LaQuisa C. Hill, MD, on Relapsed or Refractory T-ALL: New Data on CD5 CAR T Cells

LaQuisa C. Hill, MD: The purpose of this study was a phase one clinical trial that was a dose escalation study using autologous CD5 CAR T for treatment of patients with relapse/ refractory T-cell ALL. In the initial cohort, we used our standard manufacturing practice that was overall very well-tolerated. However, in the eight patients initially treated, there were minimal responses seen with only one patient achieving a MRD positive remission. We subsequently analyzed the cell products and determined that the CAR T cells had a significantly exhausted phenotype as a result of chronic CAR signaling. Therefore, we implemented a manufacturing change to include the use of TKI inhibitors dasatinib and ibrutinib in order to inhibit the chronic CAR signaling and saw a significant improvement in the naive T-cell repertoire and significant reduction in the number of exhausted T-cells in the final product. In the next cohort, we treated a total of seven patients, all manufactured using the TKI inhibition. And amongst those patients there was a total of four MRD negative remissions achieved out of seven patients treated. The CAR T cell was well-tolerated in terms of CRS and ICANS. No grade-three events occurred. However, there was an increased risk of, or observation of, EBV reactivation with two patients developing PTLD. Currently it is unclear of the direct relationship to the CD5 CAR T cells manufactured with TKI. However, we plan to continue vigilant monitoring for this unexpected side effect and have instituted mitigation plans utilizing prophylactic rituximab as well as ensuring that patients have EBV-specific virus T cells available in the event that EBV reactivation occurs. Moving forward, we will continue to try and optimize the CAR T cell product both for efficacy and safety and are looking into alternative immune effector subsets, such as virus-specific T cells as the immune factor cell of choice, as well as considering use of third-party or off-the-shelf T cells from healthy donors.