Targeting CD47 in Sézary syndrome with SIRPαFc

Johnson, Lisa D.; Banerjee, Swati; Kruglov, Oleg; Viller, Natasja Nielsen; Horwitz, Steven M.; Lesokhin, Alexander M.; Zain, Jasmine; Querfeld, Christiane; Chen, Robert; Okada, Craig; Sawas, Ahmed; O’Connor, Owen A.; Sievers, Eric L.; Shou, Yaping; Uger, Robert A.; Wong, Mark; Akilov, Oleg E.

doi:10.1182/bloodadvances.2018030577

Cited by 80 publications

(65 citation statements)

References 52 publications

(53 reference statements)

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“…After single-dose infusion of TTI-621, 4 of 5 patients had a decrease in their count and a rapid decrease of lactate dehydrogenase (LDH). Additional experiments showed that SIRPαFc increased the phagocytosis of ex vivo Sezary cells extracted from patient blood, but not non-malignant lymphocytes [36].…”

Section: Targeting Of Cd47-sirpα Using Antibodiesmentioning

confidence: 95%

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Role of CD47 in Hematological Malignancies

et al. 2020

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CD47, or integrin-associated protein, is a cell surface ligand expressed in low levels by nearly all cells of the body. It plays an integral role in various immune responses as well as autoimmunity, by sending a potent "don't eat me" signal to prevent phagocytosis. A growing body of evidence demonstrates that CD47 is overexpressed in various hematological malignancies and its interaction with SIRPα on the phagocytic cells prevents phagocytosis of cancer cells. Additionally, it is expressed by different cell types in the tumor microenvironment and is required for establishing tumor metastasis. Overexpression of CD47 is thus often associated with poor clinical outcomes. CD47 has emerged as a potential therapeutic target and is being investigated in various preclinical studies as well as clinical trials to prove its safety and efficacy in treating hematological neoplasms. This review focuses on different therapeutic mechanisms to target CD47, either alone or in combination with other cell surface markers, and its pivotal role in impairing tumor growth and metastatic spread of various types of hematological malignancies.

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Section: Targeting Of Cd47-sirpα Using Antibodiesmentioning

confidence: 95%

“…Flow cytometry performed on 25 patients with Sezary syndrome (SS) showed higher CD47 expression in tumor cells compared with benign T-cells from the same individual. Patients with high expression of CD47 had 6.5 times shorter overall survival (OS) than patients with low expression (median OS, 84.0 vs 12.9 months; P < .001) [36].…”

Section: Role Of Cd47 In Nhlmentioning

confidence: 99%

Role of CD47 in Hematological Malignancies

et al. 2020

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“…Another approach of immunogenic cell death induction is to exploit the interaction of CD47 with its ligand signal regulatory protein α (SiRPα). By targeting tumor-cell CD47 through a decoy receptor (SiRPαFc), reverting the "do-noteat-me" signal to bystander macrophages, a significant reduction of tumor load was observed in various hematologic malignancies, i.e., CTCL [76]. Perturbation of NK-cell tolerance, e.g., by anti-KIR3DL2 antibodies, is a further strategy of proven activity in other T cell tumors [76,77].…”

Section: Modulation Of Immune Cell Synapsesmentioning

confidence: 99%

“…Nevertheless, clinically proven GvL effects [48] and TCRdirected CAR-T cells in pre-clinical models [79••] implicate a therapeutic application of a T cell-mediated anti-T-PLL attack. Modulation of immune regulatory synapses, e.g., by perturbation of NK-cell tolerance (e.g., anti-KIR3DL2) or of macrophage inertia (e.g., SIRPαFc binding to CD47) represent interventional strategies of proven activity in other T cell tumors [76,77], which have yet to be evaluated for their efficacy in T-PLL anti-CDR3 CAR-T cells have not been reported in T-PLL [80].…”

Section: Outlook For Car-t Cell Therapymentioning

confidence: 99%

Advances and Perspectives in the Treatment of T-PLL

Braun

Jan

Wahnschaffe

et al. 2020

Curr Hematol Malig Rep

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Purpose of Review T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumabbased induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies. Recent Findings Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CART cell therapy are at the stage of pre-clinical assessments of activity and feasibility. Summary The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-inhuman results in T-PLL, and urgently have to be transferred to systematic clinical testing.

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“…As part of a phase 1a trial, five patients with Sezary syndrome, the leukemic variant of cutaneous T-cell lymphoma were treated with TTI-621. Treatment resulted in significant tumor load reduction and skin improvement [98]. Overall, the use of CD47-targeting therapies in clinical settings has an exciting outlook and more comprehensive analysis of its effects on macrophages and other innate or adaptive immune cells needs to be conducted.…”

Section: New Macrophage-targeting Therapies In Hematologic Malignanciesmentioning

confidence: 99%

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies

Petty

Yang

2019

Cells

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The growth of hematologic malignant cells can be facilitated by other non-tumor cells within the same microenvironment, including stromal, vascular, immune and mesenchymal stem cells. Macrophages are an integral part of the human innate immune system and the tumor microenvironment. Complex interplays between the malignant hematologic cells and the infiltrating macrophages promote the formation of leukemia, lymphoma or myeloma-associated macrophages. These pro-tumorigenic macrophages in turn play an important part in facilitating tumor growth, metastasis and chemotherapeutic resistance. Previous reports have highlighted the association between tumor-associated macrophages (TAMs) and disease progression in hematologic malignancies. This review summarizes the role of TAMs in different subtypes of leukemia, lymphoma and myeloma, focusing on new insights and targeted therapies.

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Targeting CD47 in Sézary syndrome with SIRPαFc

Cited by 80 publications

References 52 publications

Role of CD47 in Hematological Malignancies

Role of CD47 in Hematological Malignancies

Advances and Perspectives in the Treatment of T-PLL

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies

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