Kymriah (tisagenlecleucel-T)

P2, N=144, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Phase classification: P --> P2

Although the rate of neurotoxicity seems acceptable in CNS lymphomas, the risk of unusual prolonged neurologic deterioration is high in patients with grade 3-4 neurotoxicity. Special attention should be given to older patients with cognitive impairment who seem at greater risk of severe forms of neurotoxicity. Larger series are warranted to confirm these results.

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

A gene signature derived from in-house PRC2-inhibited 19BBζ CAR-T cells was enriched in tisagenlecleucel (tisa-cel) BBζ CAR-T cell therapy responders with large B-cell lymphoma. Collectively, these results demonstrate that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR-T cells to improve the efficacy in treating hematological malignancies.

In the pediatric, adolescent, and young adult (P-AYA) populations, Tisagenlecleucel (Kymriah®) exemplifies the success of CAR T-cell therapy, demonstrating significant efficacy in treating relapsed or refractory acute lymphoblastic leukemia (r/r ALL)...Addressing these barriers is critical for advancing CAR T-cell therapy in pediatric oncology, improving outcomes, and ensuring equitable access to innovative treatments for these vulnerable populations. This review aims to inform future research and policy decisions, promoting advancements in CAR T-cell therapy for P-AYA cancer patients.

P2, N=133, Recruiting, Stephan Grupp MD PhD | N=81 --> 133

P3, N=200, Recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2025 --> Mar 2026 | Trial primary completion date: Apr 2025 --> Mar 2026

P=N/A, N=500, Not yet recruiting, Novartis Pharmaceuticals

P1, N=4, Completed, Emory University | Recruiting --> Completed | N=20 --> 4 | Trial completion date: Aug 2025 --> Sep 2024 | Trial primary completion date: Aug 2024 --> Mar 2024

The review highlights that CAR T-cell therapies, mainly tisagenlecleucel (Tisa-cel) and axicabtagene ciloleucel (Axi-cel), have shown superior effectiveness in comparison to standard chemotherapy in patients with relapsed or refractory DLBCL. Lisocabtagene maraleucel (Liso-cel) showed significant improvement outcomes in event-free and progression-free survival. However, CAR T-cell therapies are associated with many side effects. The most common side effects include hematologic toxicity, prolonged neutropenia, and infections, while clinical outcomes are highly impacted by many factors, which include a pro-inflammatory state, PPM1D gene mutation, infusion timing, and circulating monocytes.

Our goal is to elucidate the role of procalcitonin (PCT), C-reactive protein (CRP) and ferritin in the context of CRS following CAR T-cell infusion to predict its severity and PICU admission.MethodsProspective observational study (2016-2022) in children and young adult who received CAR T-cell therapy (Tisagenlecleucel/ARI-0001). Biomarkers were higher in those who needed inotropic or respiratory support.ConclusionsPCT levels increase after CAR-T cell therapy in the setting of systemic inflammation and could be a predictor of PICU admission and evolution to death. Further research studying its role in the context of CRS and the differential diagnosis between infection and CRS is needed to better understand the biology of this biomarker and to define its value in clinical practice.

Of the 3,066 patients included (2,536 B cell lymphoma, 162 B cell acute lymphoblastic leukemia (ALL) and 368 multiple myeloma), 1,680 (54.8%) received axicabtagene ciloleucel, 205 (6.7%) brexucabtagene autoleucel, 44 (1.4%) lisocabtagene maraleucel and 769 (25.1%) tisagenlecleucel. All multiple myeloma patients received idecabtagene vicleucel, with none receiving ciltacabtagene autoleucel...Thus, the development of this secondary T cell malignancy might be linked to the use of CAR T cell therapy. In conclusion, our findings indicate a very low risk of T cell malignancy after CAR T cell therapy.

P1/2, N=30, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

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.