Page 106 - Haematologica Vol. 109 - July 2024

ARTICLE - CD47 inhibition is augmented with TLR3 agonism H.E. Ramsey et al.
in AML xenografts. Our study may provide greater insight into the relationship between AML cells and monocyte/ macrophage polarization which can be studied in matura- tional and mutational subsets for better understanding of how to utilize this type of immunotherapy for AML. Furthermore, we suggest that this increased phagocytic ability of poly(I:C)-treated BM results from the concomitant increase of M1-primed macrophages after treatment. In previous studies, CD11c activation in macrophages through IFN-γ use was shown to increase broad spectrum phago- cytosis, resulting in an enhancement of anti-tumor im- munity via promotion of phagocytosis.45 The increases of CD11c-positive macrophages in our study are consistent with this IFN-γ induced M1 priming, and does not require LPS administration required for response with IFN.
The ability to increase active macrophage populations within the BM of AML patients could potentiate the use of anti- CD47-based therapy, particularly when clonal leukemia has physically displaced functional hematopoietic cells, and polarized macrophages to a tumor permissive M2 subtype. Further, it may argue for incorporation of CD47 inhibition into maintenance therapy after establishing remission with VEN/AZA so normal macrophage constituency may recon- stitute a healthy BM.
Disclosures
MRS receives research funding from ALX Oncology, Astex, Incyte, Takeda and TG Therapeutics; has stock in Karyo- pharm and Ryvu; serves on advisory boards or consults or BMS, CTI, Forma, Geron, GSK, Karyopharm, Rigel, Ryvu, Taiho and Treadwell.
Contributions
Conception and design by HR and MS. Development of meth- odology by HR, AM, AG, PA, BNS and MS. Acquisition of data (provided animals, acquired and managed patient samples, provided facilities, etc.) by HR, BNS, AG, PA, LF and MS.
References
1. Kelley SM, Ravichandran KS. Putting the brakes on phagocytosis: “don’t-eat-me” signaling in physiology and disease. EMBO Rep. 2021;22(6):e52564.
2. Jaiswal S, Jamieson CHM, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138(2):271-285.
3. Sikic BI, Lakhani N, Patnaik A, et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J Clin Oncol. 2019;37(12):946-953.
4. Advani R, Flinn I, Popplewell L, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med. 2018;379(18):1711-1721.
5. Wang Y, Ni H, Zhou S, et al. Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. Cancer Immunol
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis) by HR, AM, AG, PA and MS. Writing, review, and/or revision of the manuscript by all authors. Administrative, technical, or material support (i.e., reporting or organizing data, constructing database) by all authors. Study supervision by MS.
Acknowledgments
The Vanderbilt-Ingram Cancer Center (VICC) Hematopoietic Malignancies Tissue Repository, the Vanderbilt University Medical Center Translational Pathology Shared Resource, and other VICC shared Core Services were critical in com- pletion of this work. The authors would like to acknowledge Vanderbilt SWERV writing core for the editorial guidance.
Funding
This study was supported by ALX Oncology. MRS is a Leuke- mia and Lymphoma Clinical Scholar, and receives funding from the Adventure Alle Fund, Beverly and George Rawlings Endowment, Biff Ruttenberg Foundation, and the NIH RO1 CA262287-01 and U01 OH012271-01. The Vanderbilt-Ingram Cancer Center is supported by a NIH P30 CA068485–19. The REDCap database tool is supported by grant UL1 TR000445 from NCATS/NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply en- dorsement by the US Government. Confocal microscopy was performed though the use of the Vanderbilt Cell Im- aging Shared Resource (CISR) supported by NIH grants CA68485, DK20593, DK58404, DK59637, and EY08126. The Zeiss LSM880 confocal microscope was acquired through NIH S10 OD021630 equipment grant.
Data-sharing statement
Protocols and original data from this manuscript are avail- able upon request by contacting the corresponding author.
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6. Chen SH, Dominik PK, Stanfield J, et al. Dual checkpoint
blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity. J Immunother Cancer. 2021;9(10):e003464.
7. Dheilly E, Moine V, Broyer L, et al. Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dual- targeting bispecific antibodies. Mol Ther. 2017;25(2):523-533.
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9. Kauder SE, Kuo TC, Harrabi O, et al. ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a
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