Elsevier

Immunology Letters

Volume 155, Issues 1–2, September–October 2013, Pages 43-46
Immunology Letters

Review
Acute myeloid leukemia and novel biological treatments: Monoclonal antibodies and cell-based gene-modified immune effectors

https://doi.org/10.1016/j.imlet.2013.09.013Get rights and content

Highlights

  • High rates of relapse in AML is a well-known drawback of standard therapies.

  • Need of alternative and more specific therapeutic strategies.

  • We review the passive immunotherapy approaches with mAbs or CAR-engineered cells.

  • The target antigen choice is critical for developing advanced therapies.

  • Safety issues are crucial to improve the benefit/risk ratio of AML immunotherapy.

Abstract

In the context of acute myeloid leukemia (AML) treatment, the interface between chemotherapy and immunotherapy is at present getting closer as never before. Scientific research is oriented in overcoming the main limits of actual chemotherapeutic regimens against AML, which still accounts for a considerable number of relapsed or resistant forms.

A lot of investments have been done in the use of monoclonal antibodies (mAbs) and recently gene-modified immune cells have been considered as an alternative approach whenever chemotherapy fails to eradicate the disease. In this sense, AML is a potential suitable target for immunotherapeutic approaches, due to overexpression of several tumor antigens.

Here we describe the state of the art of mAbs and cellular therapies employing engineered immune effectors, developed against specific AML antigens, in a window embracing preclinical research and translational studies to the clinical setting.

Introduction

Nowadays, the main challenge for the scientific community working on AML concerns the high rates of relapse, accounting for 50–70% within the first 3 years after achievement of complete remission [1], with better survival trend for pediatric than adult population [2]. Allogeneic hematopoietic stem cell transplantation is adopted as post-remission therapy in high-risk patients, but it still carries the major drawback of high transplant-related mortality. A growing body of evidence reveals that the limitedness of the current chemotherapeutic regimens mainly lies in the inability of properly eradicating AML and in particular the leukemic stem cells (LSCs) present in the bulk of leukemic cells [3], [4]. Therefore, researchers are moving toward more targeted strategies, investing in the immunotherapy field as a potential fertile ground complementary to standard chemotherapy. Here we compare and review passive immunotherapy approaches using both monoclonal antibodies (mAb) and cellular and gene-therapies.

Section snippets

State of the art of mAb therapy for AML

Since the early 80's, the mAb technology has been one of the first attempts of biomedical sciences in developing targeted therapeutics. However, initial studies highlighted the limitations of using unconjugated mAbs in rapidly proliferative diseases. Thus, mAbs were manipulated in the Fc portion to better stimulate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Additionally, bi-specific mAbs or mAbs conjugated with cytotoxic drugs were generated,

Adoptive T cell therapy

Adoptive cell therapy (ACT) harnesses the ability to mount specific responses of the cellular immune system by transferring ex vivo expanded autologous or allogeneic T cells into tumor-bearing patients. Indeed, donor lymphocyte infusion (DLI) have been largely used in patients with hematological malignancies. However, the limited activity of DLI in AML patients is also associated with a high incidence (40–60%) of graft versus host disease (GVHD) [25]. Thus, new therapeutic strategies have been

Conclusions

Improvements in the mAb design and the efficient transfer of CARs together with a feasible manufacturing practice (GMP) strategy to select and propagate CAR-expressing cells are currently among the newest therapeutic approaches for the treatment of resistant forms of AML. The choice of the target antigen will be detrimental in defining the best mAb or CAR to be used in this window of treatment in order to eradicate the disease while sparing the normal tissues. In the near future, we envision

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