochemotherapy followed by high dose chemotherapy and stem cell transplantation remained standard of care for relapsed/refractory large B-cell lymphoma. About half of the patients do not undergo transplantation due to disease insensitivity to 2 nd line therapy and cured in <30%. In recent years, feasibility of chimeric antigen receptor (CAR) t-cell therapies is tested as 2 nd line of treatment. In this meta-analysis, we will assess the efficacy and safety of CAR-T cell therapy as 2 nd line therapy as compared to standard therapy in large B cell lymphoma based on updated clinical trial results. Methods: A literature search was performed on PubMed and Embase with keywords for “CAR-T cell therapy” and “B-cell lymphoma” from the inception of data till 07/01/2023. PRISMA guidelines were followed while conducting this meta-analysis. A total of 3091 articles were screened and 3 randomized clinical trials (RCTs, N=865) were included based on inclusion criteria. “R” software was used to conduct this meta-analysis. Results: In 3 RCTs (N=865), 180 patients were treated with axicabtagene ciloleucel, 92 patients with lisocabtagene maraleucel, 162 patients with tisagenlecleucel, and 431 patients with standard therapy. Based on updated results of 2 trials (N=543), pooled hazard ratios (HRs) of progression free survival (PFS) was 0.47 (95% CI= 0.37-0.60, I 2=0), overall survival (OS) was 0.73 (95% CI=0.56-0.94, I 2=0), and event free survival (EFS) was 0.4 (95% CI=0.32-0.49, I 2=0) in favor of CAR-T cell therapy as compared to standard therapy. Pooled relative risk (RR) of complete response (CR) and overall response (ORR) were 1.88 (95% CI=1.57-2.25, I 2=2%), and 1.69 (95% CI=1.48-1.92, I 2=0%), respectively, in favor of CAR-T cell therapy. The Belinda RCT on tisagenlecleucel by Bishop et al. was the outlier. HR of EFS, RR of CR, and RR of ORR were 1.07 (95% CI= 0.82-1.4), 1.03 (0.73-1.47), and 1.09 (95% CI= 0.85-1.39), respectively, similar in the two groups. In 3 RCTs, RR of ≥ grade 3 any adverse effects were 1.02 (95% CI=0.92-1.12, I 2=72%), neurotoxicity was 7.35 (95% CI=0.97-55, I 2=64%), and neutropenia was 1.41 (95% CI=1.04-1.91, I 2=78%). Pooled incidence of ≥ grade cytokine release syndrome (CRS) was 5% (CI=0.03-0.08) and was 0 with standard therapy. Fig 1. Conclusion: Based on updated results, CAR-T cell therapies, axicabtagene ciloleucel and lisocabtagene maraleucel, were significantly more effective in terms of response and survival rates. ≥Grade 3 side effects were similar with CAR-T cell and standard therapy. CRS, neurotoxicity, and hematological side effects were higher with CAR-T cells. Tisagenlecleucel was found as an outlier and the efficacy was similar to standard care. More randomized double-blind large-scale phase III clinical trials are needed to confirm these results.

Safety of CAR-T Cell Therapy in Asymptomatic Patients with Positive Respiratory Viral Testing Prior to CAR-T Infusions

