Overcoming Immunotherapy Resistance With Radiation Therapy and Dual Immune Checkpoint Blockade

Davidson, T; Zhang, Henan; Dong, Haidong; Grams, Michael P.; Park, Sean S.; Yan, Yiyi

doi:10.1016/j.adro.2022.100931

Cited by 4 publications

(5 citation statements)

References 18 publications

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“…Lymphocytes : there is a growing body of evidence indicating radiation-mediated T-cell priming through the activation of host immunity (Lee et al 2009 , Victor et al 2015 , Walle et al 2018 , Davidson et al 2022 ). Tumor antigens released either from tumors in natural condition or from radiation damaged tumors lead to the priming of tumor antigen specific T-cells.…”

Section: Methodsmentioning

confidence: 99%

“…Slone et al 1979 reported that 1.67 time higher dose is required for tumor control of immuno-deficient mice compared to immuno-competent mice. Immune checkpoint inhibitors show outstanding results in a variety of cancers and combinations with radiotherapy are often desired for the synergistic effect for long lasting responses (Vaage 1973, Markovsky et al 2019, Davidson et al 2022. Thus it is crucial to develop a mechanistic model describing the dynamics of radio-immune response in order to understand the mechanism and efficiently develop clinical studies in this rapidly evolving area (Serre et al 2016, Geng et al 2017, Asperud 2020, Bekker et al 2022.…”

Section: Introductionmentioning

confidence: 99%

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Radio-immune response modelling for spatially fractionated radiotherapy

et al. 2023

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Objective: Radiation-induced cell death is a complex process influenced by physical, chemical and biological phenomena. Although consensus on the nature and the mechanism of the bystander effect were not yet made, the immune process presumably plays an important role in many aspects of the radiotherapy including the bystander effect. A mathematical model of immune response during and after radiation therapy is presented. Approach: Immune response of host body and immune suppression of tumor cells are modelled with four compartments in this study; viable tumor cells, T cell lymphocytes, immune triggering cells, and doomed cells.The growth of tumor was analyzed in two distinctive modes of tumor status (immune limited and immune escape) and its bifurcation condition. Main results: Tumors in the immune limited mode can grow only up to a finite size, named as terminal tumor volume analytically calculated from the model. The dynamics of the tumor growth in the immune escape mode is much more complex than the tumors in the immune limited mode especially when the status of tumor is close to the bifurcation condition. Radiation can kill tumor cells not only by radiation damage but also by boosting immune reaction. Significance: The model demonstrated that the highly heterogeneous dose distribution in spatially fractionated radiotherapy (SFRT) can make a drastic difference in tumor cell killing compared to the homogeneous dose distribution. SFRT can not only enhance but also moderate the cell killing depending on the immune response triggered by many factors such as dose prescription parameters, tumor volume at the time of treatment and tumor characteristics. The model was applied to the lifted data of 67NR tumors on mice and a sarcoma patient treated multiple times over 1200 days for the treatment of tumor recurrence as a demonstration.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Radio-immune response modelling for spatially fractionated radiotherapy

et al. 2023

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“…Lymphocytes: There is a growing body of evidence indicating radiation-mediated T-cell priming through the activation of host immunity (Lee et al 2009;Twyman-Saint Victor et al 2015;Walle et al 2018;Davidson et al 2022). Tumor antigens released either from tumors in natural condition or from radiation damaged tumors lead to the priming of tumor antigen specific T-cells.…”

