Durable antitumor responses to CD47 blockade require adaptive immune stimulation

Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47–SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.

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Abstract S6-7: Adaptive immune system and immune checkpoints are associated with response to pertuzumab (P) and trastuzumab (H) in the NeoSphere study

10.1158/0008-5472.sabcs12-s6-7 ◽

2012 ◽

Cited By ~ 10

Author(s):

L Gianni ◽

G Bianchini ◽

P Valagussa ◽

A Belousov ◽

M Thomas ◽

...

Keyword(s):

Immune System ◽

Adaptive Immune System ◽

Immune Checkpoints ◽

Adaptive Immune

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Localized CD47 blockade enhances immunotherapy for murine melanoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1710776114 ◽

2017 ◽

Vol 114 (38) ◽

pp. 10184-10189 ◽

Cited By ~ 48

Author(s):

Jessica R. Ingram ◽

Olga S. Blomberg ◽

Jonathan T. Sockolosky ◽

Lestat Ali ◽

Florian I. Schmidt ◽

...

Keyword(s):

Immune Therapy ◽

Regulatory Protein ◽

Cell Types ◽

Life Extension ◽

Endogenous Expression ◽

Receptor Signal ◽

Melanoma Model ◽

Immune Therapies ◽

Xenograft Models ◽

Antitumor Antibody

CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPα). Inhibitors of the CD47–SIRPα interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Endogenous expression of CD47 on a variety of cell types, including erythrocytes, creates a formidable antigen sink that may limit the efficacy of CD47-targeting therapies. We generated a nanobody, A4, that blocks the CD47–SIRPα interaction. A4 synergizes with anti–PD-L1, but not anti-CTLA4, therapy in the syngeneic B16F10 melanoma model. Neither increased dosing nor half-life extension by fusion of A4 to IgG2a Fc (A4Fc) overcame the issue of an antigen sink or, in the case of A4Fc, systemic toxicity. Generation of a B16F10 cell line that secretes the A4 nanobody showed that an enhanced response to several immune therapies requires near-complete blockade of CD47 in the tumor microenvironment. Thus, strategies to localize CD47 blockade to tumors may be particularly valuable for immune therapy.

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Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1710877114 ◽

2017 ◽

Vol 114 (49) ◽

pp. E10578-E10585 ◽

Cited By ~ 78

Author(s):

Nan Guo Ring ◽

Dietmar Herndler-Brandstetter ◽

Kipp Weiskopf ◽

Liang Shan ◽

Jens-Peter Volkmer ◽

...

Keyword(s):

Antitumor Activity ◽

Regulatory Protein ◽

Human Tumor ◽

Myeloid Cell ◽

Antibody Treatment ◽

Therapeutic Success ◽

Normal Tissues ◽

Receptor Signal ◽

Key Factor ◽

Antibody Immunotherapy

Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulatory protein-α (SIRPα) is a myeloid-specific immune checkpoint that engages the “don’t eat me” signal CD47 expressed on tumors and normal tissues. We therefore developed the monoclonal antibody KWAR23, which binds human SIRPα with high affinity and disrupts its binding to CD47. Administered by itself, KWAR23 is inert, but given in combination with tumor-opsonizing monoclonal antibodies, KWAR23 greatly augments myeloid cell-dependent killing of a collection of hematopoietic and nonhematopoietic human tumor-derived cell lines. Following KWAR23 antibody treatment in a human SIRPA knockin mouse model, both neutrophils and macrophages infiltrate a human Burkitt’s lymphoma xenograft and inhibit tumor growth, generating complete responses in the majority of treated animals. We further demonstrate that a bispecific anti-CD70/SIRPα antibody outperforms individually delivered antibodies in specific types of cancers. These studies demonstrate that SIRPα blockade induces potent antitumor activity by targeting multiple myeloid cell subsets that frequently infiltrate tumors. Thus, KWAR23 represents a promising candidate for combination therapy.

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Insights into CD47/SIRPα axis-targeting tumor immunotherapy

Antibody Therapeutics ◽

10.1093/abt/tby006 ◽

2018 ◽

Vol 1 (2) ◽

pp. 37-42 ◽

Cited By ~ 4

Author(s):

Xuyao Zhang ◽

Jiajun Fan ◽

Dianwen Ju

Keyword(s):

Cytotoxic T Lymphocyte ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Regulatory Protein ◽

Adaptive Immune System ◽

Tumor Immunotherapy ◽

Potential Side Effect ◽

Promising Therapeutic Target ◽

Programmed Death ◽

Key Points

ABSTRACT During the last decade, inhibitors targeting immune checkpoint programmed death ligand 1/PD-1 and cytotoxic T-lymphocyte-associated protein 4 have been one of the most significant advances for cancer therapy in clinic. However, most of these therapies focused on stimulating the adaptive immune system-mediated elimination of tumor. Recent studies indicated that CD47/Signal-regulatory protein alpha (SIRPα), an innate anti-phagocytic axis between cancer cells and macrophages, could be a promising therapeutic target. Here, we review the current knowledge about developing CD47/SIRPα checkpoint inhibitors, avoiding potential side effect and designing optimal combination therapies, and highlight the key points for future clinical applications of CD47/SIRPα axis-targeted tumor immunotherapy.