Introduction. Active infection is a contraindication to CAR T-cell infusion (CAR-T). Our standard institutional practice (SOP) is to perform a respiratory virus panel (RVP) prior to CAR-T infusion; however, the risk of toxicity after CAR-T in the context of an asymptomatic, incidentally noted respiratory viral infection (+RVP) during pre-CAR-T testing is unclear. We report our institutional experience for asymptomatic patients (pts) with PCR evidence of viral respiratory presence who subsequently received CAR-T. Methods. We retrospectively reviewed 306 pts with non-Hodgkin lymphomas who were treated at the Hospital of the University of Pennsylvania with commercial CAR-T products from 2018-2023. Per SOP, all pts had a PCR-based RVP test prior to lymphodepleting chemotherapy (LD); LD-CAR-T was delayed for at least 7 days for asymptomatic pts with +RVP. After 7 days, pts with continued +RVP can proceed to CAR-T if they remain asymptomatic. RVP included: adenovirus, non-SARS-CoV-2 coronavirus, human metapneumovirus, rhinovirus/enterovirus, influenza A/B, parainfluenza 1-4, respiratory syncytial virus A/B, with/without SARS-CoV-2. We selected pts who had a +RVP within 4 weeks of CAR-T and who were asymptomatic (without respiratory viral symptoms) at time of CAR-T infusion. Cytokine release syndrome (CRS) and neuro-toxicity domains defining immune effector cells (ICANS) were evaluated using ASTCT consensus grading. Any fever post-CAR-T without an alternative cause was considered CRS. Results . We identified 15 pts with +RVP who were asymptomatic at the time of CAR-T: 12 (80%) were male; median age 54 years (range 38-75); 10 (67%) had large B-cell lymphoma; 4 (27%) follicular lymphoma; 1 (7%) mantle cell lymphoma; ECOG performance status (PS) ≤1 in 14 (93%); lactate dehydrogenase (LDH) elevated in 5 (33%); 14 (93%) received bridging therapy. Overall, 11 pts (73%) had rhinovirus/enterovirus, 1 (7%) had SARS-CoV-2, 1 (7%) had non-SARS-CoV-2 coronavirus, 1 (7%) had adenovirus, and 1 (7%) had RSV A. Of these 15 pts with +RVP, 8 (53%) were asymptomatic at time of initial +RVP and 7 (47%) pts were symptomatic at time of +RVP. The median time of intial +RVP was 13 days before CAR-T; the median time of closest +RVP to CAR-T was 7 days prior to CAR-T. No patient who was asymptomatic with a +RVP developed symptoms between initial screening +RVP and CAR-T infusion. At the time of CAR-T infusion, all patients were asymptomatic and no patient required supplemental oxygen. CAR-T was administered outpatient in 9 pts (60%). Of 15 asymptomatic pts infused, 10 (67%) received tisagenlecleucel (tisa-cel), 2 (13%) axicabtagene ciloleucel (axi-cel), 2 (13%) lisocabtagene maraleucel (liso-cel), and 1 (7%) brexucabtagene autoleucel (brexu-cel). 8 of these 15 pts (53%) developed CRS (7 pts grades 1-2, one pt grade 3) and 4/15 (27%) ICANS (2 pts grades 1-2, 2 pts grades 3-4). Of the 8 patients who remained asymptomatic and received CAR-T, 6 (75%) received tisa-cel, 1 (13%) axi-cel and 1 (13%) liso-cel. 5 of these 8 pts (63%) developed CRS (all grades 1-2) and 1/8 (13%) ICANS (grade 2). Of the 7 patients whose symptoms resolved prior to CAR-T but had +RVP, 4 (57%) received tisa-cel, 1 (14%) axi-cel, 1 (14%) liso-cel, and 1 (14%) brexu-cel. 3 of these 7 pts (43%) developed CRS (2 pts grades 1-2, 1 pt grade 3) and 3/7 (43%) ICANS (1 pts grades 1-2, 2 pts grades 3-4). Discussion: In our experience, CAR-T in pts with PCR evidence of upper respiratory viral infection was generally safe in pts not requiring oxygen with a good PS who are asymptomatic or symptomatically resolved at time of CAR-T infusion. Rates of CRS and ICANS were comparable between asymptomatic pts and pts with resolved symptoms at time of CAR-T.

The Autologous Hematopoietic Stem Cells Transplantation Combination-Based Chimeric Antigen Receptor T-Cell Therapy Improves Outcomes of Relapsed/Refractory Central Nervous System B-Cell Lymphoma.

