anti-CD19 Chimeric Antigen Receptor Research Articles

Chimeric antigen receptor (CAR) T-cell therapy has advanced treatment for B-cell lymphoma (BCL), but more than 50% of patients relapse. Predicting clinical outcomes based on features at CAR T infusion remains unclear, and most trials lack racial diversity, limiting understanding of its impact on outcomes. To address these challenges, we pooled data from 9 CAR T clinical trials, consisting of 2,304 patients with BCL. The nature of this dataset, made available through the Medidata Clinical Cloud®, represents a large set of patient-level data aggregated over 9 clinical trials that has not been previously analyzed in this manner. Of the 2,304 patients, 395 (17.1%) failed screening, and 1,637 were assigned CAR T; 151 (9.22%) did not receive treatment due to adverse events, disease progression, or death, with only 12% surviving at 1 year. For treated patients, we analyzed two cohorts: large BCL (LBCL, n=958) and indolent BCL (iBCL, n=349). Multivariate Cox models revealed that low performance status and high tumor burden (ECOG ≥2, bulky disease, bridging therapy) negatively affected overall survival (OS) and progression-free survival (PFS) in LBCL, while age and shorter time from diagnosis to infusion negatively impacted OS and PFS in iBCL. Despite underrepresentation of non-white groups across all trial phases, the feasibility and effectiveness of CAR T-cell therapy were consistent across racial and ethnic groups.

Large B-cell lymphoma (LBCL) patients (pts) failing anti-CD19 Chimeric Antigen Receptor (CAR) T-cells therapy exhibit poor prognosis. Most progressions/relapses occur within 3 months from infusion while only a few events occur thereafter (late failure, LF). We analyze features, treatments and outcomes of pts with LF from DESCAR-T, a nationwide registry collecting real-life data for pts treated with approved CAR T-cell therapy in France. Between July 2018 and March 2024, 298 (39.9%) LBCL LF pts (median age 62 years, range 18-79, M 61.7%) were collected from DESCAR-T. Most pts had diffuse large B-cell lymphoma (DLBCL, n=205, 68.8%), advanced stage disease (84.6%) and age-adjusted International Prognostic Index (aaIPI) of 2-3 (59.3%) at CAR T eligibility. After failure, 76.5% pts received a systemic therapy and overall response rate (ORR) was 22.6% (complete response 18%). At a median follow-up since first late failure event of 13.8 (95% Confidence Interval [CI], 12.1-15.4) months, the median PFS-2 and OS-2 were 4.4 (95%CI, 3.8-5.8) and 13.2 (95% CI, 9.6-18) months, respectively. Compared to chemotherapy (HR=0.350, 95%CI, 0.193-0.633) and to pooled other treatments groups (HR=0.483, 95%CI, 0.290-0.805), salvage treatment with bispecific antibodies (BsAb) after CAR T failure showed better PFS-2. Radiotherapy obtained prolonged responses in some pts with 12-months PFS-2 of 41.5% (95%CI, 22.5-59.5). The present work is the first study describing LBCL pts with late failure after CAR T. BsAbs seem to be more effective compared to other strategies in LF setting and this should be considered in the design of new clinical trials.

IL-10-expressing, anti-CD19 CAR T cells for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: an open-label, single-arm, phase 1 study.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Here, we report updated clinical outcomes from ZUMA-5 in 159 enrolled patients with R/R indolent non-Hodgkin lymphoma (iNHL; 127 with FL and 31 with marginal zone lymphoma) after a median follow-up of 64.6 months. Patients underwent leukapheresis and received lymphodepleting chemotherapy and axi-cel (2 × 106 CAR T cells/kg). The overall response rate was 90% (75% complete response rate). The median duration of response was 60.4 months, and the median progression-free survival (PFS) was 62.2 months; median time to next treatment and overall survival were not reached (NR). At data cutoff, 55% of patients were alive without requiring subsequent anticancer therapy. Median lymphoma-specific PFS in patients with FL was NR; 34% had progression or death due to lymphoma or study treatment. Notably, after 30 months postinfusion, progression or lymphoma-related deaths were rare. Late-onset toxicities were infrequent and largely unrelated to axi-cel. Durable response and prolonged survival in FL were associated with robust early CAR T-cell expansion and naïve product phenotype. These findings confirm sustained responses and manageable safety with axi-cel in the long term among patients with R/R iNHL and its potential as a curative therapy in FL.

