Clinical Development of Immunotherapies for Rare Hematologic Maligancies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Clinical Development of Immunotherapeutic Strategies for Rare Hematologic Malignancies Specific Aim 1: Testing of a first-in-human; first-in-child, CD33 CAR T-cell for AML Based on a CD33 CAR T-cell construct developed in the Fry Lab,42 I led the development of a multi-center, Phase I, CD33 targeted CAR T-cell for children and young adults with relapsed refractory AML. This trial is conducted through the Pediatric Transplantation and Cell Therapy Consortium (PTCTC) with support from the Resource for Clinical Investigation in Blood and Marrow Transplantation (RCI-BMT), the Center for International Blood and Marrow Transplant Research (CIBMTR)/National Marrow Donor Program (NMDP) with cell manufacturing supported by the NCI (NCI-Frederick/BDP). I have led all aspects of the clinical implementation of this study, writing the clinical protocol and coordinating of all elements of IND submission and developing biologic correlative studies. This phase 1/2 trial aims to determine the safety and feasibility of anti-CD33 CAR expressing T-cells in children and adolescents/young adults (AYAs) with relapsed/refractory AML. Phase 1 will determine the maximum tolerated dose of CD33 CAR T-cell cells using a 3+3 trial design. Phase 2 is an expansion phase designed to evaluate the rate of response to CD33 CAR T-cells. Secondary objectives for all subjects include: 1) To determine the feasibility of manufacturing CD33 CAR T-cells from subjects with AML and 2) To determine the feasibility of infusing CD33 CAR T-cells in subjects with AML. Given the concerns for heterogeneity of CD33 expression in AML, compounded by concerns for myeloid directed toxicity of normal CD33 targeting, this trial is built to serve as a bridge to allogeneic HSCT with the dual purposes of prevention of relapse and salvage from aplasia, should that be a concern. Exploratory objectives will be performed collaboratively and include a host of biologic correlatives, including CAR T-cell expansion and persistence, CD33 expression and toxicity profiling. Enrollment is ongoing. Knowledge gained has included learning the best approach to get a patient with relapsed/refractory AML to CAR T-cell therapy and how to effectively bridge them to both apheresis and the actual CAR T-cell infusion. Importantly, a CAR T-cell product has been successfully manufactured for all patients enrolled on study, which is particularly remarkable as this has been a particular challenge for patients with AML. Future directions include exploration of biologic correlatives and incorporation of allogeneic (donor-derived) T-cells for the starting material for patients with post-HSCT relapse to improve CAR T-cell functionality and manipulating the design of the CAR construct. As of the time of this annual report, we have completed the dose-escalation phase of the study and are in the expansion phase. We are now exploring the biologic correlatives relevant to this trial Specific Aim 2: Translation of novel CAR T-cells in AML Given the ongoing clinical need for development of CAR T-cells in AML, our future endeavors will be focused on further exploring novel CAR T-cells in AML. Based on the early work emerging from our CD33 CAR T-cell trial, we anticipate that biologic correlative will be informative to helping us to understand what elements may lead to improved outcomes for CAR T-cell therapies in AML. Anticipated future efforts include development of 3 phase I studies for patients with relapsed/refractory AML; targeting FLT3 CAR (developed at the NCI), CD123 CAR, and mesothelin (in collaboration with Dr. Raffit Hassan). We anticipate that our pipeline and portfolio over the next several years will provide critical insights into improving outcomes of AML CAR T-cell therapy.