Targeting of CD28 and CD38 as a potential novel therapeutic strategy for peripheral T-cell lymphomas.

The identification of new targets and therapeutic strategies for peripheral T-cell lymphomas (PTCLs), which often have an aggressive clinical course, is needed. Bi and trispecific antibodies allowing NK or T-cell engagement toward tumor T-cells are promising new approaches. We investigated CD28 and CD38 as potential new targets and evaluated the in vitro and ex vivo effects of an anti-CD38/CD28xCD3 trispecific antibody (SAR442257) as a proof of concept. Using immunohistochemistry, multiplex fluorescent labeling (n = 226), or flow cytometry (n = 18), CD28 and CD38 were expressed by tumor cells in 57% and 42% of cases, respectively, encompassing all PTCL entities studied, except anaplastic large-cell lymphomas. 29% of cases (46/160) expressed both targets. Overall, we found higher expression of CD38 in PTCLs putatively derived from cytotoxic/innate cells and of CD28 in PTCLs derived from adaptive helper T-cells, such as follicular helper T-cell lymphomas. SAR442257 induced a significant cytotoxic effect on PTCL-derived cell lines, primary cells, and tumor lymphocytes from patient-derived xenografted mice using in vitro assays versus null mutant trispecific antibodies. These data show that CD28 and CD38 represent new potential therapeutic targets and that their dual targeting covers most PTCL entities and is efficient in vitro.