Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice

Xie, Yushu Joy; Dougan, Michael; Jailkhani, Noor; Ingram, Jessica R.; Fang, Tao; Kummer, Laura; Momin, Noor; Pishesha, Novalia; Rickelt, Steffen; Hynes, Richard O.; Ploegh, Hidde L.

doi:10.1073/pnas.1817147116

Cited by 226 publications

(204 citation statements)

References 47 publications

(68 reference statements)

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“…The low immunogenicity of the nanobodies (17,18) should make any targeted agent poorly visible to the immune system, thereby reducing systemic toxicities. An example of such an application is presented in an accompanying paper (51), which describes incorporation of the NJB2 nanobody into CAR T cells to enhance their antitumor activity. The imaging of the EIIIB-KO mice and the detection of normal mouse cartilage by NJB2 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix

Jailkhani

Ingram

Rashidian

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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127

120

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SignificanceCancers, fibroses, and inflammatory disorders are characterized by increased deposition of the extracellular matrix (ECM). ECM biomarkers that are selectively expressed at these disease sites are attractive targets for imaging and therapeutic approaches. Nanobodies against these biomarkers would be pertinent vehicles for the accumulation of imaging and therapeutic cargo at disease sites, potentially increasing specificity and reducing background. We demonstrate the specificity of one such anti-ECM nanobody by using immuno-PET/CT and show that it detects multiple models of cancer, including early lesions and metastases, and also fibroses, with excellent specificity and clarity. Thus, novel strategies for delivering imaging and therapeutic probes specifically to the ECM in disease sites may prove particularly valuable for detection and treatment of cancer in patients.

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Section: Discussionmentioning

confidence: 99%

Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix

Jailkhani

Ingram

Rashidian

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

127

120

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“…120 121 CAR T cells with anti-PD-L1 targeting have demonstrated cytotoxic activity in mice bearing melanoma and colon tumors. 122 In addition, CAR T cells have been developed with a switch receptor construct composed of extracellular PD-1 domains coupled to transmembrane and cytoplasmic CD28 signaling domains. 123 These CAR T cells have been shown to induce tumor regression in murine models of prostate cancer.…”

Section: Alternative Mechanisms Of Immune Modulation For T Lymphocytementioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

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Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

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“…This approach may employ human scFvs for CAR construct design to improve the long-term survival of CAR-T cells, whereas a potential human anti-mouse antibody reaction may eliminate CAR-T cells that use a murine scFv for binding and lead to poor persistence. In recent years, efforts have been made to replace scFvs with nanobodies derived from camelids 241 , and preclinical studies have shown that nanobody-based CAR-T cells showed improved flexibility in antigen recognition and achieved comparable efficacy when treating different tumors 242,243 . CAR-T cells attack cells expressing the CAR-recognized antigens, which are always TAAs.…”

Section: Binding Domainmentioning

confidence: 99%

Genetically engineered T cells for cancer immunotherapy

Zhou

et al. 2019

Sig Transduct Target Ther

179

102

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T cells in the immune system protect the human body from infection by pathogens and clear mutant cells through specific recognition by T cell receptors (TCRs). Cancer immunotherapy, by relying on this basic recognition method, boosts the antitumor efficacy of T cells by unleashing the inhibition of immune checkpoints and expands adaptive immunity by facilitating the adoptive transfer of genetically engineered T cells. T cells genetically equipped with chimeric antigen receptors (CARs) or TCRs have shown remarkable effectiveness in treating some hematological malignancies, although the efficacy of engineered T cells in treating solid tumors is far from satisfactory. In this review, we summarize the development of genetically engineered T cells, outline the most recent studies investigating genetically engineered T cells for cancer immunotherapy, and discuss strategies for improving the performance of these T cells in fighting cancers.

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Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice

Cited by 226 publications

References 47 publications

Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix

Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix

T lymphocyte-targeted immune checkpoint modulation in glioma

Genetically engineered T cells for cancer immunotherapy

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