Cytoreduction and the Optimization Of Immune Checkpoint Inhibition with Radiation Therapy

Gutiontov, Stanley I.; Pitroda, Sean P.; Chmura, Steven J.; Arina, Ainhoa; Weichselbaum, Ralph R.

doi:10.1016/j.ijrobp.2019.12.033

Cited by 22 publications

(14 citation statements)

References 83 publications

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“…Some of the pro-immunogenic effects of IR observed in preclinical settings include increasing susceptibility of cancer cells to cytotoxic T cell killing [4][5][6][7], augmenting antigen processing and inducing expression of unique radiation-associated peptides in cancer cells [8,9], inducing irradiated cancer cells to release or express immunogenic molecules that can enhance anticancer immune responses [8,10], and favorably modulating the tumor microenvironment (TME) for immune-mediated antitumor effects [11][12][13][14]. In clinical settings, radiotherapy is currently being explored in combination with a plethora of immune-based therapeutic approaches to optimize antitumor immunity [15,16].…”

Section: Introductionmentioning

confidence: 99%

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

139

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Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

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Section: Introductionmentioning

confidence: 99%

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

139

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“…If radiation could increase the population of pro-immunogenic T cell subtypes within the local TME, it would enhance the response to ICB. This hypothesis raises the possibility that targeting multiple metastatic sites with SBRT to achieve complete cytoreduction in the metastatic setting may become clinically relevant (44). Moreover, the irradiation of each visible metastasis addresses the challenge of heterogeneity by attempting to convert each target into an in situ vaccine (45).…”

Section: Addressing the Evasive Objective Of Durable Responses Of Radmentioning

confidence: 99%

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies

et al. 2020

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Advances in immunotherapy have achieved remarkable clinical outcomes in tumors with low curability, but their effects are limited, and increasing evidence has implicated tumoral and non-tumoral components of the tumor microenvironment as critical mediators of cancer progression. At the same time, the clinical successes achieved with minimally invasive and optically-guided surgery and image-guided and ablative radiation strategies have been successfully implemented in clinical care. More effective, localized and safer treatments have fueled strong research interest in radioimmunotherapy, which has shown the potential immunomodulatory effects of ionizing radiation. However, increasingly more observations suggest that immunosuppressive changes, metabolic remodeling, and angiogenic responses in the local tumor microenvironment play a central role in tumor recurrence. In this review, we address challenges to identify responders vs. non-responders to the immune checkpoint blockade, discuss recent developments in combinations of immunotherapy and radiotherapy for clinical evaluation, and consider the clinical impact of immunosuppressive changes in the tumor microenvironment in the context of surgery and radiation. Since the therapy-induced modulation of the tumor microenvironment presents a multiplicity of forms, we propose that overcoming microenvironment related resistance can become clinically relevant and represents a novel strategy to optimize treatment immunogenicity and improve patient outcome.

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“…Despite ICI successes, the reality is that most patients eventually experience disease progression and acquired resistance among responders is problematic ( 3 , 4 ), emphasizing the need for refining immuno-oncologic strategies in the metastatic setting. Radiotherapy (RT) is utilized in nearly two-thirds of solid tumor cases to improve local tumor control via RT-mediated DNA damage of tumor cells, but also with the added advantage of synergistic anti-tumor immune activation to potentiate ICI therapy and in sporadic instances produce distant presumably immune-mediated tumor rejection (abscopal effect) ( 2 , 5 , 6 ). Combination of ICIs and RT has thus emerged as an exciting dual modality strategy to potentiate ICI therapy and circumvent mechanisms of resistance, with isolated reports of dramatic responses in several tumor types ( 2 , 5 , 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…Radiotherapy (RT) is utilized in nearly two-thirds of solid tumor cases to improve local tumor control via RT-mediated DNA damage of tumor cells, but also with the added advantage of synergistic anti-tumor immune activation to potentiate ICI therapy and in sporadic instances produce distant presumably immune-mediated tumor rejection (abscopal effect) ( 2 , 5 , 6 ). Combination of ICIs and RT has thus emerged as an exciting dual modality strategy to potentiate ICI therapy and circumvent mechanisms of resistance, with isolated reports of dramatic responses in several tumor types ( 2 , 5 , 7 , 8 ). While RT-induced abscopal effects were first described more than 50 years ago ( 9 ), complete and durable out-of-field responses are exceptionally rare.…”

Section: Introductionmentioning

confidence: 99%

Durable Metastatic Melanoma Remission Following Pembrolizumab and Radiotherapy: A Case Report of Prophylactic Immunosuppression in a Patient with Myasthenia Gravis and Immune-Mediated Colitis

et al. 2021

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Immune checkpoint inhibitors (ICIs) and radiotherapy (RT) combinations for various metastatic cancers are increasingly utilized, yet the augmentation of anti-cancer immunity including distant tumor responses by RT remains ill-characterized. Immunosuppressive tumor microenvironments and defective anti-tumor immune activation including immune-related adverse events (irAEs) likely limit dramatic immuno-radiotherapy combinations, though it remains unclear which immune characteristics mediate dramatic systemic tumor regression in only a small subset of patients. Moreover, the efficacy of ICI treatment in patients receiving immunosuppressive therapies for autoimmune conditions or irAEs is convoluted, yet clinically valuable. Here, we report a case of a 75-year-old man with myasthenia gravis and metastatic melanoma who experienced complete and durable systemic regression after receiving pembrolizumab and single-lesion RT while on prednisone for myasthenia gravis prophylaxis and vedolizumab for immune-mediated colitis after previously experiencing mixed response on pembrolizumab monotherapy. We discuss the potential paradoxical effects and clinical considerations of immunosuppressive regimens in patients with underlying autoimmune disease or adverse immune reactions while receiving immuno-radiotherapy combinations.

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Cytoreduction and the Optimization Of Immune Checkpoint Inhibition with Radiation Therapy

Cited by 22 publications

References 83 publications

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies

Durable Metastatic Melanoma Remission Following Pembrolizumab and Radiotherapy: A Case Report of Prophylactic Immunosuppression in a Patient with Myasthenia Gravis and Immune-Mediated Colitis

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