Development of Novel Immunotherapeutic Strategies for Myeloid Malignancies

Division Of Basic Sciences - Nci

Investigators

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Abstract

Acute myelogenous leukemia (AML) represents 20% of leukemias occurring in children and in adolescents and young adults (AYAs). Treatment of patients with AML requires intensive multi-agent chemotherapy, and approximately one-third of pediatric patients will also receive allogeneic donor stem cell transplantation in first remission to achieve cure. However, only 60% of children and AYAs with AML will remain in long-term remission despite these intensive therapies. New therapeutic strategies are thus needed to increase remission rates, decrease relapse, and improve overall survival. AML CAR-T cell immunotherapy is an emerging field. Although there are established targetable antigens, the clinical experience to date with CAR T-cell targeting has been limited particularly in children. Moreover, the experience to date has demonstrated limited clinical activity and substantial challenges in getting patients to infusion -prompting the need for further investigations into optimizing CAR T-cells and other immunotherapeutic approaches in AML. Accordingly, this project leverages our decade long-experience in CAR T-cell targeting in B-ALL to extend the therapeutic index of adoptive cell therapy in AML. Specific Aim 1: Testing of CD33 CAR T-cells for AML Background: Based on a CD33 CAR T-cell construct developed in the Fry Lab,I led the development of an academic multi-center, Phase I, CD33 targeted CAR T-cells (CD33CART) for children and young adults with relapsed/refractory AML (NCT03971799). This trial has been conducted through the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) with support from the Center for International Blood and Marrow Transplant Research (CIBMTR) CRO services and National Marrow Donor Program (NMDP) as the IND sponsor. CAR T-cells are centrally manufactured at NCI Frederick in the Biopharmaceutical Development Program. I have been instrumental in leading all aspects of the clinical implementation of this study, including being the primary author of the clinical protocol and coordinating of all elements of the IND submission and clinical trial coordination. The trial began its enrollment in January 2020 at 6 centers across the country. The primary objectives of this phase 1/2 trial aim to determine the safety and feasibility of CD33CART in children and young adults with relapsed/refractory AML. The trial was done in two phases: Phase 1 served to determine the maximum tolerated dose of CD33CART cells using a 3+3 trial design; Phase 2 served as an expansion phase designed to evaluate the rate of response to CD33CART. Secondary objectives for all subjects included: 1) assessment of manufacturing feasibility of CD33CART from subjects with AML and 2) to determine the feasibility of infusing CD33CART in subjects with AML. For the treatment population that received CD33CART, secondary objectives included: 1) the incidence and severity of CRS, sinusoidal occlusion syndrome (SOS), or other CD33CART related toxicities; 2) the overall survival, event-free survival, and treatment-related mortality at Day 28 post-CD33CART; 3) the percentage of subjects treated with CD33CART who achieve morphologic remission (<5% blasts in marrow) at Day 28 post-CD33CART cell infusion (for those in Phase I); and 4) to determine the percentage of subjects able to proceed to allogeneic hematopoietic stem cell transplantation following treatment with CD33CART. Post-HSCT outcomes, including engraftment and SOS were also closely monitored for. Exploratory objectives performed collaboratively and under the guidance of the multicenter local PIs included: NGS MRD monitoring, CD33CART expansion, CD33 AML surface expression, AML surfacesome/proteogenomics and patient reported outcomes Accomplishments: As of July 2025, we have completed enrollment on this study and closed the trial to accrual. Impressively, a CD33CART product was successfully manufactured for all subjects in whom manufacturing was attempted, Preliminary data on the dose-escalation portion, the manufacturing, and biologic correlatives have been presented at international meetings. Representing one of the largest experiences in pediatric and young adult AML CAR T-cell studies, we demonstrated limited and reversible toxicities in 2 of 10 (40%) patients evaluable for response achieving a remission at the highest dose tested. CAR T-cell expansion, however, was overall limited and transient which may potentially account for the limited efficacy in comparison to outcomes seen with B-cell targeting with CAR T-cells. A final manuscript is in development and plans are being made to figure out how to best optimize this construct. In parallel and in collaboration with VOR Bio, the CD33 CAR T-cell construct was licensed and tested in allogeneic T-cell platforms. These trials have also completed and the final analysis underway. Collectively, this proof of concept will facilitate future development of cell therapy strategies in AML. Specific Aim 2: Test novel CAR T-cell constructs in patients with r/r AML Background: Given the concern that single-antigen targeting may be insufficient in AML especially since antigen expression is much more heterogeneous, exploring alternative antigens that can be targeted remains a high-priority. Accordingly, our future efforts (in active development) will focus on the clinical translation of 3 novel CAR T-cell targets to advance approaches in AML and include FLT3, CD123, and mesothelin. Accomplishments: The FLT3 CAR was fully developed in the POB, NCI with Dr. Christopher Chien (Hematologic Malignancies Section, Biologist) as one of the inventors on this effort.Clinical vector has been generated. Efforts towards IND enabling studies have been initiated by the Taylor Lab and CCE and the protocol development process has been initiated. Future Research: Based on these potential targets, we are in the process of developing several phase I dose-escalation studies over the next 3-5 years to test novel approaches in AML. While the FLT3 CAR was fully developed in the POB, the CD123 CAR, is a novel humanized CAR T-cell construct developed by Lentign with whom we have an ongoing collaboration to explore this in pediatric and young adults patients in a phase I trial. Based on ongoing efforts, we anticipate that this will be the first trial open to enrollment. Lastly, while mesothelin has emerged as a unique target in AML that is potentially amenable to CAR T-cell targeting,I have developed institutional experience in the treatment of patients receiving a mesothelin targeted T-cell receptor based on my support of a clinical trial for adults with refractory solid tumors.56 This experience will be helpful as efforts in mesothelin targeting have been advanced by our colleague Dr. Raffit Hassan in the Thoracic and GI Malignancies Branch. Specific Aim 3: Evaluate lineage switch as a form of relapse following immunotherapy. Background: Lineage switch, or the transformation of B-cell ALL to AML, is an emerging form of relapse after antigen-targeted immunotherapy. While initial experiences have been limited to case reports, we embarked on an international study to better characterize this novel form of relapse. Accomplishments: My team put together the largest case series describing lineage switch, which is the first such effort to describe the clinical manifestations and characteristics of this complexity. Given the very poor outcomes of this "ultra-rare" complication, we have established an international consortia dedicated to 1) better diagnosing this entity; 2) developing treatment approaches and 3) more comprehensively studying the underlying biology.