Targeting CD47 in Sézary Syndrome with SIRPαFc

Overview

Journal Blood Adv

Specialty Hematology

Date 2019 Apr 10

PMID 30962222

Citations 56

Authors

Lisa D S Johnson

Swati Banerjee

Oleg Kruglov

Natasja Nielsen Viller

Steven M Horwitz

Alexander Lesokhin

Jasmine Zain

Christiane Querfeld

Robert Chen

Craig Okada

Ahmed Sawas

Owen A OConnor

Eric L Sievers

Yaping Shou

Robert A Uger

Mark Wong

Oleg E Akilov

Affiliations

Soon will be listed here.

Abstract

Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma, has limited treatment options and rare occurrences of long-term remission, thus warranting research into new treatment approaches. CD47 has emerged as a promising target for multiple tumor types, but its role in SS remains unknown. Here, we show that CD47 is highly expressed on Sézary cells in the peripheral blood and skin, and the high level of CD47 expression correlates with worse overall survival (OS) in patients with SS. We also demonstrate that CD47 expression on Sézary cells is under the influence of interleukin 4 (IL-4), IL-7, and IL-13. Signal regulatory protein αFc (SIRPαFc; TTI-621), a novel CD47 decoy receptor, triggers macrophage-mediated phagocytosis of Sézary cells and, when administered in clinical trial settings, results in significant tumor load reduction. We conclude that inhibition of the CD47-SIRPα signaling pathway has therapeutic benefit for patients with SS. This trial was registered at www.clinicaltrials.gov as #NCT02663518.

Citing Articles

CD47 prevents Rac-mediated phagocytosis through Vav1 dephosphorylation.

Miller W, Mishra A, Sheedy C, Bond A, Gardner B, Montell D bioRxiv. 2025; .

PMID: 39990418 PMC: 11844498. DOI: 10.1101/2025.02.11.637707.

The role of CD47 in immune escape of colon cancer and its correlation with heterogeneity of tumor immune microenvironment.

Tian Q, Zhang C, Bao Z, Pei Z PeerJ. 2024; 12:e18579.

PMID: 39670101 PMC: 11636535. DOI: 10.7717/peerj.18579.

Deciphering the role of CD47 in cancer immunotherapy.

Liu Y, Weng L, Wang Y, Zhang J, Wu Q, Zhao P J Adv Res. 2024; 63:129-158.

PMID: 39167629 PMC: 11380025. DOI: 10.1016/j.jare.2023.10.009.

Advances in CAR-T-cell therapy in T-cell malignancies.

Zheng R, Zhu X, Xiao Y J Hematol Oncol. 2024; 17(1):49.

PMID: 38915099 PMC: 11197302. DOI: 10.1186/s13045-024-01568-z.

Cancer Therapy-induced Dermatotoxicity as a Window to Understanding Skin Immunity.

Jimenez-Andrade Y, Flesher J, Park J Hematol Oncol Clin North Am. 2024; 38(5):1011-1025.

PMID: 38866636 PMC: 11368641. DOI: 10.1016/j.hoc.2024.05.002.

References

Briski R, Feldman A, Bailey N, Lim M, Ristow K, Habermann T . Survival in patients with limited-stage peripheral T-cell lymphomas. Leuk Lymphoma. 2014; 56(6):1665-70. PMC: 4456336. DOI: 10.3109/10428194.2014.963078. View

Alberti-Violetti S, Talpur R, Schlichte M, Sui D, Duvic M . Advanced-stage mycosis fungoides and Sézary syndrome: survival and response to treatment. Clin Lymphoma Myeloma Leuk. 2015; 15(6):e105-12. DOI: 10.1016/j.clml.2015.02.027. View

Dalloul A, Laroche L, Bagot M, Mossalayi M, Fourcade C, Thacker D . Interleukin-7 is a growth factor for Sézary lymphoma cells. J Clin Invest. 1992; 90(3):1054-60. PMC: 329964. DOI: 10.1172/JCI115920. View

Folkes A, Feng M, Zain J, Abdulla F, Rosen S, Querfeld C . Targeting CD47 as a cancer therapeutic strategy: the cutaneous T-cell lymphoma experience. Curr Opin Oncol. 2018; 30(5):332-337. PMC: 6452884. DOI: 10.1097/CCO.0000000000000468. View

