Vaccination Therapy for Acute Myeloid Leukemia: Where Do We Stand?

Abstract

Immunotherapy is changing the therapeutic landscape of many hematologic diseases, with immune checkpoint inhibitors, bispecific antibodies, and CAR-T therapies being its greatest expression. Unfortunately, immunotherapy in acute myeloid leukemia (AML) has given less brilliant results up to now, and the only approved drug is the antiCD33 antibody-drug conjugate gemtuzumab ozogamicin. A promising field of research in AML therapy relies on anti-leukemic vaccination to induce remission or prevent disease relapse. In this review, we analyze recent evidence on AML vaccines and their biological mechanisms. The principal proteins that have been exploited for vaccination strategies and have reached clinical experimental phases are Wilm’s tumor 1, proteinase 3, and RHAMM. the majority of data deals with WT1-base vaccines, given also the high expression and mutation rates of WT1 in AML cells. Stimulators of immune responses such as TLR7 agonist and interleukin-2 have also proven anti-leukemic activity both in vivo and in vitro. Lastly, cellular vaccines mainly based on autologous or allogeneic off-the-shelf dendritic cell-based vaccines showed positive results in terms of T-cell response and safety, also in elderly patients. Compared to other immunotherapeutic strategies, anti-AML vaccines have the advantage of being a less toxic and a more manageable approach, applicable also to elderly patients with poorer performance status, and may be used in combination with currently available therapies. As for the best scenario in which to use vaccination, whether in a therapeutic, prophylactic, or preemptive setting, further studies are needed, but available evidence points to poorer results in the presence of active or high-burden disease. Given the poor prognosis of relapsed/refractory or high-risk AML, further research is urgently needed to better understand the biological pathways that sustain its pathogenesis. In this setting, research on novel frontiers of immunotherapy-based agents, among which vaccines represent important actors, is warranted to develop new and efficacious strategies to obtain long-term disease control by immune patrolling.

Precision Medicine Approaches in Acute Myeloid Leukemia with Adverse Genetics

“…The blockade of the PD-1-PD-L1 interaction significantly enhanced AMG330-induced leukemia cell lysis, T-cell proliferation, and IFNγ secretion [86]. Another emerging immunotherapeutic strategy against AML is represented by cancer vaccination, which can be mainly categorized into peptide vaccines and dendritic cell (DC)-based vaccines [87]. The main goal of AML vaccines is to elicit an effective cellular and/or humoral immune response.…”

“…The main goal of AML vaccines is to elicit an effective cellular and/or humoral immune response. To this end, leukemia-associated antigens (LAAs) should be highly expressed, immunogenic, and (mainly) restricted to leukemic cells [87]. LAAs more extensively investigated in phase I or II trials are Wilms tumor (WT1), mucin 1 protein (MUC1), proteinase 3 (PR3), and the receptor for hyaluronic acid-mediated motility (RHAMM), which is found overexpressed in >80% of AML patients [88]; based on the results from early trials, the setting that more likely could benefit more from interventions with peptide vaccines is represented by patients in CR or with minimal residual disease.…”

Identification of tumor antigens and immune subtypes of acute myeloid leukemia for mRNA vaccine development

“…Currently, there are several types of cancer vaccines explored in clinical trials, including DNA, peptides, dendritic cells (DCs) and RNA [ 10 ]. But for AML, only peptide and DC-based vaccines had been investigated to enhance leukemia-specific immune responses [ 11 ]. A phase II trial of WT1 (Wilms’ Tumor 1) peptide vaccination administered to 22 AML patients with a median age of 64 years after complete remission (CR1) showed that WT1 vaccinations in AML patients were safe and well tolerated, the median disease-free survival (DFS) from CR1 was 16.9 months, while the overall survival (OS) from diagnosis had not yet been reached but is poised to be ≥ 67.6 months [ 12 ], which were superior to published data for similar patients treated with conventional postremission therapies or HSCT [ 13 ], [ 14 ], [ 15 ].…”

Immunoreactivity to WT1 peptide vaccine is associated with prognosis in elderly patients with acute myeloid leukemia: follow-up study of randomized phase II trial of OCV-501, an HLA class II-binding WT1 polypeptide

“…The WT1 gene is highly expressed in hematopoietic and various solid tumors, and cancer immunotherapies targeting WT1 protein have been developed [ 6 – 8 ]. Regarding WT1 peptide vaccines, however, there are few reports of studies that have verified its clinical usefulness based on randomized trials.…”