Kymriah (tisagenlecleucel-T)

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.

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.

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.

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.

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.

Introduction Anti-CD19 chimeric antigen receptor (CAR) autologous T-cell therapy tisagenlecleucel (CTL019) has shown efficacy in pivotal trials and real-world data in relapsed/refractory pediatric B-cell precursor acute lymphoblastic leukemia (r/r B-ALL)...5%), using inotuzumab in 1 patient...5%) consisted on fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 2 days...Our experience suggests the efficacy of its use as a bridge to consolidative HSCT. Nevertheless, a larger number of patients in the context of a clinical trial would be necessary.

Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

Over the past 3 years, three phase 2 studies has been conducted to evaluate the efficacy and safety of CAR T-cells in patients with R/R FL, specifically axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel).1-5 Although it’s not possible to make a direct comparison among these three studies because of different design and population, all of them demonstrated high efficacy with an overall response rates (ORR) ranging from 86-94%, even in patients with high risk disease. The safety profile seems to be slightly better with BiTEs than with CAR T-cells, especially compared to axi-cel. The debate about how to sequence CARs versus BiTEs is still being defined, and numerous questions are open about the right setting in which to prefer one therapy over the other.

In our study, we measured GFAP and NFL both at baseline and at day 7 in 34 patients with R/R B-cell malignancies treated with CD19 CAR-T cells (15 Axi-cel, 12 Tisa-cel, 7 Brexu-cel), and explored their association with clinically relevant neurological toxicities and markers of endothelial impairment. In conclusion, our data confirm a correlation between severe ICANS and elevated serum levels of NFL and G-FAP. Interestingly, these data also correlate with markers of endothelial activation, suggesting an active role of BBB impairment and axonal neuronal damage in the pathogenesis of ICANS.

The median ratio was 1.44, lower for brexu-cel compared to tisa-cel and axi-cel. The prognostic role of the CAR+CD4 /CD8 ratio was independent of the costimulatory domain (CD28 vs. 4-1BB) of the product (OR 16.41, p = 0.041). Our data indicate a crucial role for CD8 CAR-T and the CAR+CD4 /CD8 ratio in predicting CAR-T efficacy.

Importantly, we discovered two novel CD19-CAR architectures containing the IgG4 hinge domain that mediate superior in vivo antitumor activity compared to the construct used in Kymriah, an FDA approved therapy. This novel screening approach represents a major advance in CAR engineering, enabling accelerated development of cell-based cancer immunotherapies.

Twenty-three (79.3%) pts were treated with axicabtagene ciloleucel and 6 (20.7%) with tisagenlecleucel. Imaging features extracted from pre-infusion 18F-FDG PET/CT images in combination with several clinical features could predict survival and neurotoxicity in pts with DLBCL or PMBCL treated with CAR-T cell therapy. Quantitative features extracted from the PET/CT imaging exams may be useful for patient risk stratification and neurotoxicity prediction. Validation of these classifiers in independent datasets is warranted.

Conclusions Our data suggest that the poor outcome of some LBCL pts receiving CAR T is due to the presence of high monocytes levels expressing a four-gene signature in an inflammatory microenvironment. Additionally, the pre-manufacturing combined analysis of the gene signature and of PB AMC, could be used to plan trials evaluating CAR T cells versus other newly approved therapies such as bispecific antibodies.

Disease status at lymphodepletion was complete remission (CR, n=4, 13%), partial remission (n=6, 19%), and progressive disease (n=21, 68%) and patients received either tisagenlecleucel (n=20, 65%) or axicabtagene ciloleucel (n=11, 35%) . These findings indicate that the success of CAR-T therapy could be determined by the molecular characteristics and subpopulation distribution of each patient's PBMC. The diverse immune profiles of DLBCL patients might impact the effectiveness of their immune cells in generating successful CAR-T products or providing a conducive environment for CAR T cells to combat cancer. Furthermore, these findings emphasize the potential of scRNA-seq in evaluating PBMC from CAR-T patients prior to treatment, allowing the potential calculation of an "immune potency score" associated with the probability of a positive outcome from CAR-T treatment of DLBCL patients.

Methods Adult patients with primary or transformed LBCL treated with CD19-CAR-T cells, namely axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), between 2017 and 2022 were included in this single center retrospective study...Lymphodepletion was mostly cyclophosphamide and fludarabine (82.4%)...Additionally, we identified several factors that impact IR, which in turn shapes OS. In doing so, we show that CD4+ T lymphocytes are key players in disease response post-CAR-T and suggest that tracking CD4+ recovery following CAR-T may provide both diagnostic and therapeutic benefit.

Axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) are now FDA-approved for the treatment of tFL, but limited data are available on their clinical activity in patients (pts) with tFL since outcomes in those pts were not separately reported in registrational studies. CD19-targeting CAR-T cell therapy is effective for pts with relapsed/refractory tFL, including patients with characteristics of poor prognosis, with efficacy and toxicity profiles comparable to that observed in previous DLBCL studies. Unfortunately, pts who relapse post-CAR-T therapy have limited effective therapeutic options available, and this currently remains an unmet medical need within the field.

All received fludarabine and cyclophosphamide for lymphodepleting chemotherapy. Axicabtagene ciloleucel was the most common (76%) CAR-T product, followed by tisagenlecleucel in 16% of patients... CH was frequent (24%) in this cohort of CAR-T recipients and was associated with a higher risk of ≥2 CRS after CAR-T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR-T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis Acknowledgements: Funding through the CoH Hematological Malignancies Program Pilot Project Award. The authors acknowledge the work provided by CoH Center for Informatics, notably Research Informatics, and the utilization of the POSEIDON platform and the Honest Broker process.