Kymriah (tisagenlecleucel-T)

At day+1, higher plasma levels of lipid metabolism products and lower glucose and glycoproteins levels were observed in tisa-cel compared to axi-cel-treated patients. Our data show complex metabolomic changes that track the evolution of the disease and drug activity in the first 30 days of CAR-T cell therapy. Conceivably, a pro-inflammatory drift may be linked to a forthcoming disease relapse in CAR-T patients.

Here, we profiled IR in 263 patients with relapsed/refractory large B-cell lymphoma receiving CAR-T therapy (axicabtagene ciloleucel 44.9%, lisocabtagene maraleucel 30.4%, tisagenlecleucel 24.7%). IR differences exist by product, with fastest CD4+ T cell recovery seen for tisagenlecleucel, driven primarily by more rapid recovery of the CD4+CCR7-45RA- effector memory subset. Natural killer cell, but not CD4+ T cell, recovery is significantly associated with favorable progression-free (HR: 0.647; 95% CI: 0.476-0.880) and overall survival (HR: 0.637; 95% CI: 0.441-0.920) and inversely correlated with inflammatory markers measured at time of infusion.

The development of a fatal, clonal, autonomously proliferating CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. Somatic DNMT3A and TET2 mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant. The PTCL harbored an additional somatic TET2 mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis.

P1, N=0, Withdrawn, University Health Network, Toronto | N=40 --> 0 | Recruiting --> Withdrawn

Correlative analyses suggest that most baseline high-risk disease characteristics (double-refractory disease, bulky disease, POD24, and high FLIPI) are not associated with inferior efficacy following tisagenlecleucel infusion in pts with r/r FL. Furthermore, high frequencies of MRD-negative status were achieved in a subset of evaluable pts.

P3, N=108, Recruiting, Novartis Pharmaceuticals | Trial completion date: Feb 2029 --> Jan 2031

We conclude that the addition of nivolumab based on CAR-T cell expansion in patients with SD/PD-LBCL is safe and yields promising early response rates.

CAR-MNZ bearing the CD28-OX40-CD3ζ signaling modules, and CAR-BG2, designed on the Tisagenlecleucel CAR sequence (Kymriah®), carrying the 4-1BB and CD3ζ signaling elements, were employed. CIK + Blina displayed strongest NFAT and IFN-ɣ induction, whereas CARCIK-BG2 demonstrated superior synapse formation. All the effectors have shown therapeutic activity in vivo against the CD19+ Daudi tumor model, with CARCIK cells showing a more durable response compared to CIK + Blina, likely due to the short half-life of Blina in this model.

P1, N=6, Completed, Matthew J. Frigault, M.D. | Active, not recruiting --> Completed

Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel.

This study was a prospective analysis of proinflammatory proteins and cytokines in children treated with tisagenlecleucel...None of the toxicities were fatal. All of the analyzed biomarkers rose within 14 days after CAR-T infusion, with most reaching their maximum around the third day following the procedure.

P2, N=121, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

Conclusion These results suggest that the proportion of activated CD4+ T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.

Pre-treatment malnutrition and cachexia was significantly associated with adverse CAR T patient outcomes, including mGPS cachexia status independently associated with inferior overall survival. Further research in this novel space is essential to confirm the extent and impact of nutritional issues, to assist with implementing dietetic pathways, and to identify potential interventions with a view to optimising outcomes.

P1, N=40, Recruiting, University Health Network, Toronto | Not yet recruiting --> Recruiting

P1, N=20, Recruiting, Stanford University | Not yet recruiting --> Recruiting

P1, N=20, Not yet recruiting, Stanford University

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.

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.

P1, N=6, Active, not recruiting, Matthew J. Frigault, M.D. | Recruiting --> Active, not recruiting | Trial completion date: Nov 2022 --> Dec 2024

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

A transcriptionally similar population was identified in patients following Tisagenlecleucel infusion...In vitro activated and patient-derived T-cells with the bystander phenotype efficiently killed leukemic cells through a TCR-independent mechanism. Collectively, this dataset provides the first comprehensive identification and profiling of CARneg bystander CD8+ T-cells following B-cell targeting CAR-T cell therapy and suggests a novel mechanism through which CAR-T cell infusion might trigger enhanced anti-leukemic responses.

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

P1, N=40, Not yet recruiting, University Health Network, Toronto | Initiation date: Dec 2023 --> Apr 2024

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

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

P3, N=200, Recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Dec 2023 --> Apr 2025

We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel...In addition, immunocompetent mice show an intact CD80-CD19+ B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study.

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.

P=N/A, N=200, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

Low levels of tumor-infiltrating LAG3+CD3+ exhausted T-cells and higher baseline levels of naïve CD8+ T-cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA.

P2, N=33, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=81, Recruiting, Stephan Grupp MD PhD | Trial primary completion date: Mar 2025 --> Mar 2028

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.

We performed an SLR to understand the efficacy and real-world (RW) effectiveness of non–CAR T-cell therapies for R/R LBCL including tafasitamab with lenalidomide (tafa/len), polatuzumab with bendamustine/rituximab (pola-BR), loncastuximab, selinexor, epcoritamab, and glofitamab. Currently, the evidence base, particularly RW studies, for non–CAR T-cell R/R LBCL therapies is still limited. In comparison, 78 RW CAR T-cell therapy studies were published (Jacobson et al. Tandem Meeting.

"BostonGene...announced the selection of four abstracts for oral presentation, four abstracts as poster presentations, and two abstracts for online publication at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition being held December 9-12, 2023, in San Diego, California and virtually....This presentation highlights results from the Phase 2 ELARA trial that show efficacy, safety, pharmacokinetic, and exploratory biomarker analyses in relapsed/refractory follicular lymphoma patients treated with tisagenlecleucel after a median follow-up of more than 3 years."

Pts with r/r FL maintained a high rate of durable responses more than 3 y after tisagenlecleucel infusion, including pts in high-risk subgroups such as POD24. Tisagenlecleucel's safety profile remains favorable with no new safety signals during extended follow-up. Correlative analyses suggest higher baseline levels of CD8+ naive T cells (>2.14%) are associated with improved long-term clinical outcomes.

P3, N=200, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2023 --> Apr 2024

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.

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.

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.

A significant positive correlation was observed between ALC and the CD3+ cells as well as its percentage from leukapheresis for pediatric and adult patients undergoing tisagenlecleucel CAR-T. However, no significant effects were found when detecting the association between ALC with OS or EFS. In addition, there were no significant findings between IFNγ and the duration of CRS or ICANS.