Project 1: Chimeric antigen receptor T-cell therapy for T cell malignancies

Project 1 Co-Leaders

John F. DiPersio, MD, PhD (WUSM) (Basic Science Leader)

Mike Rettig, PhD (WUSM) (Basic Science Co-Leader)

Armin Ghobadi, MD (WUSM) (Clinical Co-Leader)

Adult patients with T cell acute lymphoblastic leukemia (T-ALL) exhibit long-term event-free survival of ~40%. Patients with r/r T-ALL have approximate one year and five-year overall survival rates of only 25% and 11%, respectively. Thus, a significant unmet medical need exists for the treatment of r/r T-ALL. We were the first to develop a novel fratricide resistant ‘off-the-shelf’ universal allogeneic CART that targets CD7+ T cell malignancies (UCART7).

Aim 1.

We will perform a phase 1 trial evaluating anti-CD7 allogeneic CAR-T (UCART7) in r/r T-ALL (NCT04984356). This first-in-man trial of a universal allogeneic CART to CD7 will consist of a dose escalation phase to determine safety, tolerability, and the recommended phase 2 dose (RP2D) and then an expansion phase at the RP2D to assess efficacy.  These initial clinical data will be used to design a future registration study with the hope of getting FDA approval of UCART7 as the first allogenic CART for the treatment of r/r T-ALL. Samples will be obtained to correlate biomarkers (serum cytokines, flow cytometry and expression of specific genes in UCART) with toxicity, efficacy and expansion of UCART7.

Aim 2.

We will attempt to enhance the efficacy of UCART7 using a series of novel interventions.  These include assessing the role of long-acting cytokines such as NT-I7, N-803, membrane bound IL-15 and membrane bound IL-7.  Since CART cell therapy is also associated with life threatening toxicities such a cytokine release syndrome (CRS) we will develop in vitro and preclinical models of CRS and use specific kinase inhibitors to inhibit CRS without limiting CART function.  Finally, in order to address UCART7 resistance due to CD7 antigen loss we will develop and fratricide-resistant CD2 and CD7 dual-targeted UCART (UCART2/7).

This project will further the development of a viable ‘off-the-shelf’ therapy for the treatment of T-ALL and potentially other malignancies expressing CD7 or CD2.  Additionally, the work proposed here may provide a strategy to treat relapse after UCART7 and prevent life-threatening CRS.