Localized CD47 blockade enhances immunotherapy for murine melanoma

Ingram, Jessica R.; Blomberg, Olga; Sockolosky, Jonathan T.; Ali, Lestat; Schmidt, Florian I.; Pishesha, Novalia; Espinosa, Camilo; Dougan, Stephanie K.; García, K. Christopher; Ploegh, Hidde L.; Dougan, Michael

doi:10.1073/pnas.1710776114

Cited by 116 publications

(117 citation statements)

References 24 publications

(77 reference statements)

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“…To improve upon its therapeutic profile, a nanobody (camelid single heavy chain antibody fragment) against CD47 with ~200-fold higher binding affinity than the commercially available antimouse CD47 monoclonal antibody (miap301) was recently developed and characterized 9 . This nanobody demonstrated mild effects as a systemically administered monotherapy, potentially due to lack of Fc-mediated effector function 30 ; however, a notable therapeutic response was observed when used in combination with a tumor specific antibody and systemic immune checkpoint blockade. In this work, we engineered an E. coli strain containing a synchronized lysis circuit (eSLC) that colonizes tumors and undergoes intratumoral quorum-lysis to locally release an encoded nanobody antagonist of CD47 (eSLC-CD47nb) (Fig.…”

Section: Main Textmentioning

confidence: 99%

Programmable bacteria induce durable tumor regression and systemic antitumor immunity

Chowdhury

Hinchliffe

Castro

et al. 2019

Preprint

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Co-corresponding authors SUMMARY PARAGRAPHSynthetic biology is driving a new era of medicine through the genetic programming of living cells 1,2 . This transformative approach allows for the creation of engineered systems that intelligently sense and respond to diverse environments, ultimately adding specificity and efficacy that extends beyond the capabilities of molecular-based therapeutics 3-5 . One particular focus area has been the engineering of bacteria as therapeutic delivery systems to selectively release therapeutic payloads in vivo 6-8 . Here, we engineered a nonpathogenic E. coli to specifically lyse within the tumor microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb) 9 , an anti-phagocytic receptor commonly overexpressed in several human cancers 10,11 . We show that intratumoral delivery of CD47nb by tumor-colonizing bacteria increases activation of tumor-infiltrating T cells, stimulates rapid tumor regression, prevents metastasis, and leads to long-term survival in a syngeneic tumor model. Moreover, we report that local injection of CD47nb bacteria stimulates systemic antitumor immune responses that reduce the growth of untreated tumorsproviding, to the best of our knowledge, the first demonstration of an abscopal effect induced by a bacteria cancer therapy. Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic antitumor immunity.

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Section: Main Textmentioning

confidence: 99%

Programmable bacteria induce durable tumor regression and systemic antitumor immunity

Chowdhury

Hinchliffe

Castro

et al. 2019

Preprint

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“…Inhibition of both the CD47‐SIRPα and PD‐1‐PD‐L1 axes might therefore be expected have a synergistic antitumor action, given that blockade of CD47 is thought to exert antitumor effects by promoting the phagocytosis of tumor cells and tumor cell‐releasing substances by macrophages or DCs as well as by enhancing the cross‐priming of tumor‐specific cytotoxic T cells by these antigen‐presenting cells (Figure ) . Indeed, a nanobody (an antigen‐binding fragment of an Ab heavy chain) that reacts with CD47 and thereby inhibits the CD47‐SIRPα interaction was found to synergize with PD‐L1 antagonism to attenuate the growth of tumors formed in immunocompetent mice by s.c. injected syngeneic melanoma cells . The efficacy of combined therapy with Abs to PD‐1 and to CTLA‐4 in a mouse model of esophageal squamous cell cancer was also enhanced by blocking Abs to CD47 .…”

Section: Combination Of Blocking Abs To Cd47 or To Sirpα With Immune mentioning

confidence: 99%

“…51,52 Indeed, a nanobody (an antigen-binding fragment of an Ab heavy chain) that reacts with CD47 and thereby inhibits the CD47-SIRPα interaction was found to synergize with PD-L1 antagonism to attenuate the growth of tumors formed in immunocompetent mice by s.c. injected syngeneic melanoma cells. 60,61 The efficacy of combined therapy with Abs to PD-1 and to CTLA-4 in a mouse model of esophageal squamous cell cancer was also enhanced by blocking Abs to CD47. 62 Moreover, combined blockade of SIRPα and PD-1 had a synergistic antitumor effect in a syngeneic mouse model of colon cancer.…”