The objective is to explore the effectiveness and safety of CAR T-cell therapy in advanced relapsed/refractory central nervous system B-cell lymphoma and compare the impact of autologous stem cell transplantation (ASCT) plus CAR T-cell therapy versus sequential CART therapy on the survival of patients. The retrospective analysis was based on the data of 17 patients with advanced relapsed/refractory central nervous system B-cell lymphoma. Bridging chemotherapy was applied before CAR T-cell infusion to further reduce the tumor burden. For patients with autologous hematopoietic stem cell successful collection, CD19/20/22CAR T-cell immunotherapy following ASCT was performed with the thiotepa-containing conditioning regimen, while sequential CD19/CD20/CD22CAR T-cell therapy was applied. For lymphodepletion, patients received bendamustine or fludarabine monotherapy or fludarabine combined with cyclophosphamide pre-CART-cell infusion. Out of the 17 patients, 8 completed ASCT plus CART cell therapy, while 9 patients completed CART cell alone therapy. In efficacy assessment at 3 months after infusion, the objective response rate (ORR) was 12/17 (71%) and the complete response rate (CRR) was 11/17 (65%). The CRR of the ASCT group and non-ASCT was 100% and 44.4%, respectively (P < 0.01). The median progression-free survival was 16.3 (2.6-24.5) months, and the median overall survival was 19.3 (6-24.5) months. Patients who underwent ASCT plus CART cell therapy had significantly longer PFS (P < 0.01) and OS (P < 0.01). Grade 3 or higher immune effector cell-associated neurologic toxicity syndrome (≥grade 3 ICANS) and cytokine release syndrome (≥grade 3 CRS) events occurred in 29% and 41% of the patients, respectively. No treatment-related death occurred. The CAR T-cell therapy could augment its efficacy in the treatment of advanced relapsed/refractory CNS B-cell lymphoma, while ASCT in combination with CART can induce durable responses and OS with a manageable side effect.

Efficacy and Safety of CAR T-Cell Therapy Using a Fully Human CD19-Targeted Binder in Adults with Relapsed/Refractory B-ALL

Efficacy and Safety of CAR T-Cell Therapy Using a Fully Human CD19-Targeted Binder in Adults with Relapsed/Refractory B-ALL

Radiation prior to chimeric antigen receptor T-cell therapy is an optimizing bridging strategy in relapsed/refractory aggressive B-cell lymphoma

PurposeWe aimed to analyze the safety and efficacy of a radiation bridging regimen with or without chemotherapy compared with chemotherapy alone prior to CAR T-cell treatment for relapsed/refractory aggressive B-cell lymphoma (r/r ABL). Methods and materialsIn this study, 45 out of 105 patients enrolled in CD19/22 CAR T-cell “cocktail” clinical trial were excluded, including 34 patients without bridging treatment. Total 60 patients receiving CAR T-cell therapies with bridging regimens as chemotherapy alone (C-CAR-T group, n = 31), and radiotherapy with or without chemotherapy (R-CAR-T group, n = 29) between February 2017 and October 2020 were retrospectively analyzed. ResultsNo significant toxicities were identified in the R-CAR-T group, and no patients in either group experienced CAR-T-related deaths. However, the R-CAR-T group showed a lower incidence of cytokine release syndrome (CRS) of grade ≥ 3 relative to the C-CAR-T group (0% vs 19.4%, P = 0.036). The incidence of neurological toxicity was 9.9% and 6.9% in the C-CAR-T group and R-CAR-T group, respectively (P = 0.697). The R-CAR-T group achieved a higher overall response rate (ORR) at the day 30 assessment (82.8% vs 45.2%, P = 0.0025). Further analyzing the outcomes, the R-CAR-T group presented a better 1-year progression-free survival (PFS) rate than the C-CAR-T group (46.9% vs 22.6%, P = 0.0356). Intriguingly, the bridging radiation regimen extremely improved the 6-month PFS (50.8% vs 16. 7%, P = 0.0369) and 1-year overall survival (OS) (56.3% vs 33.3%, P = 0.0236) rates in patients with bulky disease. The study also found that conducting radiotherapy as a bridging regimen was an independent factor that predicted better PFS (HR: 0.534, 95% CI: 0.289–0.987, P = 0.045). ConclusionsOur results provide and strengthen novel insights that the use of radiotherapy as a bridging strategy was demonstrated to reduce the incidence of severe CRS and improve the PFS of patients. In subgroup analysis, it was confirmed that radiotherapy can improve PFS and OS in patients with bulky disease. These findings open new avenues to improve the efficacy and safety of CAR T-cell therapy.

