Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies

Borot, Florence; Wang, Hui; Ma, Yan; Jafarov, Toghrul; Raza, Azra; Ali, Abdullah Mahmood; Mukherjee, Siddhartha

doi:10.1073/pnas.1819992116

Cited by 107 publications

(75 citation statements)

References 27 publications

(33 reference statements)

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“…Recent preclinical studies have also explored the possibility of using gene-edited stem cells to enable CD33-directed immunotherapies in AML 247 . Interestingly, preliminary preclinical studies of GO in CML LSCs showed efficacy 248…”

Section: Table Of Contents Summarymentioning

confidence: 99%

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

2020

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For two decades, leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a hematopoietic stem cell (HSC) drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukemic events-adding further layers of context and genetic and cellular heterogeneity to AML LSCs that is not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standardof-care therapies and persist in patients, diversify clonally, and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal HSCs. These features may represent Achilles' heels against which novel therapies can be developed. Here, we

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Section: Table Of Contents Summarymentioning

confidence: 99%

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

2020

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“… 6 – 8 In addition, patients affected by acute myeloid leukemia could benefit from a combination of allo-HSC transplantation and gene therapy, via the editing of the myeloid marker CD33 in donor HSCs, in order to confer resistance to anti-CD33 targeted chemotherapy. 9 – 11 …”

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confidence: 99%

Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA− Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model

Colonna

Perez

Hoffman

et al. 2020

Transplantation Direct

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Background. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a common treatment for patients suffering from different hematological disorders. Allo-HCT in combination with hematopoietic stem cell (HSC) gene therapy is considered a promising treatment option for millions of patients with HIV+ and acute myeloid leukemia. Most currently available HSC gene therapy approaches target CD34-enriched cell fractions, a heterogeneous mix of mostly progenitor cells and only very few HSCs with long-term multilineage engraftment potential. As a consequence, gene therapy approaches are currently limited in their HSC targeting efficiency, very expensive consuming huge quantities of modifying reagents, and can lead to unwanted side effects in nontarget cells. We have previously shown that purified CD34+CD90+CD45RA− cells are enriched for multipotent HSCs with long-term multilineage engraftment potential, which can reconstitute the entire hematopoietic system in an autologous nonhuman primate transplant model. Here, we tested the feasibility of transplantation with purified CD34+CD90+CD45RA− cells in the allogeneic setting in a nonhuman primate model. Methods. To evaluate the feasibility of this approach, CD34+CD90+CD45RA− cells from 2 fully major histocompatibility complex-matched, full sibling rhesus macaques were sort-purified, quality controlled, and transplanted. Engraftment and donor chimerism were evaluated in the peripheral blood and bone marrow of both animals. Results. Despite limited survival due to infectious complications, we show that the large-scale sort-purification and transplantation of CD34+CD90+CD45RA− cells is technically feasible and leads to rapid engraftment of cells in bone marrow in the allogeneic setting and absence of cotransferred T cells. Conclusions. We show that purification of an HSC-enriched CD34+ subset can serve as a potential stem cell source for allo-HCTs. Most importantly, the combination of allo-HCT and HSC gene therapy has the potential to treat a wide array of hematologic and nonhematologic disorders.

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“…For instance, both healthy and cancerous myeloid cells express CD33 and therefore traditional CD33 CAR T-cell therapy of acute myeloid leukemia (AML), which is in phase I and I/II clinical trials, would disrupt non-cancerous normal cells too [ 115 , 116 ]. Whereas tumor-specific antigen has not been identified for many tumors like some types of AML [ 117 ], and in order to prevent previously described on-target, off-tumor occurrence, two studies have demonstrated that baring the hematopoietic stem and progenitor cells from CD33 using CRISPR-Cas9 and successful transplantation of these CD33-knockout cells resulted in the safe and fully on-target, on-tumor activity of CD33-targeted CAR T-cells against AML [ 118 , 119 ]. On the other hand, CD7 is a specific potential target for AML cells, but is observed in about 30% of all patients.…”

Section: The Deluxe Zone Of Cancer Therapy Where Crispr Meets Immunomentioning

confidence: 99%

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

et al. 2020

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Cancer immunotherapy has been emerged as a promising strategy for treatment of a broad spectrum of malignancies ranging from hematological to solid tumors. One of the principal approaches of cancer immunotherapy is transfer of natural or engineered tumor-specific T-cells into patients, a so called “adoptive cell transfer”, or ACT, process. Construction of allogeneic T-cells is dependent on the employment of a gene-editing tool to modify donor-extracted T-cells and prepare them to specifically act against tumor cells with enhanced function and durability and least side-effects. In this context, CRISPR technology can be used to produce universal T-cells, equipped with recombinant T cell receptor (TCR) or chimeric antigen receptor (CAR), through multiplex genome engineering using Cas nucleases. The robust potential of CRISPR-Cas in preparing the building blocks of ACT immunotherapy has broaden the application of such therapies and some of them have gotten FDA approvals. Here, we have collected the last investigations in the field of immuno-oncology conducted in partnership with CRISPR technology. In addition, studies that have addressed the challenges in the path of CRISPR-mediated cancer immunotherapy, as well as pre-treatment applications of CRISPR-Cas have been mentioned in detail.

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Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies

Cited by 107 publications

References 27 publications

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA− Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

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