Section: Combination Of Blocking Abs To Cd4 7 or To Sirpα With Immumentioning

confidence: 99%

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

et al. 2018

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Tumor cells evade immune surveillance through direct or indirect interactions with various types of immune cell, with much recent attention being focused on modifying immune cell responses as the basis for the development of new cancer treatments. Signal regulatory protein α (SIRPα) and CD47 are both transmembrane proteins that interact with each other and constitute a cell‐cell communication system. SIRPα is particularly abundant in myeloid cells such as macrophages and dendritic cells, whereas CD47 is expressed ubiquitously and its expression level is elevated in cancer cells. Recent studies have shown that blockade of CD47‐SIRPα interaction enhances the phagocytic activity of phagocytes such as macrophages toward tumor cells in vitro as well as resulting in the efficient eradication of tumor cells in a variety of xenograft or syngeneic mouse models of cancer. Moreover, CD47 blockade has been shown to promote the stimulation of tumor‐specific cytotoxic T cells by macrophages or dendritic cells. Biological agents, such as Abs and recombinant proteins, that target human CD47 or SIRPα have been developed and are being tested in preclinical models of human cancer or in clinical trials with cancer patients. Preclinical studies have also suggested that CD47 or SIRPα blockade may have a synergistic antitumor effect in combination with immune checkpoint inhibitors that target the adaptive immune system. Targeting of the CD47‐SIRPα signaling system is thus a promising strategy for cancer treatment based on modulation of both innate and acquired immune responses to tumor cells.

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“…For instance, CD47 is overexpressed on long‐lived memory CD4 + T cells to avoid clearance by phagocytosis, and most relevant to this review, CD47 is expressed on melanoma cells in which positively correlated with bad prognosis . As mentioned above, death of tumor cells and phagocytosis by cDC1s is an obligatory step to trigger optimal T cell responses, and as such anti‐SIRPα and anti‐CD47 immunotherapies enhanced T cell control of tumor growth and dissemination …”

Section: Immunosurveillance Mechanisms Relevant To Melanoma Controlmentioning

confidence: 83%

OMIC signatures to understand cancer immunosurveillance and immunoediting: Melanoma and immune cells interplay in immunotherapy

León‐Letelier

Bonifaz

Fuentes‐Pananá

2019

Journal of Leukocyte Biology

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Melanoma is the deadliest form of skin cancer. Cutaneous melanomas usually originate from exposure to the mutagenic effects of ultraviolet radiation, and as such they exhibit the highest rate of somatic mutations than any other human cancer, and an extensive expression of neoantigens concurrently with a dense infiltrate of immune cells. The coexistence of high immunogenicity and high immune cell infiltration may sound contradictory for cancers carrying a gloomy outcome. However, recent studies have unveiled a variety of immunosuppressive mechanisms that often permeate the tumor microenvironment and that are responsible for tumor escaping from immunosurveillance mechanisms. Nonetheless, this particular immune profile has opened a new window of treatments based on immunotherapy that have significantly improved the clinical outcome of melanoma patients. Still, positive and complete therapy responses have been limited, and this particular cancer continues to be a major clinical challenge. The transcriptomic signatures of those patients with clinical benefit and those with progressive disease have provided a more complete picture of the universe of interactions between the tumor and the immune system. In this review, we integrate the results of the immunotherapy clinical trials to discuss a novel understanding of the mechanisms guiding cancer immunosurveillance and immunoediting. A clear notion of the cellular and molecular processes shaping how the immune system and the tumor are continuously coevolving would result in the rational design of combinatory therapies aiming to counteract the signaling pathways and cellular processes responsible for immunoescape mechanisms and provide clinical benefit to immunotherapy nonresponsive patients.

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Localized CD47 blockade enhances immunotherapy for murine melanoma

Cited by 116 publications

References 24 publications

Programmable bacteria induce durable tumor regression and systemic antitumor immunity

Programmable bacteria induce durable tumor regression and systemic antitumor immunity

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

OMIC signatures to understand cancer immunosurveillance and immunoediting: Melanoma and immune cells interplay in immunotherapy

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