CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma

Advani, Ranjana H.; Flinn, Ian W.; Popplewell, Leslie; Forero, Andres; Bartlett, Nancy L.; Ghosh, Nilanjan; Kline, Justin; Roschewski, Mark; LaCasce, Ann S.; Collins, Graham P.; Tran, Tri; Lynn, Judith; Chen, James Y.; Volkmer, Jens Peter; Agoram, Balaji; Huang, Jie; Majeti, Ravindra; Weissman, Irving L.; Takimoto, Chris H.; Chao, Mark; Smith, Sonali M.

doi:10.1056/nejmoa1807315

Cited by 823 publications

(781 citation statements)

References 25 publications

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“…transformation, aberrant B cells may express nonself or neo-antigens that would allow other immune effector cells, such as T cells, natural killer (NK) cells and macrophages, to detect and eliminate them. A CD47-targeting antibody used in combination with the anti-CD20 antibody Rituximab in patients with relapsed or refractory DLBCL or FL yielded complete response in about 36% of patients 158,160. MHC class I (MHC I) proteins, which are present on most nucleated cells, mediate presentation of self, nonself and neo-peptides to cytotoxic CD8+ T cells.…”

mentioning

confidence: 99%

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Mlynarczyk

Fontán

Melnick

2019

Immunological Reviews

120

142

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Summary One of the unusual features of germinal center (GC) B cells is that they manifest many hallmarks of cancer cells. Accordingly, most B‐cell neoplasms originate from the GC reaction, and characteristically display abundant point mutations, structural genomic lesions, and clonal diversity from the genetic and epigenetic standpoints. The dominant biological theme of GC‐derived lymphomas is mutation of genes involved in epigenetic regulation and immune receptor signaling, which come into play at critical transitional stages of the GC reaction. Hence, mechanistic studies of these mutations reveal fundamental insight into the biology of the normal and malignant GC B cell. The BCL6 transcription factor plays a central role in establishing the GC phenotype in B cells, and most lymphomas are dependent on BCL6 to maintain survival, proliferation, and perhaps immune evasion. Many lymphoma mutations have the commonality of enhancing the oncogenic functions of BCL6, or overcoming some of its tumor suppressive effects. Herein, we discuss how unique features of the GC reaction create vulnerabilities that select for particular lymphoma mutations. We examine the interplay between epigenetic programming, metabolism, signaling, and immune regulatory mechanisms in lymphoma, and discuss how these are leading to novel precision therapy strategies to treat lymphoma patients.

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confidence: 99%

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Mlynarczyk

Fontán

Melnick

2019

Immunological Reviews

120

142

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“…In a phase 1 study published in 2018, 50% of 22 patients with advanced non‐Hodgkin's lymphoma treatment experienced an objective response after treatment with the combination of anti‐CD47 and rituximab. Larger studies with longer follow up are necessary to confirm these results …”

Section: Using and Targeting Hscs In Cancermentioning

confidence: 85%

Adult stem cells and regenerative medicine—a symposium report

Cable¹,

Fuchs

Weissman

et al. 2019

Annals of the New York Academy of Sciences

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Adult stem cells are rare, undifferentiated cells found in all tissues of the body. Although normally kept in a quiescent, nondividing state, these cells can proliferate and differentiate to replace naturally dying cells within their tissue and to repair its wounds in response to injury. Due to their proliferative nature and ability to regenerate tissue, adult stem cells have the potential to treat a variety of degenerative diseases as well as aging. In addition, since stem cells are often thought to be the source of malignant tumors, understanding the mechanisms that keep their proliferative abilities in check can pave the way for new cancer therapies. While adult stem cells have had limited practical and clinical applications to date, several clinical trials of stem cell–based therapies are underway. This report details recent research presented at the New York Academy of Sciences on March 14, 2019 on understanding the factors that regulate stem cell activity and differentiation, with the hope of translating these findings into the clinic.

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“…Thus, combining doxorubicin chemotherapy with PD-L1 blockade immunotherapy did not appear to have additional beneficial effects on tumor control. On the other hand, in patients with lymphoma, a recent phase 1b study showed that CD47 mAb in concert with rituximab showed enhanced effects by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (Advani et al, 2018). The authors achieved 33% complete response in patients with diffuse large B-cell lymphoma and 43% complete response in patients with follicular lymphoma (Advani et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, in patients with lymphoma, a recent phase 1b study showed that CD47 mAb in concert with rituximab showed enhanced effects by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (Advani et al, 2018). The authors achieved 33% complete response in patients with diffuse large B-cell lymphoma and 43% complete response in patients with follicular lymphoma (Advani et al, 2018). In a mouse model of breast cancer, Feliz-Mosquea et al (2018) found significantly reduced metastasis after doxorubicin and CD47 mAb combination therapy.…”

Section: Discussionmentioning

confidence: 99%

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

et al. 2019

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The long‐term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty‐eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty‐four mice (n = 6 per group) underwent pre‐ and post‐treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor‐associated macrophages (TAM) density were compared between different groups using a one‐way ANOVA. Twenty‐four additional NSG mice underwent survival analyses with Kaplan–Meier curves and a log‐rank (Mantel–Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor‐bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.

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CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma

Cited by 823 publications

References 25 publications

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Adult stem cells and regenerative medicine—a symposium report

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

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