Yescarta (axicabtagene ciloleucel)

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

P2, N=15, Active, not recruiting, Marcela V. Maus, M.D.,Ph.D. | Completed --> Active, not recruiting | Trial completion date: Oct 2023 --> Oct 2025 | Trial primary completion date: Oct 2022 --> Oct 2024

present data from pretreatment tumor biopsies taken on the ZUMA-7 trial. Their results identify tumor microenvironment (TME) contexts and level of CD19 expression as prognostic indicators for responses to axicabtagene ciloleucel (axi-cel).

Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16-24.12] p = 0.016). We conclude that a faster CAR- CD4+ T cell recovery is associated with TSA as compared to AXI/BRX. Month-1 CAR- CD4+ T cell subset recovery could represent a "red flag" for CAR-T cell therapy failure in DLBCL patients.

P2, N=700, Enrolling by invitation, Kite, A Gilead Company | Trial completion date: Mar 2041 --> Dec 2040 | Trial primary completion date: Mar 2041 --> Dec 2040

P2, N=35, Active, not recruiting, Kite, A Gilead Company | Recruiting --> Active, not recruiting

P3, N=230, Recruiting, Kite, A Gilead Company | Trial completion date: Jan 2031 --> Oct 2030 | Trial primary completion date: Jan 2031 --> Oct 2030

P2, N=396, Recruiting, SWOG Cancer Research Network | Trial primary completion date: Dec 2024 --> Dec 2025

P=N/A, N=144, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=240 --> 144 | Trial primary completion date: Jun 2028 --> Feb 2024

P3, N=359, Active, not recruiting, Kite, A Gilead Company | Trial completion date: Jan 2035 --> Oct 2024

P1/2, N=50, Recruiting, University of Washington | Trial completion date: Mar 2029 --> Mar 2030 | Trial primary completion date: Mar 2024 --> Mar 2025

P2, N=15, Completed, Marcela V. Maus, M.D.,Ph.D. | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Oct 2023

P1, N=6, Terminated, Kite, A Gilead Company | Phase classification: P1/2 --> P1

P1, N=37, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=20 --> 37

P1, N=57, Recruiting, NeoImmuneTech | Phase classification: P1b --> P1

P=N/A, N=613, Completed, Novartis Pharmaceuticals

P2, N=40, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Jul 2024 --> Feb 2024

With the simultaneous detection of the CAR-T cells and the B cell malignancy in patient peripheral blood, the HDSCA-HemeCAR workflow may be considered for risk monitoring and patient management.

P2, N=27, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Feb 2028 --> May 2026 | Trial primary completion date: Feb 2028 --> Jun 2024

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center | Phase classification: P1 --> P2

We realized the translational relevance of these findings by examining the scRNA-seq profiles of Tisa-cel and Axi-cel infusion products and show a significant correlation between GZMB and GZMA expression at the single-cell level in a T cell subset-dependent manner. Our findings highlight the importance of the redundancy in killing mechanisms of CAR T cells and how this redundancy is important for efficacious T cells.

P1, N=40, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

We analyzed 234 cases of lymphoma (189 LBCL, 20 FL, 25 MCL) treated with commercial CAR19 (100% axi-cel and brexu-cel)...Additional profiling of the B- and T-cell tumors is ongoing and will be presented to discern a shared lineage implicating infidelity or trans-differentiation versus an unrelated secondary malignancy. These additional studies in progress include direct DLBCL vs TCL comprehensive genotyping, scDNA sequencing of marrow lymphocytes and progenitors, EBV genotyping and terminal repeat analysis, and retroviral insertion site mapping.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.

P2, N=20, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Peripheral blood quantification of CAR-T vector load may have prognostic value and can aid in toxicity management for large B cell lymphoma (LBCL) patients undergoing axicabtagene ciloleucel (axi-cel) treatment... 246 samples were collected across 39 participants. CAR-T vector load was measured by Idylla (copies per uL) and ddPCR (copies per cell) (Fig. 1).

All pts received axicabtagene ciloleucel. In this small, observational, real-world study, treatment of pts with lonca prior to CAR-T infusion did not preclude subsequent responses to CD19-directed CAR-T therapy. Studies in a large pt population are warranted to confirm the findings.

Achieving and maintaining CR by 6 mo post-infusion is a potential surrogate for evaluating long-term efficacy at an earlier time-point. Based on these findings, CR should be assessed for potential surrogacy in future clinical trial design.

CAR-T treated patients at Stanford University were enrolled on an IRB-approved bio-repository protocol. Fifty-five unique patients with available quantitative flow cytometry data were identified and were treated between January 2018 and June 2022. Fifty-four of these patients received axi-cel in the 3rd line or later, with 3 median prior lines of therapy.