BackgroundAutologous chimeric antigen receptor (CAR) T-cell therapy has recently gained interest in the treatment of rheumatic and neuroimmunologic diseases.MethodsWe report a 62-year-old female patient with a 14-year history of treatment-refractory anti–GAD-positive stiff-person syndrome (SPS) and concomitant anti–AChR-positive myasthenia gravis. Despite a relatively stable disease course in the first 8 years, SPS dramatically progressed afterward. In 2023, she was able to walk less than 10–15 m and suffered from severe persistent stiffness in the left arm superimposed with painful muscle spasm attacks (MSAs). Numerous immunotherapies, including intravenous immunoglobulins, plasma exchange, steroids, azathioprine, and rituximab, were ineffective. Consequently, she was escalated to compassionate use of autologous anti-CD19 CAR T-cell therapy (KYV-101).ResultsFrom the third month post–CAR-T, we observed a substantial improvement in walking distance, pain, anxiety, and MSAs in the arm. By the sixth month, she was able to walk 500 m. The anti-GAD titers declined from 1:320 to 1:32. Side effects included grade 2 cytokine release syndrome and moderate leukopenia, without serious infections.DiscussionCAR T-cell therapy was effective at mitigating SPS symptoms, despite the long history and severe refractory disease course in our patient. Controlled trials are needed to evaluate its potential in SPS.

CAR T cells for multiple sclerosis: Engineering T cells to disrupt chronic B cell-driven neuroinflammation.

BACKGROUND. The therapy using T-cells with chimeric antigen receptor (CAR) is a novel and effective treatment option for relapsed/refractory B-cell non-Hodgkin lymphomas (r/r В-NHL). However, high cost of commercial products limits their application in real-world clinical practice. Academic approach to manufacturing CAR-T cell products can reduce the costs and improve availability and affordability of this therapy option. AIM. To assess the efficacy and safety of the use of academic CAR-T cell products in r/r В-NHL patients. MATERIALS & METHODS. From June 2021 to November 2024, this prospective study enrolled 57 r/r В-NHL patients treated at the NN Alexandrov National Cancer Centre of Belarus (Minsk, Republic of Belarus). The patients were 23–68 years of age (median 47 years), there were 32 men and 25 women. The CAR-T cell product was manufactured using lentiviral vector encoding anti-CD19 CAR. RESULTS. Generally, complete response was achieved in 37 (64.9 %) out of 57 patients. The 3-year overall survival (OS) was 63 ± 8 % (median not reached). Among patients with follicular lymphoma, complete response was achieved in 12/15 patients (80 %). The 3-year OS was 93 ± 6 %. The safety profile was acceptable: cytokine release syndrome was detected in 38.6 % of patients (predominantly grade 1–2), and neurotoxicity (ICANS) was identified in 31.6 % of patients. CONCLUSION. In r/r В-NHL treatment, academic CAR-T cell products show comparable efficacy and safety to their commercial counterparts. Their use can considerably decrease the cost and increase availability and affordability of this novel therapy option for more people.

Hematotoxicity after anti-CD19 chimeric antigen receptor T-cell therapy has drawn attention for potential long-term effects, and yet, recovery of lymphocyte subsets and immunoglobulin levels beyond B-cell aplasia remains poorly understood. We retrospectively analyzed 76 consecutive axicabtagene ciloleucel (axi-cel) recipients with relapsed/refractory aggressive B-cell lymphoma between 2020 and 2024, focusing on basic immune recovery patterns and their impact on outcomes. Median CD8+ T and NK cells increased to >300/mm3 and >100/mm3, respectively, within 2 months after infusion. CD4+ T-cell recovery was slower, with 42% cumulative incidence of >200/mm3 cell count at 12 months. B-cells were detectable in 18% at 12 months. Immunoglobulin levels initially declined and then plateaued, with 51% incidence of immunoglobulin G (IgG) levels > 400 mg/dL at 12 months. Modified EASIX > 2.00 was associated with delayed kinetics of CD3+ T-cells, CD4+ T-cells, and CD8+ T-cells, and cumulative dexamethasone dose > 120 mg with delayed recovery of CD4+ T-cells, NK cells, and IgG. At 1 month post-infusion, low CD4+ T-cell count and high CAR-HEMATOTOX predicted worse 12-month progression-free survival (hazard ratio [HR] 2.81 and 3.34) and overall survival (HR 3.21 and 4.41), respectively. After axi-cel, CD4+ T-cells and IgG recovered slowly during the first year, while CD8+ T and NK cells increased rapidly. A higher modified EASIX score may predict slower cellular recovery, while corticosteroids may delay both cellular and humoral recovery. Lower CD4+ T-cell count was associated with worse outcomes.

