INV07
Understanding mechanisms of response and resistance of CAR-T cells in hematological malignancies
F Prosper 1 2 3 4 J R Rodriguez-Madoz 1 2 3 4
1: Hemato-Oncology Program. Cima Universidad de Navarra. IdiSNA. Pamplona, Spain. 2: Hematology and Cell Therapy Department. Clinica Universidad de Navarra, IdiSNA. Pamplona, Spain. 3: Cancer Center Clinica Universidad de Navarra (CCUN). Pamplona, Spain. 4: Centro de Investigacion Biomedica en Red de Cancer (CIBERONC). Madrid, Spain.
Therapeutic strategies based on CAR-T cells have revolutionized cancer immunotherapy, representing a promising option for relapsed/refractory MM patients. Nevertheless, despite the high remission rates observed in hematological malignancies a significant number of patients still relapse. Additional limitations of CAR-T cell therapies associated with high costs or with the limited efficacy observed in patients with solid tumors require new strategies. In my presentation I will described current published and unpublished results obtained in our laboratory that addresses some of these current limitations. Using gene editing tools we have developed an allogeneic CAR-T cells against CD33 HSPC and demonstrate the possibility of generating a non immunogenic product for treatment of AML with the same efficacy as an autologous CAR-T cells. In collaboration with the immunology program of CIMA we have identified a potential extracellular matrix component that provides a potential CAR-T cell target for patients with hepatocarcinoma. Finally, using transcriptional approaches at the single cells level, we have identified potential mechanisms of response and resistance in patients treated with BCMA and CD19 CAR-T cells, as well as regulatory mechanisms behind transcriptional differences observed between patients with partial vs complete response. More importantly, by coupling scRNAseq and scTCRseq technologies with novel machine learning models, we were able to identify a mechanism and its molecular drivers that could promote CAR-T cell dysfunction and would represent a potential target to be modulated for the development of improved CAR-T therapies.
References
Rodriguez-Marquez P, et al. CAR density influences antitumoral efficacy of BCMA CAR Tcells and correlates with clinical outcome. Sci Adv. 2022 Sep 30;8(39):eabo0514. doi:10.1126/sciadv.abo0514. Epub 2022 Sep 30.
Martín-Otal C, et al. Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells. J Immunother Cancer. 2022 Aug;10(8):e004479. doi: 10.1136/jitc-2021-004479.