Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma.

Abstract

The reprogramming of a patient's immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥108/meter2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.

• Authors: Karin Straathof, Barry Flutter, Rebecca Wallace, Neha Jain, Thalia Loka, Sarita Depani, Gary Wright, Simon Thomas, Gordon Weng-Kit Cheung, Talia Gileadi, Sian Stafford, Evangelia Kokalaki, Jack Barton, Clare Marriott, Dyanne Rampling, Olumide Ogunbiyi, Ayse U Akarca, Teresa Marafioti, Sarah Inglott, Kimberly Gilmour, Muhammad Al-Hajj, William Day, Kieran McHugh, Lorenzo Biassoni, Natalie Sizer, Claire Barton, David Edwards, Ilaria Dragoni, Julie Silvester, Karen Dyer, Stephanie Traub, Lily Elson, Sue Brook, Nigel Westwood, Lesley Robson, Ami Bedi, Karen Howe, Ailish Barry, Catriona Duncan, Giuseppe Barone, Martin Pule, John Anderson
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 571 (11 25 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 33239386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen

Topics

• Child
• Humans
• Immunotherapy, Adoptive
• Neoplasm Recurrence, Local
• Neuroblastoma (therapy)
• Receptors, Antigen, T-Cell (genetics)
• Receptors, Chimeric Antigen (genetics)
• T-Lymphocytes
• Tumor Microenvironment