Modeling Promising Nonmyeloablative Conditioning Regimens in Nonhuman Primates

Abstract

Minimal conditioning or even no conditioning would be the preferred preparation for most gene therapy applications for nonmalignant diseases. However, reduced intensity conditioning (RIC) regimens in patients with nonhematologic malignancies have not led to long-term engraftment unless a selective advantage was present for the transplanted donor cells. Similar findings have also been observed in a number of large animal studies. Inadequate myelosuppression levels were thought to be responsible for the outcomes. To address this issue several innovative protocols in small animals have been presented with selective hematopoietic myelosuppression and less systemic toxicity. Such protocols promised to curb the transplant-related morbidity and mortality in myeloablative conditioning and provide effective long-term engraftment, especially in patients with gene-corrected autografts. In the present study we have tested some of these promising RIC regimens in nonhuman primates, a clinically relevant large animal model. Our data suggest that transient myelosuppression induced by anti-c-Kit antibody in conjunction with low-dose irradiation may lead to long-term engraftment, albeit at low levels. The animals with busulfan conditioning with or without anti-c-Kit that received gene-modified autologous transplants with green fluorescent protein expression had similar myelosuppression, but failed long-term engraftment and despite immunosuppressive treatment had all the hallmarks seen previously in similar models without immunosuppression. Our preliminary data expand current knowledge of RIC and emphasize the need to explore whether specific and directed myelosuppression alone is adequate in the absence of microenvironmental modulation, or whether innovative combinations are necessary for safe and effective engraftment.

Stem cell–derived CAR T cells traffic to HIV reservoirs in macaques

“…Likewise, the strong proliferative pressure induced by highly lymphodepleting TBI-based conditioning likely drove expansion and trafficking of these same immune cell populations. However, to increase the safety, feasibility, and applicability of our HSC-CAR approach for otherwise healthy people living with HIV, TBI-based conditioning should be replaced with less toxic chemotherapeutic conditioning regimens ( 75 – 77 ), or nongenotoxic, antibody-based conditioning regimens designed to establish a robust niche for HSC engraftment, while minimizing collateral damage to other hematopoietic cells ( 78 – 81 ). This strategy will enable substantial retention of endogenous HIV-specific immune cell subsets, whose function in tandem with HSC-derived CAR T cells will likely be essential for any approach designed to support long-term ART-free HIV-1 remission ( 41 , 82 ).…”

Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin

“…However, high-dose ACK2 failed to condition immunocompetent adult mice and induced anemia, neutropenia, and thrombocytopenia 41 . Although some efficacy was observed in fetal mice 42 , ACK2 required combination with sub-lethal irradiation to achieve meaningful chimerism in adult immunocompetent mice 26 and this combination showed modest efficacy in non-human primates 43 . In addition, CD117 is expressed on cardiac progenitors, gastrointestinal cells, neuronal cells, and cells of the reproductive system, raising concerns about potential off-target toxicity 44 .…”

Anti-CD117 immunotherapy to eliminate hematopoietic and leukemia stem cells

“…Similar to ACK2 in the mouse setting, JSP191 transiently depletes HSPCs in fully immunocompetent cynomolgus monkeys after a single intravenous injection [107]. When administered to macaques in a different non-human primate model, SR-1 exhibited only limited efficacy in combination with busulfan or totalbody irradiation [108]. Importantly, no effects were observed on circulating mature white blood cells or non-hematopoietic organs.…”