4-1BB (CD137) and radiation therapy: A case report and literature review

Shiao, Jay C.; Bowers, Nathan L.; Nasti, Tahseen H.; Khosa, Faisal

doi:10.1016/j.adro.2017.03.007

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…A significant increase in CD4+ and CD8+ T cells in TME has also been shown [ 112 ]. Clinical data studying the combination of a 4-1BBL agonist with radiotherapy [ 113 ] and PD-1 blockade [ 114 ] have reported sometimes impressive responses. Thus, studies combining ICI + SBRT with 4-1BB targeting of activated effector T cells seem promising.…”

Section: Perspectivesmentioning

confidence: 99%

Narrative Review of Synergistics Effects of Combining Immunotherapy and Stereotactic Radiation Therapy

et al. 2022

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Stereotactic radiotherapy (SRT) has become an attractive treatment modality in full bloom in recent years by presenting itself as a safe, noninvasive alternative to surgery to control primary or secondary malignancies. Although the focus has been on local tumor control as the therapeutic goal of stereotactic radiotherapy, rare but intriguing observations of abscopal (or out-of-field) effects have highlighted the exciting possibility of activating antitumor immunity using high-dose radiation. Furthermore, immunotherapy has revolutionized the treatment of several types of cancers in recent years. However, resistance to immunotherapy often develops. These observations have led researchers to combine immunotherapy with SRT in an attempt to improve outcomes. The benefits of this combination would come from the stimulation and suppression of various immune pathways. Thus, in this review, we will first discuss the immunomodulation induced by SRT with the promising results of preclinical studies on the changes in the immune balance observed after SRT. Then, we will discuss the opportunities and risks of the combination of SRT and immunotherapy with the preclinical and clinical data available in the literature. Furthermore, we will see that many perspectives are conceivable to potentiate the synergistic effects of this combination with the need for prospective studies to confirm the encouraging data.

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Section: Perspectivesmentioning

confidence: 99%

Narrative Review of Synergistics Effects of Combining Immunotherapy and Stereotactic Radiation Therapy

et al. 2022

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“…Moreover, 4-1BB monoclonal antibodies combined with PD-1 blockade and SBRT have been studied in murine melanoma models with encouraging rates of response (133). In addition, impressive responses have been reported clinically following the combination of a 4-1BBL agonist with radiation therapy (134) and PD-1 blockade (135), individually. As result, another strategy to improve the therapeutic response of SBRT in combination with ICB exists in the form of targeting 4-1BB on activated effector T-cells.…”

Section: Manipulation Of the Tumor Microenvironmentmentioning

confidence: 99%

The role of immunotherapy in combination with oligometastasis-directed therapy: a narrative review

Turchan¹,

Chmura²

2021

Ann Palliat Med

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Metastatic disease is a significant cause of morbidity and mortality among patients with cancer.Patients with oligometastatic cancer represent a subset of the metastatic population with a limited amount of disease that has metastasized distantly and progresses at a slow pace and thus has the potential to be cured with metastasis-directed local therapy. Recent studies examining the role of metastasis-directed therapy in patients with oligometastatic disease have primarily focused upon treatment with ablative doses of radiation, commonly referred to as stereotactic body radiation therapy (SBRT). While the use of SBRT to treat oligometastases has increased considerably in recent years, the benefit of this approach has yet to be confirmed in phase III randomized controlled trials; moreover, distant failure remains a significant problem in patients with oligometastatic disease treated with SBRT. Given the propensity for distant failure in patients with oligometastatic disease treated with SBRT, there is growing interest in the utility of combining SBRT with systemic agents such as immunotherapy. Immunotherapy, and specifically immune checkpoint blockade (ICB), represents a rapidly evolving systemic therapy option with a growing number of indications among patients with metastatic disease; however, despite its promise, only a minority of patients respond to ICB and among those who do, the majority eventually progress. SBRT and ICB are both dependent upon, and have the ability to shift, the balance between antitumor immune surveillance and immunosuppressive states in the tumor and tumor microenvironment. As a result, it has been speculated that SBRT and ICB have the potential to act synergistically when used in combination. SBRT has been demonstrated to be safe in combination with ICB in studies with short-term follow-up and although additional research is needed, preliminary prospective data support the potential efficacy of this approach. In addition to confirming the safety and efficacy of SBRT in combination with immunotherapy, further studies are needed to determine how to maximize the therapeutic ratio of this treatment paradigm for the full potential of immunotherapy in the oligometastatic population to be realized.

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“…3H3 and MAB9371 showed efficacy in both CT26 and MC-38 models (21). Most of these mAbs have been used in combination studies and demonstrated synergistic effect with checkpoint inhibitors such as anti-CTLA4 (22) and anti-PD-1 (21,23), chemotherapeutics (24,25), radiotherapy (26), and vaccines (27). However, all these CD137 mAbs are known to increase transaminases in mice when dosed repeatedly (28,29).…”

Section: Introductionmentioning

confidence: 99%

Epitope and Fc-Mediated Cross-linking, but Not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity

Thakur

et al. 2020

Molecular Cancer Therapeutics

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CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent antitumor activity with memory response while causing hepatotoxicity in mouse models. In clinical trials, the degrees of liver toxicity of anti-CD137 vary from grade 4 transaminitis (urelumab) to nonexistent (utomilumab). To exploit the antitumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong antitumor potency without significant transaminitis in vivo compared with CD137 agonists previously reported. These mAbs are crossreactive to mouse and cynomolgus monkey and showed crosslinking-dependent T-cell costimulation activity in vitro. Antitu-mor efficacy was maintained in Fc gamma receptor (FcgR) IIIdeficient mice but diminished in FcgRIIB-deficient mice, suggesting the critical role for FcgRIIB to provide cross-linking in vivo. Interestingly, a single dose of an affinity-reduced variant was sufficient to control tumor growth, but a higher affinity variant did not improve efficacy. These observations suggest that binding epitope and FcgR interaction, but not necessarily high affinity, are important for antitumor efficacy and reduced liver toxicity of CD137 mAb. Our study suggests the possibility of CD137 agonist therapy with improved safety profile in humans.

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4-1BB (CD137) and radiation therapy: A case report and literature review

Cited by 4 publications

References 14 publications

Narrative Review of Synergistics Effects of Combining Immunotherapy and Stereotactic Radiation Therapy

Narrative Review of Synergistics Effects of Combining Immunotherapy and Stereotactic Radiation Therapy

The role of immunotherapy in combination with oligometastasis-directed therapy: a narrative review

Epitope and Fc-Mediated Cross-linking, but Not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity

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