In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5573-5573
Abstract:
Introduction Autologous CAR-T has improved clinical outcomes in hematological malignancies; however need remains to improve the toxicities, relapse rates, treatment delays and costs. ACE1831 is a novel, off-the-shelf Antibody Conjugated Effector cell therapy with aCD20 linked to gd T cells by selective proprietary DNA aptamers to activation receptors without genetic modification. Data for in vitro/in vivo pre-clinical studies are presented. Methods γδ T cells were expanded from healthy donor PBMCs by cytokine stimulation and αβ T cell depletion. Both γδ T cells and αCD20 were covalently linked to selected DNA aptamers that enable conjugation, and cryopreserved. ACE1831 was evaluated for phenotype and antibody conjugation by flow cytometry, cytotoxicity and cytokine production by 4-hour co-culture with CD20+ Raji cells, and for in vivo anti-tumor activity and weight loss using SCID-Beige mice inoculated IV with 1 x 105 Raji cells, 4 doses of 1 x 107 ACE1831 on days 0, 3, 7, 10, and monitored for 123 days. All studies used cryopreserved ACE1831. Results gd T cells of ACE1831 were expanded & gt;10,000 fold with & gt;95% viability, & gt;85% Vδ2 purity, and & lt;0.03% αβ T cell impurity. γδ T cells expressed high levels of CD56, CD16, NKG2D and CD69 and low levels of PD-1 and KIRs. Following αCD20 conjugation and cryopreservation, ACE1831 drug product batches retained & gt;90% viability and cytotoxicity against CD20+ Raji cells. In the presence of cell growth media, about 30% and 10% of αCD20 were retained on the cell surface at 24 and 48 hours, respectively, and at 24 and 48 hours, ACE1831 elicited 100% and 85% specific lysis against Raji cells. At 72 hours, specific lysis was 35%; however, in combination with obinutuzumab (1,000 ng/mL), ACE1831 provided 95% specific lysis against Raji cells. Co-cultured with Raji cells, ACE1831 produced 10 times more IFNγ and TNFα than unconjugated γδ T cells, but no measurable IL-6. When co-cultured with allogeneic PBMCs, ACE1831 showed no cytotoxicity towards PBMCs and the mixture showed no increase in IFNγ, TNFα, GM-CSF, IL-2, IL-4, IL-8, IL-6, and IL-10 levels compared to the PBMCs only group. ACE1831 showed persistence in vivo for & gt;14 days after a single dose of 1 x 107 AC1831 in non-tumor inoculated SCID-Beige mice. Tumor inoculated mice treated with 4 doses of ACE1831 survived 123 days without weight loss or tumor relapse based on bioluminescence and necropsy, while mice treated with γδ T survived & lt;40 days due to tumor progression. Conclusion ACE1831, a aCD20-armed allogeneic γδ T cell product, represents a novel approach for off-the-shelf treatment for B cell malignancies. Specifically, this product candidate can offer high levels of anti-tumor activity that is extended with soluble antibody using native Fc receptor expression, and may have a low risk of GvHD and IL-6 related toxicity. These data support future clinical studies in this setting. Citation Format: Tai-Sheng Wu, Hao-Kang Li, Ching-Wen Hsiao, Yi-Hung Ou, Zih-Fei Cheng, Hsiu-Ping Yang, Sen-Han Yang, Chia-Yun Lee, Yan-Liang Lin, Thorsten Graef, Sai-Wen Tang, Sonny Hsiao. ACE1831: A novel allogeneic αCD20-conjugated Vδ2 gamma delta T product for non-Hodgkin’s lymphoma [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5573.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-5573
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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