Systemic lupus erythematosus (SLE) remains refractory to conventional immunosuppression in a subset of patients. In treatment-refractory SLE, we show that peripheral CD19⁺ B cells and bone marrow CD19⁻BCMA⁺ long-lived plasma cells are dominant autoantibody sources, motivating dual CD19 and BCMA targeting. Here we report results from a cohort of patients (14 female, one male) in an ongoing phase 1 dose-escalation trial of co-infused autologous anti-CD19 and anti-BCMA chimeric antigen receptor (CAR) T cells after fludarabine/cyclophosphamide lymphodepletion. Primary endpoints were dose-limiting toxicities (DLTs) within 28 days and adverse events within 12 weeks; key secondary endpoints comprised attainment of Lupus Low Disease Activity State (LLDAS) and DORIS remission within 12 weeks and in vivo CAR-T persistence within 24 weeks. Exploratory endpoints were the duration of post-infusion B cell depletion and time to recovery, the kinetics of immune reconstitution and longitudinal changes in autoantibody titers and serum immunoglobulin concentrations after CAR-T therapy. Over a median 712-day follow-up (range, 613-1,134), no DLTs occurred. Grade 1 cytokine release syndrome developed in 86.7% of patients, with no neurotoxicity or treatment-related deaths. The most common grade 3 or higher adverse events were neutropenia (100%), thrombocytopenia (40%) and anemia (13.3%), all of which were reversible with supportive care. By week 12, 12 of 15 patients (80%) fulfilled both the LLDAS and DORIS remission criteria. Multiomic analyses confirmed elimination of autoreactive CD19⁺BCMA⁺ clones, reconstitution of naive IgM/IgD B cells and durable downregulation of interferon-stimulated and BAFF-dependent signatures, indicating improved immune homeostasis. Longitudinal monitoring of three patients for 1 year demonstrated sustained eradication of pathogenic clones, suggesting potential cure. Dual anti-CD19/anti-BCMA CAR-T cell therapy demonstrates good safety and promising clinical efficacy in treatment-refractory SLE. This study supports the further development of this treatment approach for patients with rSLE. ClinicalTrials.gov identifier: NCT05030779 .

Therapeutic T cells with 3-in-1 strategy for the treatment of biliary tract cancer.

Most anti-CD19 chimeric antigen receptor (CAR) T-cell products have the single-chain variable fragment (scFv) derived from the FMC63 monoclonal antibody. We developed a new hybridoma clone, HI19α, which binds to distinct epitopes on CD19. CNCT19 is a second-generation CAR T-cell with a scFv derived from clone HI19α and a 4-1BB costimulatory domain. A pilot clinical trial was conducted to assess the safety and preliminary efficacy of CNCT19 cells (CNCT19s) in patients with relapsed or refractory (R/R) aggressive B-cell lymphoma. From June 2017 to March 2019, 16 patients with R/R CD19-positive aggressive B-cell lymphoma from the Institute of Hematology and Blood Disease Hospital were enrolled. All patients received lymphodepleting chemotherapy with fludarabine (25-30 mg/m2/per day on days 4, 3, and 2) and cyclophosphamide (350 mg/m2/per day on days 4 and 2) before CNCT19s infusion. The primary objective was the safety profiles. Kaplan-Meier survival analysis was used to compare the cumulative incidence rate. The study cohort comprised 14 patients diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), one patient with follicular lymphoma grade 3B (FL3B), and one patient with Richter's transformation. The patients had received a median of 3 (range 1-7) lines of prior therapy. Thirteen patients (81.3%) had disease resistant to the last-line therapy, and TP53 mutation and/or deletion were detected in 5 of 12 patients (41.7%). The median dose of CNCT19s infusion was 3.6 × 106 (range 1.8-6.5 × 106)/kg. Cytokine release syndrome occurred in 11 (68.8%) patients, all classified as grade 1. One patient (6.3%) experienced CAR T-cell-related encephalopathy syndrome. The overall response rate and the complete response rate were 75% (12/16) and 43.8% (7/16), respectively. After a median follow-up of 54.0 months, the estimated 5-year progression-free survival and overall survival rates were 25.0% and 37.5%, respectively. CNCT19s exhibited favorable safety profiles and efficacy in patients with R/R DLBCL and FL3B. Long-term follow-up confirmed the curative potential of CNCT19s in R/R aggressive B-cell lymphoma. ClinicalTrials.gov, NCT03029338.

Isolated oral CD30+/CD4+ CAR+ T cell lymphoma in long-term remission after radiotherapy.

