Abstract 4019: Development of mRNA chimeric antigen receptor T cells targeting MET in aggressive B-cell lymphomas

Abstract

Abstract Multiple versions of CAR T cells targeting the cell surface protein CD19 are approved by the FDA to treat refractory B-cell malignancies. However, durable remissions range from 60% in B-cell leukemias to 40% in B-cell lymphomas. Major reasons for resistance to CD19-CAR treatment relate to heterogeneous or loss of CD19 expression. In addition, CD19-CAR leads to B-cell depletion which increases the risk for infection. These limiting factors necessitate research into alternative targets for CAR therapy against B-cell lymphomas.Using a large data set from clinical trials, we found that approximately 30-70% of diffuse large B-cell lymphomas (DLBCL) express MET. We hypothesize that these MET-positive B-cell lymphomas can potentially be targeted with chimeric antigen receptor (CAR) T-cells against MET receptor. We constructed a second-generation anti-MET-CAR by fusing the scFv fragment of an anti-MET monoclonal antibody with the human CD28 hinge/transmembrane/cytoplasmic domain and CD3ζ cytoplasmic domain. Stable MET-CAR Jurkat cells showed increased CD69 expression upon stimulation by MET-positive lymphoma cell lines such as Karpas-422 and OCI-LY3. Using primary human T cells, we further demonstrated that the mRNA MET-CAR T-cells mediated cytotoxicity against DLBCL cell lines. Of note, while CD19-CAR T-cells showed only low level of cytotoxicity against the CD19-/MET+ OCI-LY3 cell line, MET-CAR T cell was able to mediate substantial tumor cell lysis.In summary, the preliminary data demonstrate that MET-CAR is capable of mediating cytotoxicity against MET-positive DLBCL. Some cell lines such as OCI-LY3 are negative for CD19 but positive for MET expression, and MET-CAR is capable of mediating cell lysis while CD19-CAR is ineffective. These results suggest that some large B-cell lymphomas negative for CD19, either intrinsic or secondary to loss of CD19 as a result of resistance mechanism, may show MET expression and will likely benefit from MET-targeted immunotherapy. Citation Format: Po-Han Chen, Rianna Raghunandan, Markus Muschen, Samuel G. Katz. Development of mRNA chimeric antigen receptor T cells targeting MET in aggressive B-cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4019.