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J2 - Cell Therapy and Cell-Based Gene Therapy Trails

6: Allogeneic NKT Cells Expressing a CD19-Specific CAR in Patients with Relapsed or Refractory B cell Malignancies: An Interim Analysis

Type: Oral Abstract Session

Presentation Details
Session Title: Clinical Trials Spotlight Symposium

T cells expressing CD19-specific chimeric antigen receptors (CARs) mediate high complete response rates in patients with B cell malignancies. However, autologous cell products are costly and time-consuming to produce and demonstrate variability in potency and toxicity. Monomorphic CD1d-restricted Vα24-invariant natural killer T cells (NKTs) are not alloreactive like HLA-restricted T cells and therefore can be made from allogeneic donors without risking graft-versus-host disease. We generated a bank of healthy donor NKTs that co-express a CD19-specific CAR, IL-15, and shRNA targeting beta-2-microglobulin and CD74 to downregulate HLA class I and II expression, respectively. Five lots of allogeneic CD19-CAR-NKTs have been produced for this bank with each lot averaging 14.8 ± 2.5 days in culture, yielding 1.18 - 2.27x10(10) cells per lot and an average NKT purity of 99.0% ± 1.02%. We are assessing the safety, persistence, and efficacy of this allogeneic product in ANCHOR (NCT00840853), a first-in-human phase 1 dose-escalation trial for patients with relapsed/refractory B cell non-Hodgkin's lymphoma (NHL) and relapsed acute B lymphoblastic leukemia (ALL). No dose-limiting or grade 2+ toxicities related to CAR-NKTs have been observed in patients treated on three dose levels (DLs): 1x107 (DL1), 3x107(DL2), and 1x108 (DL3) CAR-NKT cells/m2. So far, seven NHL patients have been infused on three DLs, and two ALL patients have been infused on DL1. Three NHL patients achieved an initial partial response four-to-six weeks after infusion that in two cases evolved into a complete response (CR)(patients NHL-2 and NHL-4) by three months post-infusion. Additionally, one ALL patient (ALL-1) achieved a CR with incomplete hematologic recovery. We detected expansion of CAR-NKTs in the peripheral blood of patients NHL-5 (DL2) and NHL-7 (DL3) that peaked one week after infusion, and CAR-NKTs were also found in biopsied tumor tissue from patient NHL-3 at one week and NHL-2 at five weeks post-infusion. In patient NHL-2, who achieved a CR at three months post-infusion, we detected a population of recipient NKTs that underwent a 2000-fold expansion event, with numbers peaking at six weeks post-infusion and remaining elevated through 12 weeks. Our data indicate that allogeneic CAR-NKTs are well tolerated and can mediate objective responses in relapsed/refractory NHL/ALL patients, suggesting that NKTs represent a promising platform for “off-the-shelf” cancer immunotherapy.

Plain Language Summary
T cells engineered with special tumor-targeting receptors, known as CARs, demonstrate significant potential in treating blood cancers. However, producing these cells individually for each patient is costly, time-consuming, and varies in effectiveness. To address these challenges, we have utilized a unique type of immune cell called natural killer T cells (NKTs). Unlike T cells from another person, NKTs do not trigger dangerous immune reactions. We have established a bank of CAR-modified NKTs from healthy donors. The safety and efficacy of these cells are being tested in a clinical trial involving patients with two types of blood cancer that have recurred after prior treatments. So far, the treatment has proven to be safe. Some patients have experienced a partial or complete response, signifying a reduction or disappearance of the cancer. These preliminary findings indicate that donor-derived NKTs might offer a versatile and effective approach for treating blood cancers.

Leonid S. Metelitsa, Amy N. Courtney, Carlos A. Ramos

Baylor College of Medicine, Houston, TX"

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