IntroductionUrokinase-type plasminogen activator (uPA) is upregulated in prostate cancer, but its comprehensive impact on the immune microenvironment and the underlying mechanisms remains to be fully elucidated.MethodsuPA expression was analyzed in clinical prostate cancer specimens and correlated with CD8⁺ T cell infiltration. Tumor growth was assessed in the uPA-deficient (uPA–/–)and the uPA inhibitor UK122-treated mouse model. Immune infiltration was evaluated by CyTOF and flow cytometry. Anti-CD19 chimeric antigen receptor (CAR)-engineered WT or uPA–/– CD8⁺ T cells were tested for cytotoxicity against RM1-CD19 cells. The combination of UK122 and anti-PD-1 therapy was assessed.ResultsElevated uPA in prostate cancer specimens inversely correlated with CD8⁺ T cell infiltration. Both genetic uPA ablation and UK122 significantly attenuated tumor growth by enhancing antitumor immunity. uPA deficiency markedly increased CD8⁺ T cell infiltration. uPA–/– CD8⁺ T cells exhibited enhanced cytotoxicity compared to WT CD8⁺ T cells. Tumor-infiltrating uPA–/– CD8⁺ T cells showed higher PD-1 expression. UK122 synergized with anti-PD-1 therapy to promote tumor regression.DiscussionuPA is a significant immunosuppressive regulator in prostate cancer. Its inhibition enhances CD8⁺ T cell function and synergizes with immune checkpoint blockade, supporting uPA targeting as a novel strategy to improve prostate cancer immunotherapy efficacy.

Posterior reversible encephalopathy syndrome: evolving insights in diagnosis, management, and outcomes.

CAR binding efficacy and off-target interactions for common CAR detection reagents.

Orthogonal CRISPR systems for targeted integration and multiplex base editing enable nonviral engineering of allogeneic CAR-T cells.

T-cell therapies have transformed cancer treatment. Although surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell-mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8+ T cells expressing β1,6-GlcNAc-branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR-Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8+ T cells resulted in improved cancer cell killing. These findings prompted the assessment of whether MGAT5 deletion in anti-CD19 chimeric antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 knockout anti-CD19-CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8+ T-cell function in cancer and provide a strategy to enhance the antitumor activity of native and CAR T cells.

This study aims to evaluate the impact of levetiracetam (LVT) prophylaxis on the incidence and severity of immune effector cell-associated neurotoxicity syndrome (ICANS) in patients undergoing anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy for LBCL (large B-cell lymphoma). A propensity score-matched cohort of 254 patients was analyzed, comparing those receiving LVT prophylaxis (LTV-yes) with those not receiving it (LTV-no), in a 1:1 ratio. The results showed no significant difference in the occurrence of ICANS of any grade between the 2 groups (32.3% in LVT-no vs 37.1% in LVT-yes; P = .29), or in severe ICANS (grades 2-4, 15.1% vs 16.1% [P = .80]; grade 3-4, 7.9% vs 9.7% [P = .71]). The use of LVT was associated with a higher incidence of early immune effector cell-associated hematotoxicity (ICAHT), with grade 2 to 4 ICAHT occurring in 37.3% vs 63.9% (P < .001) of patients in the LVT-no and LVT-yes groups, respectively. Overall survival and progression-free survival did not differ significantly between the 2 groups (P = .337 and .670). Nonrelapse mortality rates were comparable (P = .77). These findings suggest that routine use of LVT as prophylaxis for ICANS in CAR-T therapy is not effective, and further research is needed to refine its role in selected populations or after ICANS treatment.

High-grade B-cell lymphomas [HGBL, including double-hit/triple-hit (HGBL-DH/TH) and HGBL not otherwise specified (HGBL-NOS)] have a poor prognosis upon failure of first-line therapy. Anti-CD19 chimeric antigen receptor (CAR) T-cells for third-line aggressive large B-cell lymphomas resulted in long-term remission in up to 40% of patients. This study evaluated factors that can predict outcomes in HGBL compared to Diffuse Large B-cell lymphomas (DLBCL). We assessed the predictive value of the subtype (HGBL versus DLBCL) using weighted log-rank tests and weighted Cox models, and overall survival (OS) following CAR T-cells failure. The prospective study cohort comprised 432 patients [HGBL (n=78); DLBCL (n=354)] with a median follow-up of 22.8 months for HGBL and 18 months for DLBCL. Interestingly, there was no statistically significant difference in progression-free survival (PFS) and OS between patients with HGBL-DH/TH lymphomas versus other high-grade histotypes. CAR T-cells expansion in HGBL did not correlate with response. Before weighting, a significant difference in OS was observed between HGBL versus DLBCL (24-month OS: 37% vs. 49%, p=0.0036). After weighting, the difference in 2-year OS remained significant (37% versus 44%, p=0.0343), and it was related to an inferior survival following CAR T-cells failure. The 2-year NRM and incidence of secondary malignancies were similar in HGBL and DLBCL patients (11% versus 11%, p=0.830; 6.4% versus 11.4%, p=0.844). Among patients failing CAR T-cells, the 1-year OS post failure was significantly higher in transformed than de novo DLBCL and HGBL (59% versus 32% versus 11%, <0.0004). Earlier use of CAR T-cells may improve the outcome of HGBL. NCT06339255.

Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy.