Exploring the rationale for combining ionizing radiation and immune checkpoint blockade in head and neck cancer

Morisada, Megan V.; Chamberlin, Michael M.; Allen, Clint

doi:10.1002/hed.25101

Cited by 11 publications

(9 citation statements)

References 81 publications

(162 reference statements)

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“…Thus, while TIL appeared to be sensitive to IRinduced DNA damage, accumulation of PD-1 high TIL occurred between 1 and 3 d after IR, supporting previous work demonstrating the ability of 8 Gy IR to stimulate antitumor immunity. 7 Wee1 kinase inhibition and IR enhance tumor cell susceptibility to CTL killing through distinct mechanisms. 7,13 Using tumor cells engineered to express the MHC class I-restricted epitope of ovalbumin as a model antigen, and OT-I CTL as effectors, we explored the effects of combination IR and AZD1775 on CTL killing using impedance analysis.…”

Section: Resultsmentioning

confidence: 99%

“…4 Ionizing radiation (IR) enhances anti-tumor immunity through STINGdependent type I interferon production in response to cytosolic DNA and increased tumor cell immunogenicity. [5][6][7] Accordingly, IR enhances responses to PD-axis ICB. 8 Following IR-induced DNA damage, tumor cells activate the G2/M cell cycle checkpoint to allow DNA repair before cell cycle progression, promoting resistance.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition

et al. 2019

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Tumor cells activate the G2/M cell cycle checkpoint in response to ionizing radiation (IR) and effector immune cell-derived granzyme B to facilitate repair and survival. Wee1 kinase inhibition reverses the ability of tumor cells to pause at G2/M. Here, we hypothesized that AZD1775, a small molecule inhibitor of Wee1 kinase, could sensitize tumor cells to IR and T-lymphocyte killing and improve responses to combination IR and programmed death (PD)-axis immune checkpoint blockade (ICB). Multiple models of head and neck carcinoma, lung carcinoma and melanoma were used in vitro and in vivo to explore this hypothesis. AZD1775 reversed G2/M cell cycle checkpoint activation following IR, inducing cell death. Combination IR and AZD1775 induced accumulation of DNA damage in M-phase cells and was rescued with nucleoside supplementation, indicating mitotic catastrophe. Combination treatment enhanced control of syngeneic MOC1 tumors in vivo, and on-target effects of systemic AZD1775 could be localized with targeted IR. Combination treatment enhanced granzyme B-dependent T-lymphocyte killing through reversal of additive G2/M cell cycle block induced by IR and granzyme B. Combination IR and AZ1775-enhanced CD8 + celldependent MOC1 tumor growth control and rate of complete rejection of established tumors in the setting of PD-axis ICB. Functional assays demonstrated increased tumor antigen-specific immune responses in sorted T-lymphocytes. The combination of IR and AZD1775 not only lead to enhanced tumor-specific cytotoxicity, it also enhanced susceptibility to T-lymphocyte killing and responses to PD-axis ICB. These data provide the pre-clinical rationale for the combination of these therapies in the clinical trial setting.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition

et al. 2019

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“…Several studies have indicated that single high-dose or hypofractionated RT given before or during ICB provides a greater degree of antitumor immunity than does hyperfractionated RT or RT after ICB. 43,44 Radiation field size, dose, and fractionation are also critical considerations when combining RT and ICB. Circulating lymphocytes are extremely radiosensitive and protracted treatment courses over a large area exposes more circulating lymphocytes to killing by RT than single session or hypofractionated RT courses.…”

Section: Discussion and Literature Reviewmentioning

confidence: 99%

Abscopal Effect Following Immunotherapy and Combined Stereotactic Body Radiation Therapy in Recurrent Metastatic Head and Neck Squamous Cell Carcinoma: A Report of Two Cases and Literature Review