Rook A, Vowels B, Jaworsky C, Singh A, Lessin S . The immunopathogenesis of cutaneous T-cell lymphoma. Abnormal cytokine production by Sézary T cells. Arch Dermatol. 1993; 129(4):486-9. View

Chao M, Tang C, Pachynski R, Chin R, Majeti R, Weissman I . Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood. 2011; 118(18):4890-901. PMC: 3208297. DOI: 10.1182/blood-2011-02-338020. View

Rendtlew Danielsen J, Knudsen L, Dahl I, Lodahl M, Rasmussen T . Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma. Br J Haematol. 2007; 138(6):756-60. DOI: 10.1111/j.1365-2141.2007.06729.x. View

Majeti R, Chao M, Alizadeh A, Pang W, Jaiswal S, Gibbs Jr K . CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009; 138(2):286-99. PMC: 2726837. DOI: 10.1016/j.cell.2009.05.045. View

Yurkovetsky Z, Kirkwood J, Edington H, Marrangoni A, Velikokhatnaya L, Winans M . Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b. Clin Cancer Res. 2007; 13(8):2422-8. DOI: 10.1158/1078-0432.CCR-06-1805. View

10.

Chao M, Majeti R, Weissman I . Programmed cell removal: a new obstacle in the road to developing cancer. Nat Rev Cancer. 2011; 12(1):58-67. DOI: 10.1038/nrc3171. View

11.

Noble A, Mehta H, Lovell A, Papaioannou E, Fairbanks L . IL-12 and IL-4 activate a CD39-dependent intrinsic peripheral tolerance mechanism in CD8(+) T cells. Eur J Immunol. 2016; 46(6):1438-48. PMC: 5071739. DOI: 10.1002/eji.201545939. View

12.

Rook A, Kubin M, Cassin M, Vonderheid E, Vowels B, Wolfe J . IL-12 reverses cytokine and immune abnormalities in Sezary syndrome. J Immunol. 1995; 154(3):1491-8. View

13.

Vezzoni M, Lucchini R, Giardini R, Raineri M, Murone M, Vezzoni P . Lactate dehydrogenase levels in cellular extracts of human malignant lymphomas. Tumori. 1983; 69(4):279-82. DOI: 10.1177/030089168306900401. View

14.

Petrova P, Nielsen Viller N, Wong M, Pang X, Lin G, Dodge K . TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding. Clin Cancer Res. 2016; 23(4):1068-1079. DOI: 10.1158/1078-0432.CCR-16-1700. View

15.

Soto-Pantoja D, Stein E, Rogers N, Sharifi-Sanjani M, Isenberg J, Roberts D . Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert Opin Ther Targets. 2012; 17(1):89-103. PMC: 3564224. DOI: 10.1517/14728222.2013.733699. View

16.

Krampitz G, George B, Willingham S, Volkmer J, Weiskopf K, Jahchan N . Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A. 2016; 113(16):4464-9. PMC: 4843455. DOI: 10.1073/pnas.1600007113. View

17.

Oldenborg P, Zheleznyak A, Fang Y, Lagenaur C, Gresham H, Lindberg F . Role of CD47 as a marker of self on red blood cells. Science. 2000; 288(5473):2051-4. DOI: 10.1126/science.288.5473.2051. View

18.

Vignali D . Multiplexed particle-based flow cytometric assays. J Immunol Methods. 2000; 243(1-2):243-55. DOI: 10.1016/s0022-1759(00)00238-6. View

19.

Saed G, Fivenson D, Naidu Y, Nickoloff B . Mycosis fungoides exhibits a Th1-type cell-mediated cytokine profile whereas Sezary syndrome expresses a Th2-type profile. J Invest Dermatol. 1994; 103(1):29-33. DOI: 10.1111/1523-1747.ep12388985. View

20.

Ring N, Herndler-Brandstetter D, Weiskopf K, Shan L, Volkmer J, George B . Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc Natl Acad Sci U S A. 2017; 114(49):E10578-E10585. PMC: 5724266. DOI: 10.1073/pnas.1710877114. View