Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia?

Georgina J Clark,Edward Abadir,Pablo A Silveira,Stephen Larsen,Robin E Gasiorowski

doi:10.3390/jcm9020554

Abstract

From monoclonal antibodies (mAbs) to Chimeric Antigen Receptor (CAR) T cells, immunotherapies have enhanced the efficacy of treatments against B cell malignancies. The same has not been true for Acute Myeloid Leukemia (AML). Hematologic toxicity has limited the potential of modern immunotherapies for AML at preclinical and clinical levels. Gemtuzumab Ozogamicin has demonstrated hematologic toxicity, but the challenge of preserving normal hematopoiesis has become more apparent with the development of increasingly potent immunotherapies. To date, no single surface molecule has been identified that is able to differentiate AML from Hematopoietic Stem and Progenitor Cells (HSPC). Attempts have been made to spare hematopoiesis by targeting molecules expressed only on later myeloid progenitors as well as AML or using toxins that selectively kill AML over HSPC. Other strategies include targeting aberrantly expressed lymphoid molecules or only targeting monocyte-associated proteins in AML with monocytic differentiation. Recently, some groups have accepted that stem cell transplantation is required to access potent AML immunotherapy and envision it as a rescue to avoid severe hematologic toxicity. Whether it will ever be possible to differentiate AML from HSPC using surface molecules is unclear. Unless true specific AML surface targets are discovered, stem cell transplantation could be required to harness the true potential of immunotherapy in AML.

Highlights

Until recently, therapeutic options for Acute Myeloid Leukemia (AML) had changed very little
Requiring an allo-HSCT is a major disadvantage of any potential future therapy, as most patients with AML are ineligible for allo-HSCT
The concept of bridging to allo-HSCT may change with AML immunotherapy

Summary

Introduction

Therapeutic options for Acute Myeloid Leukemia (AML) had changed very little. Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is an established cellular therapy in AML, but the toxicity and limited efficacy, especially in high risk patients, allows for potential improvement. In this procedure, patients undergo conditioning chemotherapy with or without radiotherapy followed by transfusion of donor hematopoietic cells. As AML and HSPC share antigens, it is possible that the step of disease depletion with immunotherapy prior to allo-HSCT can act as a form of conditioning This application would have the advantage of depleting residual disease and reducing nonhematologic toxicity by potentially replacing nonspecific conditioning agents that eliminate host HSPC. With increasingly potent therapeutics available, avoiding hematologic toxicity while remaining effective against AML may require an allo-HSCT as a rescue

Alternate Surface Targets

Intracellular Targets

Alternate Effector

Strategies Incorporating Allogeneic Hematopoietic Stem Cell Transplantation

Findings

Conclusions