A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers.

Šikić, Branimir I.; Narayanan, Sujata; Colevas, A. Dimitrios; Padda, Sukhmani K.; Fisher, George A.; Supan, Dana; Wakelee, Heather A.; Aoki, Rhonda; Pegram, Mark D.; Villalobos, Víctor M.; Liu, Jie; Chao, Mark; Volkmer, Jens-Peter; Majeti, Ravindra; Weissman, Irving L.

doi:10.1200/jco.2016.34.15_suppl.3019

Cited by 36 publications

(20 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In TTI-621 trials, 4/5 patients receiving 0.3 mg/kg dosages developed G3 and G4 platelet count events while maintaining stable hemoglobin levels (5). In contrast, out of the 16 patients in Hu5F9-G4 trial, there were 11 incidences of G1 and 5 incidences of G2 anemia, with no reported platelet events (7). These results show that the decoy receptor TTI-621 has a lower impact on RBCs compared to Hu5F9-G4, in spite of a higher general toxicity to other cells due to the strong ADCC from IgG1.…”

Section: Comparison Of the Trial Results And Clinical Perspectivesmentioning

confidence: 72%

Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy

Huang

Gao

et al. 2017

J. Thorac. Dis.

View full text Add to dashboard Cite

Targeting CD47 is in the spotlight of cancer immunotherapy. Blocking CD47 triggers the recognition and elimination of cancer cells by the innate immunity. There are three CD47 antagonists in phase I clinical trials, but their potential efficacies are highly controversial. We raise our concern that NOD-based xenograft hosts tend to overestimate, while syngeneic mouse models could substantially underestimate the efficacy of anti-CD47 therapy. Such discrepancy may be resulted from specific reagent that alters CD47 clustering, and the highly variable avidities of interspecies and intraspecies CD47-SIRPα interaction. This problem can be addressed by alternative animal models for better recapitulation of human CD47-SIRPα interaction. Both fragment crystallizable (Fc) fragment-dependent effects, like antibody-dependent cellmediated cytotoxicity (ADCC), and Fc-independent CD47 intrinsic functions are involved in anti-CD47 therapy.The latter may be SIRPα-dependent or SIRPα-independent, such as the case of calreticulin. It has not reached a consensus which of the factors predominate the process, but the answer to this question will determine the optimal pharmaceutical and clinical design of CD47 targeting strategies.

show abstract

Section: Comparison Of the Trial Results And Clinical Perspectivesmentioning

confidence: 72%

Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy

Huang

Gao

et al. 2017

J. Thorac. Dis.

View full text Add to dashboard Cite

show abstract

“…Preclinical data for CD47 antibodies that inhibit CD47-SIRPa interaction have generally found that TSP1-CD47 interactions are also inhibited, and such antibodies consequently alter blood pressure by an NO-dependent mechanism when injected intravenously (10) and, by enhancing red blood cell clearance, can induce anemia (144,194,239). Thus, systemic cardiovascular side effects need to be considered and monitored.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

show abstract

“…Several molecules targeting CD47/SIRPα axis are being developed as therapeutic agents for treatment of different tumor types (Table ). However, initial data from phase 1 trials are not as promising as the preclinical data suggested .…”

Section: Boosting the Antitumoral Effects Of Macrophages By Tam Repromentioning

confidence: 99%

“…This is particularly relevant for the treatment of patients with solid tumors. Expression of CD47 on peripheral blood cells poses an additional challenge, as CD47 targeting agents induce enhanced clearance of these cells leading to toxicities like anemia and neutropenia which have been reported in the clinical studies . These effects are not only a safety concern but also limit the effective dose that can be administered to patients to enable antitumoral activity.…”

Section: Boosting the Antitumoral Effects Of Macrophages By Tam Repromentioning

confidence: 99%

A drug development perspective on targeting tumor‐associated myeloid cells

et al. 2017

View full text Add to dashboard Cite

Despite decades of research, cancer remains a devastating disease and new treatment options are needed. Today cancer is acknowledged as a multifactorial disease not only comprising of aberrant tumor cells but also the associated stroma including tumor vasculature, fibrotic plaques, and immune cells that interact in a complex heterotypic interplay. Myeloid cells represent one of the most abundant immune cell population within the tumor stroma and are equipped with a broad functional repertoire that promotes tumor growth by suppressing cytotoxic T cell activity, stimulating neoangiogenesis and tissue remodeling. Therefore, myeloid cells have become an attractive target for pharmacological intervention. In this review, we summarize the pharmacological approaches to therapeutically target tumor-associated myeloid cells with a focus on advanced programs that are clinically evaluated. In addition, for each therapeutic strategy, the preclinical rationale as well as advantages and challenges from a drug development perspective are discussed.

show abstract

A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers.

Cited by 36 publications

References 0 publications

Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy

Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

A drug development perspective on targeting tumor‐associated myeloid cells

Contact Info

Product

Resources

About