Development of Novel Therapies for Acute Lymphoblastic Leukemia

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Overall summary: The most active efforts over the past several years have been directed to advancing CAR T-cell therapies. Based upon POB efforts in CD19 CAR T-cell and CD22 CAR T-cell trials, my team has taken a lead in the conduct of novel CAR T-cell based trials. This has provided the foundation for future iterations of CAR T-cell therapies, particularly as we move towards combinatorial targeting strategies and trials targeting novel antigens. CD22 CAR T-cells: Based on our experience to date, we are the first group to demonstrate clinical activity of CD22 CAR T-cells and have the largest experience to date. Our follow up manuscript describing our research outcomes was published in the Journal of Clinical Oncology in 2020 and we continue to explore how to further optimize this therapy. Our 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, the role of antigen expression density impacting effective CAR T-cell response first became clinically apparent in this trial. Through ongoing efforts, we have now enrolled and treated over 80 subjects on this trial, the majority of whom had received prior CD19-targeting. We have incorporated new scientific aims, opened new treatment cohorts, and implemented novel toxicity mitigating strategies, including those that address hemophagocytic lymphohistiocytosis (HLH)-like manifestations of CAR T-cell therapy. Importantly, we have identified unique aspects of CD22 CAR T-cell targeting that are distinct from those reported in CD19 targeting. We remain deeply invested in exploring the role of a minor manufacturing change on toxicity and are systematically exploring other attributes of CAR toxicity, which are particularly relevant as the field of targeted immunotherapies expands to improve outcomes for other types of refractory cancers and goes beyond CD19 targeting. Perhaps the greatest recognition of the impact of this work is FDA granting of Breakthrough Therapy Designation for our CD22 CAR T-cell construct (August 2019) and we are working to make this therapy more broadly available. 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 the experiences with a clinically active CD22 CAR T-cell construct, we learned that targeting a different antigen on the same malignancy can have unique aspects on toxicity. Furthermore, in the context of this clinical trial, a single change was made to the upfront selection of the apheresis product prior to CAR T-cell manufacturing with no other downstream changes. Interestingly, this led to a heightened CAR-mediated inflammatory response necessitating a dose modification. Based on these two observations, along with the breakthrough therapy designation, current and future research efforts are focused on 1) Developing a pivotal CD22 CAR T-cell trial; 2) Enhancing the understanding of the pathophysiology that led to the unique characteristics of the toxicity profile of CD22 targeting and 3) Evaluating the impact of manufacturing on CAR T-cell responses. CD19/22 CAR: Due to the risk of antigen negative escape following single antigen targeted strategies and building upon our prior experiences with CD19 and CD22 targeting, a combinatorial CAR T-cell approach to prevent antigen negative relapse was developed in the Pediatric Oncology Branch. Utilizing a bispecific CAR approach to simultaneously target two antigens, the goal is to cover a broader range of the phenotypic variability in leukemia and avoid selection for a dim or negative population, with the ultimate goal to prevent antigen escape as a mechanism of relapse. This novel CAR construct was fully developed in the POB/NCI and tests the functionality of a simultaneous CD19/CD22 targeted approach for the treatment of patients who are both CD19 and CD22 positive. Notably, the two ScFv incorporated into this bispecific construct were derived from the active CD19 and CD22 CAR constructs that were both individually tested and confirmed to have efficacy as single antigen targeted CAR T-cells in the POB/NCI. This trial is now actively accruing, and a second version of a combinatorial construct is planned to go out into the clinic by early 2022. We have demonstrated both feasibility of manufacturing and a high response rate. Active efforts include understanding how different CAR T-cell promoters may impact CAR response, and how prior CAR T-cell therapy may impact future CAR T-cell options. TSLPR CAR T-cells: BCR-ABL1-like or Ph-like ALL is a high-risk subgroup of patients with ALL, defined by an activated kinase profile similar to that of BCR-ABL1- rearranged (Ph+) ALL, yet lacking the specific translocation. Thymic Stromal Lymphopoetin (TSLP) is a cytokine that plays a critical role in regulation of the immune response and in the differentiation of hematopoietic cells. It binds to the TSLP receptor (TSLPR), which is a heterodimeric complex encoded by Cytokine Receptor-Like Factor 2 (CRLF2), and IL-7ra subunit that when activated induces JAK/STAT pathway signaling. Recently published data indicate that when TSLPR is overexpressed, this pathway is associated with poor prognosis in high-risk disease, which makes TSLPR represents a promising target for future study. A novel TSLPR targeted CAR was developed in the Fry Lab. We are actively developing a phase I trial which we plan to bring to the clinic in 2022. This will be the first in human testing of anti-TSLPR CAR adoptive cell therapy. Antigen Modulation: Based on our work with CD22 CAR, we have demonstrated that cell surface antigen density is critical for the efficacy of CD22 CAR therapy and durability of remission. Bryostatin1 has been identified to increase CD22 expression and in a mouse model, when used as a primer before CD22 CAR, demonstrated enhanced cytokine production and improved CAR functionality, as well as a prolonged durability of remission, providing a proof of concept that increasing antigen expression optimizes CD22 CAR responses. Given the preclinical data which demonstrated that Bryostatin1-induced upregulation of CD22 in ALL may improve responsiveness to anti-CD22 targeted therapies, we are developing a phase 1 study to specifically test Bryostatin1 and its effects on CD22 expression in children and young adults with CD22+ leukemias.