Choi

Sansoni

Lovin

et al. 2019

Ann Otol Rhinol Laryngol

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Objective: We present two patients with recurrent, metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum-based chemotherapy and radiotherapy (RT) with complete response via abscopal effect following combined immunotherapy (IT) and stereotactic body radiation therapy (SBRT). We review the literature for patients undergoing combined treatment with IT and RT to identify potential cases of abscopal response. Study Design: This is a case series with a contemporary review of the literature. Methods: Retrospective chart review identified two patients with potential abscopal responses after IT and RT for R/M HNSCC. The MEDLINE database was queried using the search terms “abscopal AND head and neck squamous cell carcinoma” and “immunotherapy AND stereotactic body radiation therapy.” Results: Two patients with metastatic HNSCC developed complete responses via a possible abscopal effect following combined SBRT and IT. Interim follow-up of both patients revealed a sustained, complete response. We examine the immunogenic effects of RT and report the first cases of potential abscopal effect for R/M HNSCC. We also review several preclinical studies demonstrating the synergistic efficacy of combined RT and IT with a discussion of possible mechanism. Conclusion: Observation of abscopal effect with combined IT and RT is currently under investigation through several preclinical studies and trials. To the best of our knowledge, these are the first two reported cases of abscopal effect for patients with HNSCC. We report two patients with R/M HNSCC with sustained, complete response after systemic IT and local RT.

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“…The remarkable series of clinical successes and FDA approvals for immune checkpoint blockade antibodies in the last decade may represent only the first phase of a dramatic shift in cancer treatment away from genotoxic agents and toward immunotherapy [34–36]. Antibodies targeting the programmed cell death protein-1/-ligand 1 (PD-1/PD-L1) immune evasion pathway have shown robust clinical responses by reactivating antitumor immunity in a wide range of malignancies [37–39]. Matching the proper drug to each patient is a fundamental challenge for targeted therapies that is particularly problematic for checkpoint blockade [40, 41], where patient-specific molecular tests are lacking [42].…”

Section: Discussionmentioning

confidence: 99%

Nondestructive, multiplex three-dimensional mapping of immune infiltrates in core needle biopsy

Lee

Bindokas

Lingen

et al. 2019

Laboratory Investigation

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Enumeration of tumor-infiltrating lymphocytes (TILs) in H&E stained tissue sections has demonstrated limited value in predicting immune responses to cancer immunotherapy, likely reflecting the diversity of cell types and immune activation states among tumor infiltrates. Multiparametric flow cytometry enables robust phenotypic and functional analysis to distinguish suppression from activation, but tissue dissociation eliminates spatial context. Multiplex methods for immunohistochemistry (IHC) are emerging, but these interrogate only a single tissue section at a time. Here, we report transparent tissue tomography (T3) as a tool for three-dimensional (3D) imaging cytometry in the complex architecture of the tumor microenvironment, demonstrating multiplexed immunofluorescent analysis in core needle biopsies. Using T3 imaging, image processing and machine learning to map CD3 + CD8 + cytotoxic T cells (CTLs) in whole core needle biopsies from Her2 + murine mammary tumors and human head and neck surgical specimens revealed marked inhomogeneity within single needle cores, confirmed by serial section IHC. Applying T3 imaging cytometry, we discovered a strong spatial correlation between CD3 + CD8 + CTLs and microvasculature in the EGFR + parenchyma, revealing significant differences among head and neck cancer patients. These results show that T3 offers simple and rapid access to three-dimensional and quantitative maps of the tumor microenvironment and immune infiltrate, offering a new diagnostic tool for personalized cancer immunotherapy.

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Exploring the rationale for combining ionizing radiation and immune checkpoint blockade in head and neck cancer

Cited by 11 publications

References 81 publications

Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition

Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition

Abscopal Effect Following Immunotherapy and Combined Stereotactic Body Radiation Therapy in Recurrent Metastatic Head and Neck Squamous Cell Carcinoma: A Report of Two Cases and Literature Review

Nondestructive, multiplex three-dimensional mapping of immune infiltrates in core needle biopsy

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