Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters

Schmidberger, Heinz; Rapp, Matthias; Ebersberger, Anne; Hey-Koch, Silla; Loquai, Carmen; Grabbe, Stephan; Mayer, Arnulf

doi:10.1007/s00066-018-1356-5

Cited by 33 publications

(17 citation statements)

References 19 publications

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“…Similarly, the majority of currently ongoing trials employ concurrent use. By contrast, Schmidberger et al [34] pointed out in their retrospective analysis of 41 melanoma patients with brain metastasis that applying RT before immunotherapies prolonged survival. They showed that patients treated with ipilimumab after RT had a median survival of 11 months, compared with three months for the patients who received ipilimumab prior to RT.…”

Section: Reviewmentioning

confidence: 97%

Abscopal Effect of Radiotherapy in the Immunotherapy Era: Systematic Review of Reported Cases

Dağoğlu¹,

Karaman²,

Çağlar³

et al. 2019

Cureus

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Mounting evidence suggests that radiation stimulates the immune system and this contributes to the abscopal effect, which is defined as “response at a distance from the irradiated volume.” Though identified more than 50 years ago, the abscopal effect is revisited today. One rationale is that the abscopal effect is often observed with efficient immunotherapy. Here, we give an overview of the clinical data on the abscopal effect, generated by a combination of immunotherapy and radiotherapy (RT). Only papers that included RT in combination with immunotherapy were evaluated according to four main categories including RT parameters, sequencing of therapies, the definition of the abscopal effect, and patient selection. Twenty-four cases in 15 reports were reviewed. The results varied. Patient ages ranged from 24 to 74. RT dose (median total dose 18-58 Gy) varied. Biologically effective dose (BED) 10 was calculated to be a median 49.65 Gy (28-151 Gy). The time to a documented abscopal response ranged from less than a month to 12 months. The large variation concerning fractionation and sequencing of therapies indicates that these conflicting points need to be resolved, to generate for the abscopal effect to be clinically significant.

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Section: Reviewmentioning

confidence: 97%

Abscopal Effect of Radiotherapy in the Immunotherapy Era: Systematic Review of Reported Cases

Dağoğlu¹,

Karaman²,

Çağlar³

et al. 2019

Cureus

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“…Tumor xenograft models and treatment regimens MDA-MB-231 cells (1×10 7 ) or triple negative breast cancer (TNBC) patient-derived tumor xenograft (PDTX) tissues were subcutaneously implanted into the right flank of NSG or humanized NSG mice. When tumors reached 80-100 mm 3 , mice were treated with either phosphate buffered saline (PBS) or anti-PD-1 monoclonal antibody (BE0188, clone J116, Bioxcell, New Hampshire, USA) of 200 µg/mouse by intraperitoneal injection, every 3 days, up to six times. The tumor size was measured every 2 or 3 days using a caliper, and tumor volumes were calculated using the modified ellipsoid formula (1/2 × (length × width 2 ).…”

Section: Materials and Methods Micementioning

confidence: 99%

Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

Park

Pandey

Chang

et al. 2020

J Immunother Cancer

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BackgroundWell-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.MethodsHumanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.ResultsBusulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.ConclusionsOur CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.

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“…A retrospective analysis of patients treated for brain metastases of malignant melanoma revealed that inhibition of the PD-1 axis was more effective than inhibition of CTLA-4 in combination with external beam radiotherapy and that concurrent dosing (at least 4 weeks within the two treatments) was necessary to induce best responses [163]. Independent retrospective studies and one meta-analysis confirmed these results [145,[164][165][166][167][168][169][170][171] (Table 4), also showing the superiority of combining radiation with PD-1 inhibitors compared to combination with other agents such as v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) or dual specificity mitogen-activated protein kinase kinase (MEK) inhibitors [172,173] (Table 4). One retrospective study showed longer overall survival of patients irradiated more than 16 weeks after initiation of ipilimumab, compared to patients irradiated within 16 weeks of starting ipilimumab treatment [174].…”

Section: Current Clinical Insights On Irradiation and Immune Checkpoimentioning

confidence: 95%

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

Kabiljo

Harpain

Carotta

et al. 2019

Cancers

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Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials.

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Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters

Cited by 33 publications

References 19 publications

Abscopal Effect of Radiotherapy in the Immunotherapy Era: Systematic Review of Reported Cases

Abscopal Effect of Radiotherapy in the Immunotherapy Era: Systematic Review of Reported Cases

Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

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