CARving the Path to Allogeneic CAR T Cell Therapy in Acute Myeloid Leukemia.

Oren Pasvolsky,David Marin,Farhad Ravandi,Katy Rezvani,Elizabeth Shpall,May Daher,Naval Daver,Gheath Alatrash,Partow Kebriaei

doi:10.3389/fonc.2021.800110

Abstract

Despite advances in the understanding of the genetic landscape of acute myeloid leukemia (AML) and the addition of targeted biological and epigenetic therapies to the available armamentarium, achieving long-term disease-free survival remains an unmet need. Building on growing knowledge of the interactions between leukemic cells and their bone marrow microenvironment, strategies to battle AML by immunotherapy are under investigation. In the current review we describe the advances in immunotherapy for AML, with a focus on chimeric antigen receptor (CAR) T cell therapy. CARs constitute powerful immunologic modalities, with proven clinical success in B-Cell malignancies. We discuss the challenges and possible solutions for CAR T cell therapy development in AML, and examine the path currently being paved by preclinical and clinical efforts, from autologous to allogeneic products.

Highlights

Acute Myeloid Leukemia—The Unmet NeedTraditional intensive chemotherapy regimens for acute myeloid leukemia (AML) have generated long term survival rates of up to 50% in younger patients, and lower than 40% in patients over the age of 60 [1, 2]
Cytopenias and infectious complications could potentially be more prominent than those previously reported in clinical trials with chimeric antigen receptor (CAR) T cells in lymphomas, owing to older age of AML patients, previous intensive therapies and treatment related morbidity, especially when using CARs in the R/R setting
At least to date, limited clinical experience has not substantiated these concerns for excessive graft versus host disease (GVHD) in the setting of allogeneic CARs

Summary

INTRODUCTION

Traditional intensive chemotherapy regimens for AML have generated long term survival rates of up to 50% in younger patients, and lower than 40% in patients over the age of 60 [1, 2]. Cytopenias and infectious complications could potentially be more prominent than those previously reported in clinical trials with CAR T cells in lymphomas, owing to older age of AML patients, previous intensive therapies and treatment related morbidity, especially when using CARs in the R/R setting. At least to date, limited clinical experience has not substantiated these concerns for excessive GVHD in the setting of allogeneic CARs. In a report of 20 patients who received allogeneic CD19 targeting CAR Ts for B cell malignancies relapsing after alloHCT, none developed new GVHD, whereas 8 of the 20 patients responded (including 6 CRs) [72]. CRISPR/Cas gene editing has enabled construction of anti-CD7 allogeneic CAR Ts that lack both CD7 and T cell receptor alpha chain (TRAC) expression These fratricide-resistant allo CARs have in vivo and in vitro efficacy against T cell acute lymphoblastic leukemia (T-ALL). In efforts to improve response, adoptive transfer of haplo-identical killer immunoglobulin-like receptor–human leukocyte antigen (KIRHLA) mismatched NK cells have been used in children with AML, with reports demonstrating good tolerance but mixed results with respect to efficacy [81, 82]

Not eligible for allo-HCT

CONCLUSION AND FUTURE STRATEGIES

Findings

Results