Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas

Daniel Atar; Anna-Sophia Mast; Sophia Scheuermann; Lara Ruoff; Christian Martin Seitz; Patrick Schlegel

doi:10.3390/biomedicines10102420

Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas

Biomedicines. 2022 Sep 28;10(10):2420. doi: 10.3390/biomedicines10102420.

Authors

Daniel Atar¹, Anna-Sophia Mast¹, Sophia Scheuermann^{1

2}, Lara Ruoff¹, Christian Martin Seitz^{1

2}, Patrick Schlegel^{1

2

3

4

5}

Affiliations

¹ Department of Pediatric Hematology and Oncology, University of Tuebingen, 72076 Tuebingen, Germany.
² DFG Cluster of Excellence 2180 Image-Guided and Functional Instructed Tumor Therapy (iFIT), University of Tuebingen, 72076 Tuebingen, Germany.
³ School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia.
⁴ Cellular Cancer Therapeutics Unit, Children's Medical Research Institute, Sydney 2145, Australia.
⁵ Department of Pediatric Hematology and Oncology, Westmead Children's Hospital, Sydney 2145, Australia.

Abstract

CD19CAR T cells facilitate a transformational treatment in various relapsed and refractory aggressive B-lineage cancers. In general, encouraging response rates have been observed in B-lineage-derived non-Hodgkin's lymphomas treated with CD19CAR T cells. The major cause of death in heavily pretreated NHL patients is lymphoma progression and lymphoma recurrence. Inefficient CAR T cell therapy is the result of the limited potency of the CAR T cell product or is due to loss of the targeted antigen. Target antigen loss has been identified as the key factor that can be addressed stringently by dual- or multitargeted CAR T cell approaches. We have developed a versatile adapter CAR T cell technology (AdCAR) that allows multitargeting. Screening of three different B-lineage lymphoma cell lines has revealed distinct immune target profiles. Cancer-specific adapter molecule combinations may be utilized to prevent antigen immune escape. In general, CD19CAR T cells become non-functional in CD19 negative lymphoma subsets; however, AdCAR T cells can be redirected to alternative target antigens beyond CD19, such as CD20, CD22, CD79B, and ROR-1. The capability to flexibly shift CAR specificity by exchanging the adapter molecule's specificity broadens the application and significantly increases the anti-leukemic and anti-lymphoma activity. The clinical evaluation of AdCAR T cells in lymphoma as a new concept of CAR T cell immunotherapy may overcome treatment failure due to antigen immune escape in monotargeted conventional CAR T cell therapies.

Keywords: B-cell lymphoma; adapter CAR T cell; combinatorial immunotargeting; immune escape.

Grants and funding

The authors acknowledge financial support by the Deutsche Forschungsgemeinschaft DFG (German Research Foundation) to P.S. and C.M.S. (project number 411791562) and the iFIT Cluster of Excellence (EXC 2180) funded by the DFG.