We analyzed Medicare FFS claims data, focusing on the utilization patterns across three CAR-T products—Breyanzi, Kymriah, and Yescarta – which are indicated for the treatment of LBCL. CAR-T therapy for the treatment of LBCL has become more common within the Medicare population, primarily in the inpatient setting. This study helps understand providers' cost and associated patient care around CAR-T administration. The data shows that the average cost received by hospitals encompasses the expenses related to both the CAR-T drug and the medical services delivered to patients.

P3, N=300, Recruiting, Kite, A Gilead Company

After axi-cel, three (19%) patients had grade 3 ICANS which resolved with dexamethasone and anakinra or tocilizumab. CRP and ferritin levels were typically modestly elevated after axi-cel. Severe CRS was not observed and high-grade ICANS was uncommon.

Comparators were axicabtagene ciloleucel (Axi-cel), lisocabtagene maraleucel (Liso-cel), tisagenlecleucel (Tisa-cel), loncastuximab tesirine (Lonca), polatuzumab vedotin + bendamustine + rituximab (Pola-BR), rituximab + gemcitabine + oxaliplatin (R-GemOx), tafasitamab + lenalidomide, and epcoritamab. Over 3 years, the estimated cumulative per-patient cost of glofitamab is projected to be the lowest when compared with per-patient costs of other available T-cell engaging therapies, resulting in cost savings after its formulary adoption for the treatment of R/R DLBCL after ≥2 lines of therapy.

A micro-costing analysis was developed to compare practice efficiency of treating patients with R/R DLBCL using epcoritamab versus comparator treatments (glofitamab, polatuzumab/bendamustine/rituximab [pola-BR], tafasitamab/lenalidomide [tafa-len], and axicabtagene ciloleucel [axi-cel]) over a time horizon of up to 1 year. Due to its unique SC administration, epcoritamab improves institutional practice efficiency despite more frequent dosing, saving personnel costs and inpatient costs. This could help to alleviate capacity constraints at infusion centers and ease patient scheduling. The resources saved (staff time, chair time, inpatient monitoring) can be redirected to other institutional needs, improving the availability and quality of healthcare services for patients.

The cure rate with first line of therapy (R-CHOP) reaches up to 70%...All patients received lymphodepletion (LD) therapy with fludarabine and cyclophosphamide (Flu/Cy)...Tocilizumab was used in 72...Dexamethasone (Dexa) was used in CRS in 36... In this single-center retrospective analysis of CAR T-cell therapy in relapsed or refractory NHL or FL in adults, the rates of durable responses were like the real-world data. The best response rate was higher in Axi-Cel group; however, the follow-up duration of disease response is shorter in Axi-Cel group. The toxicity profile is similar in both groups with a bit higher of Grade-III-IV ICANS in Tica-Cel group.

This economic analysis revealed lower overall per-patient weighted average costs associated with liso-cel compared with axi-cel and tisa-cel, primarily due to lower CRS and NE rates versus axi-cel and lower NE rates versus tisa-cel. In comparison with axi-cel and tisa-cel, liso-cel demonstrated robust economic and clinical value, with lower rates of CRS and/or NEs associated with substantial cost savings per AE event.

Pts received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days...Prior CD19 CAR T-cell product type was lisocabtagene maraleucel, n=4 (50%); axicabtagene ciloleucel, n= 3 (37%); or tisagenlecleucel, n=1...CONCLUSIONIn LBCL pts with disease relapse or progression after a first CD19 CAR T-cell therapy, we observed low response rates and lack of durable responses after treatment with the fully human scFv-bearing product JCAR021, prompting early study termination. Lower CAR T-cell expansion during manufacturing in CAR-exposed pts suggest pre-existing T-cell dysfunction as a potential mechanism of failure.

From July 2021 until January 2023, 27 patients received CAR T-cell therapy (25 Axi-Cel, 2 Brexu-Cel) after Fludarabine and Cyclophosphamide lymphodepletion for relapsed/refractory large B-cell lymphomas (24), mantle lymphoma (2), or follicular lymphoma (1)...All patients received Filgrastim from D0...05. 012

All patients were treated in our center with either commercial CAR-T cell products (Axicabtagenee ciloleucel, Tisagenlecleucel, Lisocabtagen maraleucel) or with the investigational medicinal product MB-CART19...Consistent with reduced toxicity, AID patients received less tocilizumab and glucocorticoid treatment...Taken together, we observed less toxicities and severe adverse events in AID patients than in NHL patients despite similar CAR-T cell expansion and dynamics. The lack of CAR-T cell persistence and the early recurrence of B cells in AID patients is so far not explained and could provide novel insights in the biological processes controlling long-term CAR-T cell persistence.