The Biological Landscape of Immunotherapy in AML

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Background

The functional interplay between acute myeloid leukemia (AML) cells and the bone marrow (BM) microenvironment is a distinctive characteristic of this hematological neoplasm. AML cells interact with a variety of cells of different origin, among which, immune cell subsets crucially influence the proliferation, survival and drug resistance of AML by creating an immunosuppressive microenvironment, where both innate and adaptive immune responses are profoundly deregulated. This massive immune dysregulation, which eventually leads to leukemia escape from natural immune control, is a critical feature in leukemia growth and progression. The understanding of the factors responsible for the escape from immune destruction in AML, which become more prominent with disease progression, is necessary for the development of innovative immunotherapeutic treatment modalities in AML.

The hypothesis of harnessing the immune system against cancer, including AML, has been postulated for a very long time and several clinical attempts have been made in this field. In the hematological field, 40 years of allogeneic stem cell transplantation represent the most convincing proof-of-concept that the immune system powerfully recognizes and attacks leukemic cells, thus dramatically improving survival of AML patients.

In AML as well in other diseases, the recent advances in basic immunology are offering a new opportunity to translate the findings provided by preclinical scientists into eventually effective therapeutical strategies. In particular, a better knowledge of the mechanisms leading to immunological tolerance, as well as the identification of critical regulators, such as immunological checkpoints, are pacing the way for a fast-track development of a huge amount of novel drugs and therapeutic strategies. The main aim of the new therapies is to harness the immune system against AML both by implementing the cytotoxic effector pathways (CTLs, NK cells, and CIKs) and/or by inhibiting the tolerogenic mechanisms (Tregs and MSCs).

A better understanding of the immunological landscape of AML and the biology beyond it may, thus, aid the design of much more immune-targeting therapies for AML. In this article collection, we will discuss advances in understanding these processes, focusing on the biological and clinical relevance of immunotherapy in AML.

AML is a genetically heterogeneous disease, characterized by clonal proliferation of myeloid precursors. Despite our improved understanding of the biology underlying AML, the therapeutic approach of AML had not substantially changed over the last 40 years. Standard frontline therapy comprises 3+7 like induction chemotherapy, introduced in the 1970s, followed by consolidation cycles or allogeneic stem cell transplantation (alloSCT), based on the patient’s risk of relapse. Unfortunately, prognosis remains relatively poor with long-term overall survival (OS) achieved in approximately 40% of young adults, and only 10-15% of elderly patients (>65 years) with AML. Most patients are either primary refractory to induction therapy or subsequently relapse following a brief remission likely due to persistence of chemo-resistant leukemia stem cells or low volume minimal residual disease. However, major breakthroughs have been achieved in deciphering the genetic landscape of AML and its impact on prognostication, therapy selection, and outcomes in patients with AML. The significant interest in developing immune therapies in AML comes from the fact that leukemias were the first to successfully implement allogeneic stem cell transplant (ASCT). This was further fueled by recent successes including the FDA approval of the bispecific T-cell engager (BiTE) blinatumomab and the conjugated CD22-targeted antibody inotuzumab in patients with relapsed in B-acute lymphoblastic leukemia (B-ALL), the FDA approval of the CD33-targeted antibody gemtuzumab ozogamicin (GO) in frontline and relapsed AML, the approval of the CD19-targeted chimeric antigen receptor therapy CTL019 for younger patients with relapsed B-ALL, as well as the remarkable breakthroughs with checkpoint inhibitors in solid tumors and some lymphomas.

Targeting specific tumor-related antigens with antibody-based therapies and engaging the patient’s own immune system to attack cancer cells have recently become areas of significant clinical research in many hematologic malignancies, including AML and myelodysplastic syndrome (MDS). In a series of clinical manuscripts authored by experts in the field, we plan to focus on mechanism-based overview of novel “immunotherapeutic” agents in AML currently being evaluated in clinical trials, with a focus T-cell engaging therapies being evaluated in AML in clinical trials, including bispecific antibodies and DARTs, immune checkpoint inhibitor-based therapies, therapeutic vaccines, and CART cell approaches. We will discuss completed and ongoing trials with these modalities, efficacy and safety signals, ideal therapeutic settings for these therapies, mechanisms of resistance, the importance and incorporation of predictive biomarkers in clinical trials, and the overall potential for future development of each of these agents in the AML landscape in the next 3-5 years.

Keywords: AML, Bone marrow, leukemia, immune-targeting therapies, immunotherapy

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