BCMA CAR-T Therapy Is Safe and Effective for Refractory/Relapsed Multiple Myeloma With Central Nervous System Involvement.

Central nervous system (CNS) involvement is a rare complication of multiple myeloma (MM) that portends an extremely poor prognosis. Although chimeric antigen receptor (CAR)-T cell therapy is considered a promising strategy for patients with MM, the role of CAR-T cell therapy in MM involving the CNS has not been fully elucidated. In this study, we retrospectively analyzed 4 cases of B-cell maturation antigen CAR-T cell therapy for patients with relapsed/refractory MM involving the CNS. Patients received a range of 2-7 lines of prior therapy, including 1 autologous hematopoietic stem cell transplant. The most common adverse event was cytokine release syndrome, which was observed in all 4 patients, including 2 with grade 1 and 2 with grade 2. No patient was complicated with immune effector cell-associated neurotoxicity syndrome. Within the follow-up (median: 257 d, range: 116-392 d), 3 of 4 patients reached complete remission (CR), and 1 patient reached partial response. At the data cutoff, 1 patient continued to remain in CR at day 220, and the patient with partial response died at day 116. The other 2 patients relapsed at 317 and 111 days with CR durations of 287 and 81 days, respectively. Our results show promising effectiveness and acceptable safety of CAR-T cell therapy for heavily pretreated patients with CNS MM.

Determinants of response and mechanisms of resistance of CAR T-cell therapy in multiple myeloma.

BCMA-specific CAR T-cells have substantial therapeutic potential in multiple myeloma (MM), but most patients eventually relapse. Determinants of response and mechanisms of resistance are most likely multifactorial and include MM-related factors, premanufacturing T-cell characteristics, CAR T-cell-related features, and several components of the immunosuppressive microenvironment. Efforts to improve the potency and safety of CAR T-cell therapy include optimizing CAR design, combinatorial approaches to enhance persistence and activity, treatment of less heavily pretreated patients, and dual-antigen targeting to prevent antigen escape. We expect that these rationally designed strategies will contribute to further improvement in the clinical outcome of MM patients.

The efficacy and safety of CAR-T cell therapy in patients with refractory ALL and concomitant HBV infection.

The efficacy and safety of CAR-T cell therapy in patients with refractory ALL and concomitant HBV infection.

Efficacy and toxicity for CD22/CD19 chimeric antigen receptor T-cell therapy in patients with relapsed/refractory aggressive B-cell lymphoma involving the gastrointestinal tract

Gastrointestinal (GI) tract is the most common site of extranodal involvement in non-Hodgkin lymphoma. Life-threatening complications of GI may occur because of tumor or chemotherapy. Chimeric antigen receptor (CAR) T-cell therapy has been successfully used to treat refractory/relapse B-cell lymphoma, however, little is known about the efficacy and safety of CAR-T cell therapy for GI lymphoma. Here, we reported the efficacy and safety of CAR-T cell therapy in 14 patients with relapsed/refractory aggressive B-cell lymphoma involving the GI tract. After a sequential anti-CD22/anti-CD19 CAR-T therapy, 10 patients achieved an objective response, and seven patients achieved a complete response. CAR transgene and B-cell aplasia persisted in the majority of patients irrespective of response status. Six patients with partial response or stable disease developed progressive disease; two patients lost target antigens. Cytokine release syndrome (CRS) and GI adverse events were generally mild and manageable. The most common GI adverse events were diarrhea (4/14), vomiting (3/14) and hemorrhage (2/14). No perforation occurred during follow-up. Infection is a severe complication in GI lymphoma. Two patients were infected with bacteria that are able to colonize at GI; one died of sepsis early after CAR-T cells infusion. In conclusion, our study showed promising efficacy and safety of CAR-T cell therapy in refractory/relapsed B-cell lymphoma involving the GI tract. However, the characteristics of CAR-T–related infection in GI lymphoma should be further clarified to prevent and control infection.

