Kokalaki, E;
Ma, B;
Ferrari, M;
Grothier, T;
Hazelton, W;
Manzoor, S;
Costu, E;
... Pule, M; + view all
(2023)
Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR.
Molecular Therapy
, 31
(7)
pp. 2089-2104.
10.1016/j.ymthe.2023.03.020.
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Abstract
CAR T cells recognizing CD19 effectively treat relapsed and refractory B-ALL and DLBCL. However, CD19 loss is a frequent cause of relapse. Simultaneously targeting a second antigen, CD22, may decrease antigen escape, but is challenging: its density is approximately 10-fold less than CD19, and its large structure may hamper immune synapse formation. The characteristics of the optimal CD22 CAR are underexplored. We generated 12 distinct CD22 antibodies and tested CARs derived from them to identify a CAR based on the novel 9A8 antibody, which was sensitive to low CD22 density and lacked tonic signaling. We found no correlation between affinity or membrane proximity of recognition epitope within Ig domains 3–6 of CD22 with CART function. The optimal strategy for CD19/CD22 CART co-targeting is undetermined. Co-administration of CD19 and CD22 CARs is costly; single CARs targeting CD19 and CD22 are challenging to construct. The co-expression of two CARs has previously been achieved using bicistronic vectors. Here, we generated a dual CART product by co-transduction with 9A8-41BBζ and CAT-41BBζ (obe-cel), the previously described CD19 CAR. CAT/9A8 CART eliminated single- and double-positive target cells in vitro and eliminated CD19- tumors in vivo. CAT/9A8 CART is being tested in a phase I clinical study (NCT02443831).
| Type: | Article |
|---|---|
| Title: | Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ymthe.2023.03.020 |
| Publisher version: | https://doi.org/10.1016/j.ymthe.2023.03.020 |
| Language: | English |
| Additional information: | © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | B-ALL, CAR screening, CAR sensitivity, CD19 CAR, CD22 CAR, Chimeric antigen receptor (CAR) T cell therapy, binder screening, dual targeting |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10169866 |
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