CD19 mutation

ctDNA molecular response assessment using PhasED-Seq is prognostic for outcomes in pts receiving Lonca monotherapy. ctDNA levels as early as C2D1 can predict outcomes and are indicative of a fast response to Lonca. Furthermore, molecular responses can deepen with additional cycles.

All pts received lymphodepletion with intravenous fludarabine (250 mg/m2) and cyclophosphamide (25 mg/m2) on days -4, -3, and -2. In this first-in-human phase I trial, AT101 was tolerable with limited and manageable toxicities. Notable preliminary efficacy was observed at the RP2D with no evidence of disease relapse after achieving a CR. These results warrant the pursuit of the planned phase II expansion cohort.

Currently, h1218-CART19 (AT101) is in a phase 1 clinical trial in Korea for relapsed and refractory B-cell Non-Hodgkin’s lymphoma patients. Keyword : CD19, CAR T cells, Lymphoma

In this study, we developed a Volasertib antibody-drug conjugate (V-ADC) using -CD19 antibody Inebilizumab to increase the targeting specificity for B-cell lymphoma cells and minimize the side effects of Volasertib. In conclusion, starvation and lysosomal cathepsin activation increased V-ADC-induced apoptotic cell death in CD19 overexpression Z138 cell lines. We are actively investigating the in vivo therapeutic effects of V-ADC in patient-derived xenograft (PDX) animal models of MCL and other aggressive B-cell lymphomas.

The primary objective is to determine the safety, the maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of AT101 in participants following lymphodepletion with cyclophosphamide and fludarabine (250 mg/m2 and 25 mg/m2). As of January 11, 2023, AT101 has been infused to six patients in cohort 1 and three patients in cohort 2. Detailed results will be presented at the meeting.

Mutations of CD19 exon2-4 leads to the variation on protein structure, which hindered targeted killing process of CAR-T cells and finally resulted in CD19-negative relapse. On the other hand, OBSCN and RHOH may play a role in promoting leukemia proliferation and decreasing apoptosis, and the lower expression of OBSCN and RHOH may be risk factors associated with CD19-negative relapse. In addition, lower expression of RHOH was unfavourable for the infiltration of TN, TEM, TM and TILs in tumor microenvironment, which lead to the weakening anti-tumor effect of immunocytes.

We originally applied cell-free DNA (cfDNA) analysis to a cohort (n=65) of patients receiving axicabtagene ciloleucel (axi-cel) to identify determinants of resistance and characterize molecular thresholds predictive of treatment failure... Pre-treatment and dynamic ctDNA levels predict treatment failure of LBCL after CAR19 therapy, and a novel CAR outcome score incorporating week 4 ctDNA and week 1 cfCAR19 levels is strongly predictive of outcome. Genomic determinants of resistance to CAR19 therapy are diverse, including recurrent mutations in genes controlling B-cell identity (IRF8, PAX5), and those influencing the composition of the tumor microenvironment and heterotypic cell-cell interactions (TMEM30A). Additional immunological escape mechanisms arise under selective pressure from CAR19 cells.

Across patients, pre-existing mutations and genomic instability were not significant predictors of subsequent CD19- relapse across patients, with sample size as a potential limiting factor. Together, our results clarify and strengthen the relationship between genomic events and CD19- relapse, demonstrating this intriguing mechanism of resistance to a targeted cancer immunotherapy.

A statistically significant difference in CXCR4 MUT level was observed between patients treated at the time of enrollment and those still in WW. However, a longer FU is needed to better clarify the clinical implications of CXCR4 mutations in our series.

Pretreatment reduced expression or mono-allelic loss of CD19 did not affect responses, suggesting CAR-19 therapy success and resistance are due to multiple mechanisms. Our study shows tumor-intrinsic genomic alterations are key among the complex interplay of factors that underly CAR-19 efficacy and resistance for large B-cell lymphomas.

Pts were pre-conditioned with fludarabine (25-30 mg/m2) and cyclophosphamide (200-300 mg/m2) daily for 3 days. PrimeCAR platform could produce CAR T cells in very short time with high percentage of Tscm. Treatment of r/r B-ALL at very low dose resulted in excellent safety profile, while exhibited a promising efficacy. That make this PrimeCAR platform potential for outpatient administration in the future.

To achieve conditional knockout of Cdk8 in Cdk19-deficient background, Cdk19-/- mice were crossed with previously developed mice with floxed Cdk8 (McCleland et al., ibid) and with ROSA tamoxifen-inducible Cre recombinase...The newly developed mice with constitutive Cdk19 and inducible Cdk8 knockout will be used to study the different physiological roles of Mediator kinase, to evaluate the stromal effects of Mediator kinase inhibition on tumor growth and to predict potential side effects of long-term CDK8/19 inhibitor therapy. (Supported by Megagrant 14.W03.31.0020 from the Ministry of Science and Education of the Russian Federation).

To characterize the genomic mechanisms involved in diffuse large B cell lymphoma (DLBCL) resistance to CAR-19, we interrogated whole genome sequencing (WGS) from 28 relapsed/refractory (r/r) aggressive lymphoma patients treated with axicabtagene ciloleucel (axi-cel)...The melphalan-related signature (SBS-MM1) was identified in 4 out 5 patients who received high dose melphalan followed by autologous stem cell transplant, and 75% of patients exposed to platinum had evidence of one of the three known platinum signatures... Leveraging the high resolution of WGS, we observed that markers of genomic complexity (chromothripsis and APOBEC) and specific genomic alterations ( RHOA and RB1 deletion) associate with resistance to CAR-19 immunotherapy for aggressive B-cell lymphomas. Fifteen out of sixteen patients (93.8%) who relapsed on CAR-19 contained at least one of the described genomic alterations. Recent data demonstrate that an immunosuppressed TME leads to CAR-19 failure in patients, and animal studies show activation of host T cells by CAR-T cells.

CDK19 could be a prognostic marker in HCC, and its therapeutic potential in HCC needs further study.

Methods To characterize the genomic mechanisms involved resistance to CAR-19, we interrogated whole genome sequencing (WGS) from 28 relapsed/refractory (r/r) aggressive lymphoma patients uniformly treated with axicabtagene ciloleucel (axi-cel)...Recent patient data demonstrate that an immunosuppressed TME leads to CAR-19 failure. Combining these findings with our genomics findings, successful CAR-19 therapy must overcome the immune-exhausted TME to mobilize the host immune system and eliminate the tumor.

During study participation extensive neurological testing and serum IgM and anti MAG testing will be performed. In total 40 patients will be included and the MAGNAZ study expects to start in Q4 2021.