Antigen Loss after Targeted Immunotherapy in Hematological Malignancies

Key points

Introduction

Over the past decades, the advances in chemotherapy and hematopoietic cell transplantation have dramatically improved the outcomes of hematological malignancies, especially in the pediatric population. The 5-year survival rates have now exceeded 90% for children with acute lymphoblastic leukemia (ALL), classic Hodgkin lymphoma, and non-Hodgkin lymphomas (NHLs). ¹ However, long-term survival rates for these entities have plateaued after years of steady progress, and the limitations and disadvantages of conventional therapies are becoming increasingly apparent. A significant proportion of patients are still refractory to conventional treatment, or experience relapse after an initial response. Therefore, enormous effort has been devoted to developing novel therapeutic strategies that are more effective and less toxic.

Recent years have witnessed significant progress in the understanding of how the immune system interacts with tumors. This progress has led to novel immunotherapy to direct the humoral and/or cell-mediated adaptive immunity against tumor cells. The goal of immunotherapy is to enhance both the magnitude and specificity of antitumor immune responses, which can be achieved by two main approaches, namely checkpoint inhibition and targeted immunotherapies. Checkpoint inhibition aims to tip the balance from immune escape/tolerance to the antitumor immune response by blocking the T-cell inhibitory pathways through checkpoint inhibitors such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) blockers. Unlike checkpoint inhibition, the goal of targeted immunotherapies is to induce specific immune response against tumor antigens. Despite the remarkable breakthrough in immunotherapy, a lingering problem, as with any antineoplastic agents, is the acquired resistance developed in residual neoplastic cells, which eventually leads to disease relapse. A common mechanism is the modulation of target tumor antigens. This mechanism not only poses a tremendous challenge in the treatment because of its impact on the efficacy and durability of immunotherapy but also complicates the diagnosis of residual or relapsed diseases either by flow cytometry or immunohistochemistry, because the phenotypic changes interfere with the phenotypic characterization of neoplastic cells.

Hematological malignancies, in particular leukemia, are known to have unstable immunophenotype. Phenotypic changes at relapse, either loss of initially present aberrancies or emergence of new aberrancies, occur in 50% to 90% of patient with ALL or acute myeloid leukemia (AML) undergoing conventional chemotherapy. ^2 , 3 The use of targeted immunotherapy adds another layer of complexity, because it frequently results in loss or downregulation of the target antigens at relapse. Importantly, the antigens targeted by immunotherapies are often the same markers used for phenotypic characterization, because of their lineage specificity; that is, cluster of differentiation (CD) 19, CD20, and CD22 in B-cell malignancies. Thus, downregulation of these antigens creates a “moving target” for disease detection and causes diagnostic dilemmas. Few studies have evaluated the dynamics of antigen expression after therapy, and some have investigated the molecular mechanisms underlying these posttherapy antigen modulations. However, many questions remain to be answered.

This article provides an overview on current targeted immunotherapies in hematological malignancies, and summarizes available data regarding how antigen loss occurs after these therapies, as well as the implications these changes have for treatment and diagnosis. It is hoped that this review will instigate more investigations in this field.

Overview of targeted immunotherapies

The currently available targeted immunotherapies can be divided into 4 main classes ( Table 1 ): (1) conventional monoclonal antibody therapy; (2) antibody-drug conjugates, comprising monoclonal antibodies and cytotoxic agents covalently conjugated through chemical linkers; (3) engineered monoclonal antibodies, also known as bispecific T-cell engagers (BiTEs), which bind both CD3 and a surface antigen on tumor cells and direct T cells to target tumor cells; and (4) adoptive cell transfer therapy with T cells engineered to express chimeric antigen receptors (CARs) or tumor antigen-specific T-cell receptors (TCRs).