Targeting the niche: depleting haemopoietic stem cells with targeted therapy

Abstract

Haemopoietic stem cell transplantation is an expanding procedure worldwide but is associated with significant morbidity and mortality. Depletion of resident haemopoietic stem and progenitor cells (HSPC) is required for both autologous and allogeneic haemopoietic stem cell transplantation. Current conditioning protocols utilise chemotherapy or radiation to effectively reduce HSPC but are toxic in both the short and long term. The initial trials to use monoclonal antibodies to target HSPC were limited with marginal efficacy but platforms including antibody drug conjugates and chimeric antigen receptor T cells have made targeted conditioning strategies achievable. In this review we summarise the work developing targeted conditioning that may replace or reduce alkylating agents and total body irradiation. The prospect of conditioning with significantly reduced toxicity will improve outcomes and open transplantation to patients unable to tolerate current conditioning protocols.

Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins

“…Our approach still requires bone marrow transplantation of HSPCs, but on-going improvements of HSC mobilization and conditioning regimens will facilitate this procedure 54,55 . In addition, we will explore alternative DNA donor delivery system, e.g.…”

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

“…Recent advances in antibody-based therapeutics have presented the possibility of targeted conditioning agents. 13,48 Clinical trials have begun with unconjugated antibodies as conditioning agents (NCT02963064). The potent effect demonstrated by DCR-2-PBD against healthy HSPCs suggests that therapeutic derivatives targeting CD300f may be incorporated into conditioning for nonmalignant disorders of erythropoiesis or immunodeficiency either as part of an allo-HSCT or a gene-modified autologous HSCT.…”

“…12 The development of antibody-based therapies depleting hematopoietic stem and progenitor cells (HSPCs) as part of allo-HSCT conditioning is expanding. 13 Such therapies may reduce or eliminate traditional methods of depleting HSPC such as alkylating agents and irradiation. Preclinical studies demonstrate that antibody-drug conjugate (ADC)-based conditioning limits damage to bone marrow (BM) architecture and accelerates immune recovery compared with traditional conditioning.…”

Recent advances in primary immunodeficiency: from molecular diagnosis to treatment

“…Rat anti-CD45 mAbs were used together with anti-CD52 (alemtuzumab) and cyclophosphamide in a small group of patients with IEIs and pre-existing organ toxicity with good outcome 187 . Further trials of radioisotope-labeled anti-CD45 mAb are ongoing in patients with myeloid disorders (ClinicalTrials.gov Identifiers: NCT00119366 and NCT01300572), and antibody-drug conjugates have shown promising results in several animal models [188][189][190][191][192] . Similarly, a mAb against CD117 (or c-Kit), necessary for survival, proliferation, and differentiation of hematopoietic stem cells and early progenitors, has demonstrated good preclinical results in animal models and is being tested in patients with SCID (ClinicalTrials.gov Identifier: NCT02963064) [193][194][195] .…”