Clinical Development of Novel Therapies for Acute Lymphoblastic Leukemia

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Project 1: Development of Novel CAR T-cells for B-cell Acute Lymphoblastic Leukemia Specific Aim 1: Test Novel CAR T-cell constructs targeting non-CD19 antigens in ALL From the very inception of the CD22 targeted CAR T-cell trial, there was clear demonstration that this construct was clinically active in patients with CD19 negative/dim/positive disease and that modulation of CD22 antigen expression was an important determinant of durable CAR T-cell responses and/or relapse. My prior efforts in establishing a baseline for CD22 expression in children with r/r ALL, in collaboration with the NCI flow cytometry team, whose group is able to quantify antigen expression, were critical to understanding mechanisms of resistance to CD22 CAR. Indeed, antigen expression density impacting effective CAR T-cell response first became clinically apparent in this trial. Based on the response rate, we received FDA granting of "Breakthrough Therapy Designation" for our CD22 CAR T-cell construct (August 2019). This designation, based on an application that I fully authored, arises from our study's 70% complete remission rate and my section's cumulative experience with the largest cohort of ALL patients treated by CD22 CAR T-cell targeting. The FDA breakthrough therapy designation is for the treatment of children and young adults, 3-30 years of age, with CD22+ B-cell ALL that is either refractory or in second or later relapse, and that is either CD19 negative or relapsed/refractory to CD19 targeting. This represents the first designation for an effective salvage therapy specifically for children and young adults who fail CD19 targeting and encompasses the goals of our section: to develop novel therapies for unmet needs. Based on a vested interest in exploring limitations of CD22 targeting and mechanisms of resistance, over the past year in the past year I have embarked on studying the role of splicing as a mechanism of CD22 loss following inotuzumab treatment-- with a 2022 "Bench to Bedside" award as a Cancer Moonshot supplement (collaboration with Dr. Andrei Thomas-Tikhonenko), and am leading an internal consortium to identify mechanisms of CD22 escape following CD22-targeted therapies--FLEX award with Drs. Naomi Taylor and Jack Shern (POB). Additional collaborative efforts to further explore the biology of resistance are underway and include explorations of the impact of various modalities of manufacturing or elements of the starting apheresis material on toxicity (co-led by Dr. Naomi Taylor). A registration study for the use of CD22 CAR T-cells for adults with diffuse large B-cell lymphoma will be actively accruing by the end of the 2023 calendar year. Specific Aim 2: Evaluate the Ability of Combinatorial Targeted Strategies to Prevent Antigen Negative Relapse Despite the high degree of efficacy of CD22 CAR T-cells, antigen escape remained problematic and was the leading cause of relapse following single-antigen targeting. Based on the hypothesis that simultaneous targeting of two antigens will help prevent antigen escape as a mechanism of relapse by covering a broader range of the phenotypic variability in leukemia and avoid selection for a dim or negative population, our group has been systematically testing novel combinatorial CD19/22 bispecific CAR T-cell constructs in pediatric ALL by translating constructs developed in the POB. Our first experience with CD19/CD22 CAR T-cells, a trial on which I fully led the clinical development and opened in 2018, has allowed us to identify both key salient features and limitations of this novel construct and to compare this to our prior trials with single antigen targeting. While highly effective in inducing remission, this contrast suboptimally targeted CD22 and lacked persistence, leading to development of a subsequent construct which is currently in the clinic. Based on early experience, this novel construct has improved persistence and efficacy and will be further explored. Specific Aim 3: Interrogate the toxicity profile of novel CAR T-cell constructs. Alongside the development of novel CAR T-cell constructs, a major focus of my program is to comprehensively evaluate CAR T-cell associated toxicity. This incorporates deep interrogation of the underlying biology and pathophysiology to better understand the clinical manifestations that patients experience and how to best treat them. Active ongoing efforts include the exploration of how changes in manufacturing may impact outcomes. More recently, I have led the field in defining and describing hemophagocytic lymphohistiocytosis like toxicities in the context of CAR T-cells and have ongoing efforts to further explore this. Our recent publication helps to firmly establish HLH as a CAR T-cell associated toxicity, laying a foundation for future efforts. Our team is also vested in more rigorously understanding neurotoxicities and why they may differ across constructs. In this regard, we recently reported on the lack of CD22 expression on mural cells as a potential factor that may explain why CD22 associated neurotoxicity is lower than what has been seen with CD19 CAR T-cells (where CD19 is expression on brain mural cells which line the blood brain barrier). Other efforts in exploring toxicity and optimization of patient outcomes include incorporation of patient reported outcomes on our studies, and a concentrated effort in collaboration with extramural investigators (led by me) to dedicate research to the study of late effects.