Optimizing Hematopoietic Stem Cell Transplantation For The Treatment Of Hematological Malignancies

Washington University, Saint Louis MO

Investigators

Linked publications & trials

Abstract

Project Summary/Abstract Hematopoietic cell transplantation (HCT) is the only curative therapy available for many hematological malignancies as well as some non-malignant diseases such as hemoglobinopathies, autoimmune diseases, and inherited metabolic disorders. Key obstacles to the success of HCT include collecting optimal numbers of hematopoietic stem cells (HSCs) for HCT and/or gene therapy, toxicities due to nontargeted chemotherapy- and irradiation-based conditioning, control of graft-versus-host disease (GVHD) after allogeneic HCT (allo-HCT) and treating disease recurrence both before and after HCT. I have focused my career over the last 30 years on overcoming these obstacles to HCT using a translational research approach. In the last project period, I designed, led, and/or completed correlative studies for 15 clinical trials, including studies that led to the FDA- approval of ruxolitinib (JAK1/2 inhibitor) for the treatment of steroid refractory GVHD in 2019 and motixafortide (CXCR4 inhibitor) plus G-CSF for HSC mobilization for autologous HCT in multiple myeloma (MM) in 2023. I completed first-in-human clinical trials of the bispecific antibodies Flotetuzumab and AMV564 in patients with relapsed or refractory (r/r) AML, treated the first patient with multiple myeloma (MM) with our home-grown CS1 chimeric antigen receptor T cell (CART) produced in our new GMP facility, developed an ‘off-the-shelf’ universal allogeneic CART targeting CD7 (UCART7) that lacks CD7 and TRAC to minimize the risk of fratricide and GVHD, respectively, and completed a global (12 sites; 7 domestic and 5 international) Phase I trial testing UCART7 in patients with r/r T-ALL/LBL that led to an upcoming Phase II registration trial. I also discovered a novel conditioning strategy combining CD45- or cKit-targeted antibody-drug conjugates (ADCs) with JAK1/2 inhibitors to enable robust donor engraftment in fully major histocompatibility complex (MHC)-mismatched mice. My research program over the next seven years will continue to use our strengths in preclinical modeling, cancer genomics, CART immunotherapy and the design and execution of early phase clinical trials to 1) develop novel very late antigen 4 (VLA-4) inhibitors for HSC mobilization, gene therapy and GVHD prevention, 2) test if targeting human CD45 or cKit with ADCs or human CD47 and cKit with naked antibodies, inhibitors, or bispecific molecules in the presence of JAK1/2 inhibitors can serve as effective conditioning regimens in humanized mouse models and primates, and 3) develop novel CART against T-ALL, AML, and MM. Three obstacles to successful CART therapy are: 1) limited CART expansion and persistence, 2) CRS/ICANS, and 3) on-target/off-tumor toxicities. I will test if long-acting cytokines of IL-7, IL-15 and/or IL-21 enhance CART expansion, persistence, and function. To address toxicity, we will continue testing duvelisib in humans and define the mechanism/s whereby PI3K-γ,δ inhibitors, JAK1/2 inhibitors and CD40L/CD40 blockade reduces CRS/ICANS without inhibiting CART. To minimize on-target/off-tumor toxicities, we will engineer epitopes on CART and/or donor HSCs used in allo-HCT to provide selective resistance to CART without altering the function of the edited protein.