CD28 and CD38 Identified as Novel Targets for Peripheral T-Cell Lymphoma Therapy
CD28 and CD38 have been identified as new therapeutic targets for peripheral T-cell lymphomas, with a trispecific antibody showing in vitro efficacy. The targets are expressed in 57% and 42% of PTCL cases respectively, covering most entities. Separately, low CD38 expression on circulating tumor-reactive T cells predicts better response to immune checkpoint inhibitors in lung cancer.
Researchers have identified CD28 and CD38 as new potential therapeutic targets for peripheral T-cell lymphomas (PTCLs), with a trispecific antibody showing promising in vitro efficacy. The study found that CD28 and CD38 were expressed by tumor cells in 57% and 42% of PTCL cases respectively, with 29% of cases expressing both targets, covering most PTCL entities except anaplastic large-cell lymphomas.
Using immunohistochemistry, multiplex fluorescent labeling, or flow cytometry across 226 cases, the research revealed 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. An anti-CD38/CD28xCD3 trispecific antibody (SAR442257) induced a significant cytotoxic effect on PTCL-derived cell lines, primary cells, and tumor lymphocytes from patient-derived xenografted mice in in vitro assays compared to null mutant trispecific antibodies.
Separately, another study analyzing circulating tumor-reactive T cells (cTR-Ts) in non-small cell lung carcinoma patients found that pre-treatment cTR-Ts in responders to immune checkpoint inhibitors were characterized by relatively low expression of exhaustion-related CD38. Following the first dose of treatment, cTR-Ts of responders transitioned toward a TCF7+ stem-like phenotype, suggesting that the phenotypic state and transition of cTR-Ts may reflect their functional potential after tumor infiltration and are associated with therapeutic outcomes.
The identification of CD28 and CD38 as targets represents a significant advance for PTCLs, which often have an aggressive clinical course and require new therapeutic strategies. Bi and trispecific antibodies allowing NK or T-cell engagement toward tumor T-cells are promising new approaches for these challenging malignancies.