Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2020-10-05

AUTHORS

Nirav N. Shah, Bryon D. Johnson, Dina Schneider, Fenlu Zhu, Aniko Szabo, Carolyn A. Keever-Taylor, Winfried Krueger, Andrew A. Worden, Michael J. Kadan, Sharon Yim, Ashley Cunningham, Mehdi Hamadani, Timothy S. Fenske, Boro Dropulić, Rimas Orentas, Parameswaran Hari

ABSTRACT

Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies1–5. Despite impressive outcomes, relapse with CD19− disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB–CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 105–2.5 × 106 cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 106 cells per kg was chosen for expansion. Grade 3–4 cytokine release syndrome occurred in one (5%) patient, and grade 3–4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 106 cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse. More... »

PAGES

1569-1575

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41591-020-1081-3

DOI

http://dx.doi.org/10.1038/s41591-020-1081-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1131424617

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/33020647


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