Anti-CD117 immunotherapy to eliminate hematopoietic and leukemia stem cells

Abstract

Precise replacement of diseased or dysfunctional organs is the goal of regenerative medicine and has appeared to be a distant goal for a long time. In the field of hematopoietic stem cell transplantation, this goal is now becoming tangible as gene-editing technologies and novel conditioning agents are entering the clinical arena. Targeted immunologic depletion of hematopoietic stem cells (HSCs), which are at the very root of the hematopoietic system, will enable more selective and potentially more effective hematopoietic stem cell transplantation in patients with hematological diseases. In contrast to current conditioning regimes based on ionizing radiation and chemotherapy, immunologic conditioning will spare mature hematopoietic cells and cause substantially less inflammation and unspecific collateral damage to other organs. Biological agents that target the stem cell antigen CD117 are the frontrunners for this purpose and have exhibited preclinical activity in depletion of healthy HSCs. The value of anti-CD117 antibodies as conditioning agents is currently being evaluated in early clinical trials. Whereas mild, antibody-based immunologic conditioning concepts might be appropriate for benign hematological disorders in which incomplete replacement of diseased cells is sufficient, higher efficacy will be required for treatment and elimination of hematologic stem cell malignancies such as acute myeloid leukemia and myelodysplastic syndrome. Antibody−drug conjugates, bispecific T-cell engaging and activating antibodies (TEAs), or chimeric antigen receptor (CAR) T cells might offer increased efficacy compared with naked antibodies and yet higher tolerability and safety compared with current genotoxic conditioning approaches. Here, we summarize the current state regarding immunologic conditioning concepts for the treatment of HSC disorders and outline potential future developments.

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

“…RAS proteins are encoded by three proto-oncogenes ( H-RAS , K-RAS , and N-RAS ) that regulate differentiation and growth of many cell types, including myeloid cells. RAS proteins are membrane-associated GTPases that regulate serine or threonine kinases of the MAP kinase cascade and mutations of RAS often constitutively activate RAS/MEK and RAS/PI3K signaling by accumulating intercellular RAS GTP [ 32 ]. Large scale studies have consistently reported RAS signaling deregulation due to mutations of RAS genes in MDS.…”

“…Large scale studies have consistently reported RAS signaling deregulation due to mutations of RAS genes in MDS. RAS mutations are detected at an overall rate of 3–5% with N-RAS genes being the most frequently mutated and K-RAS accounting for the remaining RAS mutations [ 13 , 32 ]. N-RAS mutations at codon 12 account for 55% of all RAS mutations followed by N-RAS mutations at codons 31 and 61 (12% each) and K-RAS mutation at codon 12 (21%) [ 33 ].…”

Therapy Development by Genome Editing of Hematopoietic Stem Cells

“…The same is also true for other PIDs, where alternative conditioning has to be evaluated on an individual basis [254], and for hemoglobinopathies [255,256]. For other disorders, such as FA, efficient therapy is possible without conditioning altogether [14], while innovative, selective conditioning methods, such as cell-type-specific drug delivery targeting CD117 or CD300f, and the use of non-genotoxic agents, such as saporin, are being investigated for a range of disorders to minimize the risk of treatment-related hematopoietic malignancies [55,[257][258][259].…”

Membrane-Wrapped Nanoparticles for Enhanced Chemotherapy of Acute Myeloid Leukemia

“…Doxorubicin (DOX), clinically known as adriamycin, was selected as the drug cargo because it has been used to treat leukemias, lymphomas, and other cancers, usually in combination with a cytarabine. , Anthracyclines like DOX inhibit the functionality of the enzyme topoisomerase-II (TOP2), resulting in DNA damage and apoptotic cell death (Figure B). − This DNA breakage is marked by the highly specific and sensitive event of the phosphorylation of histone H2AX at the serine-139 residue, resulting in γH2AX . While most commonly cited, this is not the only mechanism by which DOX induces cell death.…”

“…Based on these studies, we postulated that CHRF MWNPs would be similar to Mk microparticles and CHRF microparticles in their ability to target CD117+ cells at higher levels than non-targeted counterparts. CD117, or c-Kit, is a transmembrane receptor present on HSPCs, erythroid, myeloid, and megakaryocytic precursors as well as up to 87% of AML cell lines. − It is one of the “most promising target antigens” for treatment of AML and other HSPC disorders . By specifically reaching CD117+ cells, MWNPs would be able to avoid downstream, differentiated, healthy bone marrow cells, limiting side effects and making recovery from chemotherapy and preparation for bone marrow transplants a less taxing process .…”