Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface

Gubbels, Jennifer A. A.; Gadbaw, Brian; Buhtoiarov, Ilia N.; Horibata, Sachi; Kapur, Arvinder; Patel, D.J.; Hank, Jacquelyn A.; Gillies, Stephen D.; Sondel, Paul M.; Patankar, Manish S.

doi:10.1007/s00262-011-1072-9

Cited by 37 publications

(31 citation statements)

References 54 publications

(61 reference statements)

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“…The impact of hu14.18-IL2 on tumor growth following radiation in FcγR-deficient mice was modest, albeit significant (Figure 3C), yet did not impact animal survival (Figure 3D). This tumor-growth inhibition by IC (but not by mAb) in FcγR-deficient mice may reflect the capacity of hu14.18-IL2 to tether effector cells to tumor cells via IL2 receptors, as previously reported (32). …”

Section: Resultssupporting

confidence: 79%

In SituTumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments

et al. 2016

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Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment anti-tumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL-2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T cell response. Given the T cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared to combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T cell checkpoint blockade, with immediate implications for clinical evaluation.

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Section: Resultssupporting

confidence: 79%

In SituTumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments

et al. 2016

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“…Such treatments might also be expected to synergize with any direct therapeutic effect of the antibody mediated by the antibody itself or through interaction with innate effectors such as NK cells that express Fc receptors. Preclinical studies in mice as well as clinical trials in patients with neuroblastoma revealed that T cells and NK cells were important in the anti-tumor effects [70-73]. Interestingly, it appears that therapeutic efficacy of these complete antibody-IL-2 fusions, may not be simply due to enhanced delivery of cytokine to the tumor.…”

Section: Antibody-cytokine Fusionsmentioning

confidence: 99%

“…Interestingly, it appears that therapeutic efficacy of these complete antibody-IL-2 fusions, may not be simply due to enhanced delivery of cytokine to the tumor. Rather, the biological activity of the antibody-IL-2 fusions appears in part to be due to the increased killing of tumor cells as a result of increased conjugate formation due to binding of IL-2 receptors on immune cells [73,74]. Thus in essence, the IL-2 conjugated antibody forms a “bridge” between cytotoxic cells and the target tumor cells.…”

Section: Antibody-cytokine Fusionsmentioning

confidence: 99%

Challenges and developing solutions for increasing the benefits of IL-2 treatment in tumor therapy

Skrombolas¹,

Frelinger²

2014

Expert Review of Clinical Immunology

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Summary Interleukin-2 (IL-2) is a cytokine with pleiotropic effects on the immune system. Systemic IL-2 treatment has produced durable responses in melanoma and renal cancer patients, but unfortunately this is effective only in a fraction of patients. Moreover, IL-2 treatment also engenders serious side effects, which limit its clinical utility. It is now appreciated that IL-2 not only stimulates NK and effector T cells but also has a critical role in the generation and maintenance of regulatory T cells, which act to dampen immune responses. Thus, successful immunotherapy of cancers using IL-2 has to address two fundamentally important issues: (1) how to limit side effects yet be active where it is needed, and (2) how to preferentially activate effector T cells while limiting the stimulation of Tregs. Strategies are now being developed to address these critical obstacles that may lead to a renaissance of IL-2 therapy.

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“…Preclinical studies showed that this fusion protein (or immunocytokine) had far superior antitumor activity when compared to comparable doses of ch14.18 mAb and IL-2 given simultaneously as individual agents 101 . A study evaluating immunocytokine-facilitated conjugate formation between NK cells and tumor cells demonstrated that tumor cells coated with immunocytokine were bound to NK cells not only through the Fc region of the immunocytokine but also through the IL-2 moiety 102,103 . NK cells bound to tumor cells formed activated immune synapses, defined by the localization of LFA-1 and CD2, along with clustering of NK cell CD25 into the synapse.…”

Section: Enhancing Nk Cell Function With Monoclonal Antibodiesmentioning

confidence: 99%

NK Cell-based Immunotherapies in Pediatric Oncology

McDowell

Hank

DeSantes

et al. 2015

Journal of Pediatric Hematology/Oncology

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The past decade has seen several anti-cancer immunotherapeutic strategies transition from “promising preclinical models” to treatments with proven clinical activity or benefit. In 2013, the journal Science selected the field of Cancer Immunotherapy as the overall number-1 breakthrough for the year in all of scientific research. In the setting of cancer immunotherapy for adult malignancies, many of these immunotherapy strategies have relied on the cancer patient’s endogenous anti-tumor T cell response. While much promising research in pediatric oncology is similarly focused on T cell reactivity, several pediatric malignancies themselves, or the chemo-radiotherapy used to achieve initial responses, can be associated with profound immune suppression, particularly of the T cell system. A separate component of the immune system, also able to mediate anti-tumor effects and less suppressed by conventional cancer treatment, is the NK cell system. In recent years, several distinct immunotherapeutic approaches that rely on the activity of NK cells have moved from preclinical development into clinical testing, and some have shown clear antitumor benefit. This review provides an overview of NK cell-based immunotherapy efforts that are directed towards childhood malignancies, with an emphasis on protocols that are already in clinical testing.

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Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface

Cited by 37 publications

References 54 publications

In SituTumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments

In SituTumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments

Challenges and developing solutions for increasing the benefits of IL-2 treatment in tumor therapy

NK Cell-based Immunotherapies in Pediatric Oncology

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