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The structural features that distinguish PD-L2 from PD-L1 emerged in placental mammals

Journal of Biological Chemistry ◽

10.1074/jbc.ac119.011747 ◽

2019 ◽

Vol 295 (14) ◽

pp. 4372-4380 ◽

Cited By ~ 4

Author(s):

Elliot A. Philips ◽

Antonio Garcia-España ◽

Anna S. Tocheva ◽

Ian M. Ahearn ◽

Kieran R. Adam ◽

...

Keyword(s):

Adaptive Immune System ◽

Structural Features ◽

Inhibitory Receptor ◽

Programmed Death Ligand 1 ◽

Lower Affinity ◽

Adaptive Immune ◽

Programmed Death ◽

D Region ◽

Antigen Presenting ◽

Cell Death Protein

Programmed cell death protein 1 (PD-1) is an inhibitory receptor on T lymphocytes that is critical for modulating adaptive immunity. As such, it has been successfully exploited for cancer immunotherapy. Programmed death ligand 1 (PD-L1) and PD-L2 are ligands for PD-1; the former is ubiquitously expressed in inflamed tissues, whereas the latter is restricted to antigen-presenting cells. PD-L2 binds to PD-1 with 3-fold stronger affinity compared with PD-L1. To date, this affinity discrepancy has been attributed to a tryptophan (W110PD-L2) that is unique to PD-L2 and has been assumed to fit snuggly into a pocket on the PD-1 surface. Contrary to this model, using surface plasmon resonance to monitor real-time binding of recombinantly-expressed and -purified proteins, we found that W110PD-L2 acts as an “elbow” that helps shorten PD-L2 engagement with PD-1 and therefore lower affinity. Furthermore, we identified a “latch” between the C and D β-strands of the binding face as the source of the PD-L2 affinity advantage. We show that the 3-fold affinity advantage of PD-L2 is the consequence of these two opposing features, the W110PD-L2 “elbow” and a C–D region “latch.” Interestingly, using phylogenetic analysis, we found that these features evolved simultaneously upon the emergence of placental mammals, suggesting that PD-L2–affinity tuning was part of the alterations to the adaptive immune system required for placental gestation.

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Cancer Immunotherapy Comes of Age

Journal of Clinical Oncology ◽

10.1200/jco.2011.38.0899 ◽

2011 ◽

Vol 29 (36) ◽

pp. 4828-4836 ◽

Cited By ~ 278

Author(s):

Suzanne L. Topalian ◽

George J. Weiner ◽

Drew M. Pardoll

Keyword(s):

Cancer Immunotherapy ◽

Antitumor Immunity ◽

Ex Vivo ◽

Adaptive Immune System ◽

Therapeutic Modality ◽

Immune Memory ◽

Immune Checkpoints ◽

Cancer Therapies ◽

Treatment Regimens ◽

Antitumor Antibodies

Cancer immunotherapy comprises a variety of treatment approaches, incorporating the tremendous specificity of the adaptive immune system (T cells and antibodies) as well as the diverse and potent cytotoxic weaponry of both adaptive and innate immunity. Immunotherapy strategies include antitumor monoclonal antibodies, cancer vaccines, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate immune cells or block immune inhibitory pathways (so-called immune checkpoints). Although clear clinical efficacy has been demonstrated with antitumor antibodies since the late 1990s, other immunotherapies had not been shown to be effective until recently, when a spate of successes established the broad potential of this therapeutic modality. These successes are based on fundamental scientific advances demonstrating the toleragenic nature of cancer and the pivotal role of the tumor immune microenvironment in suppressing antitumor immunity. New therapies based on a sophisticated knowledge of immune-suppressive cells, soluble factors, and signaling pathways are designed to break tolerance and reactivate antitumor immunity to induce potent, long-lasting responses. Preclinical models indicate the importance of a complex integrated immune response in eliminating established tumors and validate the exploration of combinatorial treatment regimens, which are anticipated to be far more effective than monotherapies. Unlike conventional cancer therapies, most immunotherapies are active and dynamic, capable of inducing immune memory to propagate a successful rebalancing of the equilibrium between tumor and host.

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