CAR-T Cells Session 2

VORTRAGSFOLIEN 1-8

CD19 CAR T Therapy n children with r/r ALL: adaptive split dosing improves safety and maintains efficacy of the approach

Olga Molostova

The authors conclude:

• Risk-adapted CAR-T dosing strategy allowed to maintain a high rate of remission and to reduce the risk of severe toxicity among patients with high initial leukemia burden.

• Single dose of fresh CD19 CAR-T at 0.lx10⁶/kg induced MRD-negative CR among patients with high leukemia burden.

• Locally manufactured CAR-T approach allows for flexible and robust delivery to patients in need.

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Cytokine Release Syndrome in Patients With Relapsed/Refractory Multiple Myeloma Treated with Ciltacabtagene Autoleucel in the Phase 1b/2 CARTITUDE-1 Study

Andrzeij Jakubowiak, Yi Lin, Thomas Martin, et al.

The authors conclude:

• CRS after cilta-cel treatment was low grade and manageable in most patients with R/R MM

• Increasing severity of CRS and supportive measures for CRS

- Were associated with peak IL-6, IL-10, and IFN-y cytokine levels

- Were not associated with baseline or peak CRP and ferritin levels

• CRP and ferritin trends follow cytokine levels and can be useful in monitoring CRS

• Due to the low rate (5%) of grade 3 or higher CRS and median time to CRS onset of 7.0 days, outpatient dosing of cilta-cel is being explored in the phase 2 CARTITUDE-2 (NCT04133636) and phase 3 CARTITUDE-4 (NCT04181827) studies.

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Pharmacological Profile and Clinical Outcomes of KTE-X19 by Prior Bruton Tyrosine Kinase Inhibitor Exposure or Mantle Cell Lymphoma Morphology in Patients with Relapsed/Redractory Mantle Cell Lymphoma in the ZUMA-2 Trial

Michael L. Wang, John M. Rossi, Javier Munoz, et al.

The authors conclude:

• Pretreatment patient and product characteristics were largely comparable across MCL morphologies and subsets with different prior therapies

• High rates of response were achieved across MCL morphology and prior BTKi subgroups

• The translational findings corroborate the clinical findings regarding toxicities across these groups

- The rate of Grade 3 or higher neurologic events and CRS trended lower in patients who had not received prior ibrutinib

- Patients previously treated with lbrutinib showed trends toward relatively increased CAR T-cell expansion and circulating inflammatory cytokines and chemokines

- Patients previously treated with acalabrutinib showed a trend toward decreased CAR T-cell expansion and circulating T1-related cytokines and chemokines.

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Real-World Experience of Axicabtagene Ciloleucel for the treatment of Relapsed or Refractory Large B-Cell Lymphoma in Spain

Mi Kwon, Rebeca Bailén, Lucia Lopez Corral, et al.

The authors conclude:

• This Spanish multicenter retrospective analysis shows encouraging results of axi-cell treatment in patients with R/R aggressive B-cell lymphoma in the real-world setting

• Significant toxicity events were less frequent than those reported in the pivotal trial and previous real-world studies, however, deaths associated with toxicity occurred

• With a still limited follow-up time, response outcomes are favorable

• Further analysis is needed to identify prognostic factors.

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Humoral response to pneumococcal antigens declines after CD19-targeted CAR T cell therapy

Dasom Lee, Michael Jain, Julio Chavez, et al.

The authors conclude:

• In lymphoma patients undergoing CD19 CAR T cell therapy, pneumococcal lgG titers were low at baseline and decreased at day+90 and day+180.

• PCV13 vaccination at day+90 (n=9) or day+180 (n=7) after CART cell therapy did not induce protective humoral immunity against pneumococcus.

• Protective humoral immunity at baseline may be the key to ongoing protection in the first year after CAR T cell therapy.

• A very small percentage of our patients received IVIG infusion, and results may differ in patients that receive IVIG as standard practice post CD19 CART.

• Ongoing work in our laboratory will determine if PCV13 vaccination after CART cell therapy induces T cell responses against the vaccine's adjuvant protein, and if the recovery of normal B cells post CAR T allows for humoral response to vaccination.

• Clinical trials are needed to determine the optimal schedule of vaccination, before or after CAR-T, to develop protective immunity against pneumococcus or other infections.

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Decreased Neuroprotective Analytes on Day of Infusion of Chimeric Antigen Receptor (CAR) T cells are Associated with Neurotoxicity

Madhavi Lakkaraja, Kinga Hosszu, Devin McAvoy, et al.

The authors conclude:

• Neurotoxicity is a major side effect of CAR T cells.

• Pilot data suggests 13 analytes identified in patients who developed neurotoxicity which was lower at baseline (ECE 1, COH15, KLB, GPNMB, KIR2DL3, IMPA 1, CLSTN 1, LEPR, FGFR2, NPM1, IL32, IL3RA, GGTS).

• These analytes are all known to be neuroprotectlve.

• The 4 analytes, which increased from baseline in patients who developed neurotoxlclty, have been associated with cellular stress and one is neuroprotective.

• These findings suggest that patients at risk for neurotoxicity may be identified at the infusion of CAR-T cells, which can potentially guide to give pre-emptive treatment.

• Results to be confirmed in a larger dataset.

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Comparison of two kinds of ATG on outcomes of haplo- SCT for Refractory/Relapsed and high-risk B-Cell ALL after CAR-T therapy

Yan-Li Zhao, Jian-Ping Zhang, De-Yan Liu, et al.

The authors conclude:

Both types of ATG {ATLG versus rATG) led to comparable clinical outcomes with respect to GVHD prophylaxis and viral infection in this cohort of relatively homogenous patient population treated with CD19 CAR-T followed by bridging to haplo-SCT with TBI.

Larger, randomized clinical studies are currently underway to further confirm these results.

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A GD-2 specific CAR-T cells incorporating CD28.4-1BB costimulatory domains for treatment of GD2+ sarcomas

Antonio Camera

The author concludes:

• GD2 disialoganglioside is abundantly expressed in pediatric sarcoma cells, making it a suitable target for anti-GD2 CAR-T cell approach
• GD2-CAR T cells showed a significant anti-sarcoma activity in both in vitro and in vivo models
• Infusion of GD2-CAR T cells in sarcoma patients was associated with a high level of expansion of the drug product, as well as with significant control of the tumor.