Section: Radio-immune Response Modelmentioning

confidence: 99%

“…(Slone, Peters, and Milas 1979) reported that 1.67 time higher dose is required for tumor control of immuno-deficient mice compared to immuno-competent mice. Immune checkpoint inhibitors show outstanding results in a variety of cancers and combinations with radiotherapy are often desired for the synergistic effect for long lasting responses (Markovsky et al 2019;Davidson et al 2022;Vaage 1973). Thus it is crucial to develop a mechanistic model describing the dynamics of radio-immune response in order to understand the mechanism and efficiently develop clinical studies in this rapidly evolving area (Serre et al 2016;Geng, Paganetti, and Grassberger 2017;Asperud 2020;Asperud 2020;Bekker et al 2022).…”

mentioning

confidence: 99%

Radio-Immune Response Modelling for Spatially Fractionated Radiotherapy

Cho

Yoon

Suh

et al. 2023

Preprint

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Radiation-induced cell death is a complex process influenced by physical, chemical and biological phenomena. Strong dose gradient may intensify the complexity and reportedly creates significantly more cell death known as bystander effect. Although consensus on the nature and the mechanism of the bystander effect were not yet made, the immune process presumably plays an important role in many aspects of the radiotherapy including the bystander effect. Immune response of host body and immune suppression of tumor cells are modelled with four compartments in this study; viable tumor cells, T cell lymphocytes, immune triggering cells, and doomed cells. The growth of tumor was analyzed in two distinctive modes of tumor status (immune limited and immune escape) and its bifurcation condition. Tumors in the immune limited mode can grow only up to a finite size, named as terminal tumor volume analytically calculated from the model. The dynamics of the tumor growth in the immune escape mode is much more complex than the tumors in the immune limited mode especially when the status of tumor is close to the bifurcation condition. Radiation can kill tumor cells not only by radiation damage but also by boosting immune reaction. The model demonstrated that the highly heterogeneous dose distribution in spatially fractionated radiotherapy (SFRT) can make a drastic difference in tumor cell killing compared to the homogeneous dose distribution. SFRT can not only enhance but also moderate the cell killing depending on the immune response triggered by many factors such as dose prescription parameters, tumor volume at the time of treatment and tumor characteristics. The model was applied to the lifted data of 67NR tumors on mice and a sarcoma patient treated multiple times over 1200 days for the treatment of tumor recurrence as a demonstration.

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“…While there is a possibility of immunotherapy resistance, it should be understood that this is only for a subset of cancer patients. Notably, there are promising clinical trials underway that are investigating overcoming immunotherapy resistance, one being NCT05304546, a Phase 2 trial using pembrolizumab, encorafenib, or binimetinib to overcome primary resistance to immunotherapy (singular inhibitor or immune checkpoint blockade) in Stage IV or inoperable stage III metastatic melanoma patients with a BRAF V600 E/K mutation [ 113 , 114 ].…”

Section: Future Directions: Advancement In Cancer Therapiesmentioning

confidence: 99%

Antibody Diversity in Cancer: Translational Implications and Beyond

et al. 2022

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Patients with cancer tend to develop antibodies to autologous proteins. This phenomenon has been observed across multiple cancer types, including bladder, lung, colon, prostate, and melanoma. These antibodies potentially arise due to induced inflammation or an increase in self-antigens. Studies focusing on antibody diversity are particularly attractive for their diagnostic value considering antibodies are present at an early diseased stage, serum samples are relatively easy to obtain, and the prevalence of antibodies is high even when the target antigen is minimally expressed. Conversely, the surveillance of serum proteins in cancer patients is relatively challenging because they often show variability in expression and are less abundant. Moreover, an antibody’s presence is also useful as it suggests the relative immunogenicity of a given antigen. For these reasons, profiling antibodies’ responses is actively considered to detect the spread of antigens following immunotherapy. The current review focuses on expanding the knowledge of antibodies and their diversity, and the impact of antibody diversity on cancer regression and progression.

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Overcoming Immunotherapy Resistance With Radiation Therapy and Dual Immune Checkpoint Blockade

Cited by 4 publications

References 18 publications

Radio-immune response modelling for spatially fractionated radiotherapy

Radio-immune response modelling for spatially fractionated radiotherapy

Radio-Immune Response Modelling for Spatially Fractionated Radiotherapy

Antibody Diversity in Cancer: Translational Implications and Beyond

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