Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis

Kaczanowska, Sabina; Beury, Daniel W.; Gopalan, Vishaka; Tycko, Arielle K.; Qin, Haiying; Clements, Miranda E.; Drake, Justin; Nwanze, Chiadika; Murgai, Meera; Rae, Zachary; Wang, Ju; Alexander, Katherine; Kline, Jessica; Contreras, Cristina F.; Wessel, Kristin M.; Patel, Shil; Hannenhalli, Sridhar; Kelly, Michael C.; Kaplan, Rosandra N.

doi:10.1016/j.cell.2021.02.048

Cited by 128 publications

(102 citation statements)

References 107 publications

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“…7G), a combination treatment could empower the patient's own immune system and provide hope for cure to adult and frail patients that cannot be exposed to intensive chemotherapy or HCT, including those with measurable minimal residual disease that we demonstrate to be essential for the potent anti-leukemic immunity observed upon AXL inhibition. In line with our finding, myeloid cells engineered to express high levels of IL12 have recently been shown to reverse immune suppression and activate anti-tumor immunity in pre-clinical models of metastasis (58). Additionally, we show that rewiring of the myeloid compartment in our setting, kick starts the immunity cycle (59) and results in major changes in downstream effector cells, including productive engagement of NK cells, suppression of T regulatory cells, as well as potent CD8 response, the latter being most prominently seen in Ph + B-ALL.…”

Section: Discussionsupporting

confidence: 88%

AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia

et al. 2021

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Acute leukemias are systemic malignancies associated with a dire outcome. Due to low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages towards a tumor promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates anti-leukemic immunity and elicits effective and lasting NK-and T-cell dependent immune response against naive and treatment resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD1 checkpoint blockade in PD1-refractory leukemias. Lastly, we provide proof-of-concept that a clinical grade AXL inhibitor can be used in combination with standard of care therapy to cure established leukemia, regardless on AXL expression in malignant cells.

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Section: Discussionsupporting

confidence: 88%

AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia

et al. 2021

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“…Kaczanowska and colleagues engineered murine hematopoietic stem/progenitor cells (HSPCs) with a lentiviral vector to express the IL-12 transgene. 77 The GEMs counteracted the immunosuppressive program in the pre-metastatic niche in a murine rhabdomyosarcoma model through recruitment and activation of the innate and adaptive immune systems. This process led to a decrease in primary tumor burden as well as inhibition of metastases and prolonged survival of tumor-bearing mice.…”

Section: Alternative Engineering and Molecular Reprograming Of Macrophages Into Potent Cancer Eradicating Cellsmentioning

confidence: 99%

CARs and beyond: tailoring macrophage-based cell therapeutics to combat solid malignancies

Abdin

Paasch

Morgan

et al. 2021

J Immunother Cancer

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Recent understanding of the role and contribution of immune cells in disease onset and progression has pioneered the field of immunotherapies. Use of genetic engineering to deliver, correct or enhance immune cells has been clinically successful, especially in the field of cancer immunotherapy. Indeed, one of the most attractive approaches is the introduction of chimeric antigen receptors (CARs) to immune cells, such as T cells. Recent studies revealed that adapting this platform for use in macrophages may widen the spectrum of CAR applications for better control of solid tumors and, thus, extend this treatment strategy to more patients with cancer. Given the novel insights into tumor-associated macrophages and new targeting strategies to boost anticancer therapy, this review aims to provide an overview of the current status of the role of macrophages in cancer therapy. The various genetic engineering approaches that can be used to optimize macrophages for use in oncology are discussed, with special attention dedicated to the implication of the CAR platform on macrophages for anticancer therapy. The current clinical status, challenges and future perspective of macrophage-based drugs are highlighted.

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“…In a very recent study from Kaczanowska et al, they conceptually advance the idea of an early hematopoietic cell transfer through the use of genetically engineered myeloid cells (GEMys) [87]. In this paper, the therapeutic intervention was altering myeloid cells themselves to modulate the tumor microenvironment, instead of relying on other cells to drive their differentiation and functional program [87]. This paper from the Kaplan group follows on their previous work in pre-metastatic niches that was published within the last 15 years.…”

Section: Early Hematopoietic Cells As Immunotherapymentioning

confidence: 99%

Myelopoiesis during Solid Cancers and Strategies for Immunotherapy

Wildes

Dean

Flores

2021

Cells

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Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and checkpoint blockade has meaningfully changed the oncology landscape. While remarkable clinical advances in adaptive immunity are occurring, modulation of innate immunity has proven more difficult. The myeloid compartment, including macrophages, neutrophils, and dendritic cells, has a significant impact on the persistence or elimination of tumors. Myeloid cells, specifically in the tumor microenvironment, have direct contact with tumor tissue and coordinate with tumor-reactive T cells to either stimulate or antagonize cancer immunity. However, the myeloid compartment comprises a broad array of cells in various stages of development. In addition, hematopoietic stem and progenitor cells at various stages of myelopoiesis in distant sites undergo significant modulation by tumors. Understanding how tumors exert their influence on myeloid progenitors is critical to making clinically meaningful improvements in these pathways. Therefore, this review will cover recent developments in our understanding of how solid tumors modulate myelopoiesis to promote the formation of pro-tumor immature myeloid cells. Then, it will cover some of the potential avenues for capitalizing on these mechanisms to generate antitumor immunity.

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Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis

Cited by 128 publications

References 107 publications

AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia

AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia

CARs and beyond: tailoring macrophage-based cell therapeutics to combat solid malignancies

Myelopoiesis during Solid Cancers and Strategies for Immunotherapy

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