CAR-T Cells Session 1

VORTRAGSFOLIEN 1-8

CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy, in Relapsed/Refractory Multiple Myeloma.

Deepu Madduri, Jesus G. Berdeja, Saad Z. Usmani et al. 

Authors Conclusion: 

• Cilta-cel has a manageable safety profile at the recommended phase 2 dose

- CRS was mostly grades 1/2; median time to onset of CRS was 7 days (range, 1-12)

- CAR-T-related neurotoxicities occurred in 20 patients (20.6%); 10.3% had grade  3 or higher

• Low dose of cilta-cel yielded early, deep, and durable responses in heavily pretreated relapsed/refractory MM 

- 96.9% ORR, with sCR 67.0%

- Median PFS not reached; 12-month PFS rate was 76.6%, OS rate was 88.5%

• Cilta-cel is under further investigation in other populations of patients with MM in earlier-line settings - Outpatient administration is being studied in CARTITi.JDE-2 (NCT04133636) and CARTITUDE-4 (NCT04181827).

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Prophylactic Steroid Use With Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Large B-Cell Lymphoma

Olalekan O. Oluwole, Krimo Bouabdallah, Javier Munoz, et al al.

Authors Conclusion: 

• Prophylactic corticosteroids and early corticosteroid and/or tocilizumab intervention have the potential to improve the benefit/risk profile of CAR T-cell therapy: - Incidence of Grade 3 or higher CRS was lower in Cohort 6 (0%) than in Cohorts 1+2 (13 °/o) • Median CRS duration was shorter and time to CRS onset was delayed in Cohort 6 versus Cohorts 1 +2 • Notably, 27/40 patients (68°/o) in Cohort 6 did not experience CRS or NEs within 72 hours of axi-cel infusion.

- No negative impact on axi-cel efficacy or CAR T-cell expansion 

• No impact on ORRs. CR rates. and ongoing response rates at a median follow-up of 8.9 months

- Lower levels of inflammatory cytokines that are correlates of toxicities1 in Cohort 6 versus Cohorts 1+2

• Prophylactic corticosteroid use may affect the production of cytokines by various immune cells to a greater extent relative to CART-cell proliferative capability.

• Differences in rate of Grade 3 or higher CRS and time to onset of CRS observed between patients in Cohort 6 and Cohorts 1 +2 were maintained after propensity score-based matching, and response rates remained comparable and were corroborated by CAR T-cell levels - After propensity score-based matching, the incidence, severity, and onset of NEs were generally similar between Cohort 6 and Cohorts 1 +2

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Matching-Adjusted Indirect Comparison (MAIC) of Lisocabtagene Maraleucel (liso-cel) vs. Axicabtagene Ciloleucel (axi-cel) and Tisagenlecleucel in Relapsed/Redractory (R/R)  Large B-Cell Lymphoma (LBCL)

David G. Maloney, John Kuruvilla, Christopher P. Fox, et al.

Authors Conclusion: 

• MAIC-weighted outcomes suggest that liso-cel provides a well-balanced overall efficacy and safety profile for the treatment of R/R LBCL - Better efficacy and comparable safety vs tisagenlecleucel - Better safety and comparable efficacy vs axi-cel.

• Without head-to-head clinical trials, these indirect comparisons aimed to narrow between-study differences and create fair comparisons of the 3 CAR T cell therapies - Despite the rigorous process that identified clinically important factors, there is no guarantee that all relevant CAR T cell therapy clinical factors were included - Although TRANSCEND had the largest sample size tlhat enabled adjustments, not all factors identified in the process were included due to inconsistent reporting across trials.

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Strategies to increase CAR-T-cell safety and to prevent epitope masking in CAR+ B-cell leukemia blasts

Concetta Quintarelli

Authors Conclusion: 

• Although the presence of large amounts of CD 19+ cells in the starting material did not affect the transduction level of DPs, B leukemia blast contamination was found to inversely correlate with the time of manufacturing.
• CAR design affects the CIS masking of the target antigen.
• The presence of the suicide gene inducible caspase 9 in the construct allowed to control CAR+ leukemic cells in both in vitro and in vivo experiments.

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Contribution of Age and the HCT-CI to Predict CRS and ICANS Severity in NHL-Patients Receiving CD-19 CAR-T-cell Therapy

Jordan Gauthier, Ash Cearley, Paula Perkins, et al.

Authors Conclusion: 

• Tumor burden and CART-cell product type were strongly associated with CRS and ICANS severity • Age or HCT-CI did not improve CRS severity prediction in NHL patients treated with CD19 CART-cells • Age improved ICANS severity prediction and older age was associated with higher ICANS severity independently of the CART cell product and tumor burden

• Limitations:

Analyses underpowered to detect subtle effect sizes/interaction effects
HCT-Cl was designed for a different therapy (HCT) and different outcome (non-relapse mortality)

• Next steps:
Further improve models in larger/independent cohort+ incorporation of biomarkers

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Outcomes of Treatment With the CAR-T Cell Therapy Lisocabtagene Maraleucel in the Nonuniversity Setting: Initaial Results From the OUTREACH Study.

John E. Godwin, Michael Maris, Don A. Stevens, et al. 

Authors Conclusion: 

• Patients with R/R aggressive LBCL were successfully treated with liso-cel and monitored for CART cell therapy-related toxicities at nonuniversity medical centers in outpatient and inpatient settings using standard operating procedures and multidisciplinary teams

• Incidences of severe CRS and NEs in the overall study population were low, as was tocilizumab and/or corticosteroid use

• Grade 3 or higher CRS and NEs were reported in O and 3 patients (7%), respectively

• Liso-cel treatment resulted in a best ORR of 77% and a CR rate of 57% in the overall population

• Similar results were observed for outpatients and inpatients

• These data support the safety of liso-cel administration at nonuniversity medical centers and in the outpatient setting.

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Building of the Go-CAR-T Initiative to promote use of data collected from patients treated with CAR-T Cells at EU or EBMT-affiliated programs

Christian Chabannon

Authors Conclusion: 

• The registry is up and running

The number of registered patients treated with approved CAR-T cells is growing and is expected to grow even faster with the introduction of new CAR-T Cells on the market

Data are progressively maturing

• Rules to transparently access and use the data in the context of joint studies are progressively set in place

Actual studies are currently built to address the use of CAR-T cells for EU patients wit r/rDLBCL 

• Difficulties are real and must be overcome, but the stakes are high: we need a harmonized and central registry to avoid fragmentation and heterogeneity of data, with the ultimate goal of a global evaluation of the performances of this new class of therapeutics.

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Engineered CAR.CD123 NK cells as an innovative "off the shelf" strategy to treat CD123pos childhood Acute Myeloid Leukaemia

Simona Caruso

Authors Conclusion: 

1) CAR.CD123-NK cells show a strong antitumor activity not only against CD123 positive cell lines but also on primary malignant cells of AML patients.

2) CAR.CD123-NK cells don't significantly affect the primary hematopoietic precursor in healthy donor BM.

3) NK cells engineered with CAR.CD123 are able to mediate significantly antitumor responses against AML malignancies, in in vivo mouse model.

4) Ex-vivo expanded CAR.CD123-NK cells could be universally applied for 'off-the-shelf' immuno-gene­therapy and their innate allo-reactivity can be safely harnessed to potentiate allogeneic cell therapy