Possible Factors on Efficacy and Safety of CAR-T Therapy in Relapsed or Refractory Aggressive B-Cell Lymphoma

Background:Recent advances have improved the treatment of B-cell malignancies, but patients who have disease resistant to primary or salvage treatment or who relapse after transplantation have an extremely poor prognosis. Studies of chimeric antigen receptor T-cell (CAR-T) therapy have shown high response rates and long response duration in refractory B-cell lymphomas after the failure of conventional therapy, which suggest that this therapy may be potentially curative. To explore the possible factors on efficacy and safety of CAR T-Cell therapy in relapsed or refractory aggressive B-cell lymphomas, we conducted the clinical trial of CAR-T Cell Treating Relapsed/Refractory B-cell lymphomas (NCT03196830).Methods:From March 2017 to April 2018, 25 patients were enrolled into our clinical trial. According to the surface expression of tumor cells by either flow cytometry or immunohistochemistry, different targets of CAR T-cells were infused, ionly anti-CD19 (n=11), sequential infusion of anti-CD22 and anti-CD19 (n=8), and sequential infusion of anti-CD20 and anti-CD19 (n=6). Patients received conditioning treatment (low-dose cyclophosphamide, 300 mg/m² per day, and fludarabine, 30 mg/m² per day) on days -5, -4, and -3 before the administration of autologous CAR T-cells. The primary endpoint was the proportion of patients with an objective response. Secondary endpoints included safety and biomarker assessments.Results:Among the 25 patients who were enrolled, response was successfully evaluatedfor 24. The objective response rate was 75%, and the complete response rate was 33%. With a median follow-up of 3.2 months, 54% of the patients continued to have a response, with 25% continuing to have a complete response. Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 24% and 16% of the patients, respectively. One of the patients died during treatment. Serum biochemical index analysis confirmed the associations of peak serum interleukin-2, -6, -10, INF-γ, ferritin, C-reactive protein (CRP) concentrations and the level of lactate dehydrogenase (LDH) before therapy with the grade 3 or higher CRS, as well as peak serum interleukin-6, -10, INF-γ, CRP, ferritin and the level of LDH before therapy with grade 3 or higher neurologic events.Conclusion:Our study demonstrates the efficacy and safety of CAR-T therapy relapsed or refractory aggressive B-cell lymphoma. The level of LDH before therapy was higher in patients who developed grade 3 or serious CRS, which suggest that we should improve safety by reducing tumor burden before CAR T-cells infusion. Due to the small number of enrolled cases, no significant improvement of efficacy was observed, this result needs to be further confirmed by expanding the number of study cases. DisclosuresNo relevant conflicts of interest to declare.

From mono- to bivalent: improving theranostic properties of target modules for redirection of UniCAR T cells against EGFR-expressing tumor cells in vitro and in vivo.

CAR-modified T cells show impressive results in clinical trials. However, cytokine release syndrome and “on-target, off-tumor” reactions represent most concerning side effects. To improve the safety of CAR-T cell therapy, we established a switchable CAR platform termed UniCAR system consisting of two components: UniCAR-modified T cells and tumor-specific target modules (TM). For treatment of EGFR+ epithelial tumors, we recently described a monovalent nanobody-based α-EGFR TM, either expressed in bacteria or eukaryotic cells. In spite of the identical primary sequence the eukaryotic TM showed a reduced killing capability and affinity. Here we describe a novel bivalent α-EGFR-EGFR TM. As expected, the avidity of the bivalent TM is higher than that of its monovalent counterpart. Binding of neither the monovalent α-EGFR TM nor the bivalent α-EGFR-EGFR TM to EGFR effected the EGF-mediated signaling. While the monovalent α-EGFR TM could only mediate the killing of tumor cells expressing high levels of EGFR, the bivalent α-EGFR-EGFR TM could redirect UniCAR T cells to tumor cells expressing low levels of EGFR. According to PET experiments in vivo, the increased avidity of the bivalent α-EGFR-EGFR TM improves the enrichment at the tumor site and its use for PET imaging.