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An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models.

ABSTRACT: PURPOSE:This study examined tumor growth delay resulting from partial irradiation in preclinical mouse models. METHODS AND MATERIALS:We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2 × 2 cm collimator on a microirradiator. Radiation response was modulated by treatment with anti-CD8 and anti-intercellular adhesion molecule (anti-ICAM) antibodies. Similar experiments were performed using the less immunogenic Lewis lung carcinoma mouse model. Tumor growth delay and ?-H2AX phosphorylation were measured, and immune response was assessed by immunofluorescence and flow cytometry at 1 and 7 days after radiation therapy. Tumor expression of cellular adhesion molecules was also measured at different times after radiation therapy. RESULTS:Partial irradiation led to tumor responses similar to those of fully exposed tumors in immunocompetent mice, but not in nude mice. After a single dose of 10 Gy, infiltration of CD8+ T cells was observed along with increased expression of ICAM. The response to 10 Gy in hemi-irradiated tumors was abrogated by treatment with either anti-CD8 or anti-ICAM antibodies. Similar responses were obtained in the less immunogenic Lewis lung carcinoma mouse model delivering 15 Gy to half the tumor volume. Treatment with FTY720, a compound that inhibits T-cell egress from lymph nodes, did not affect tumor response at the time of CD8+ T cells infiltration in the nonirradiated area of the tumor. This result indicated that the most likely source of these cells is the irradiated portion of the hemi-irradiated tumors. In addition, a significant abscopal effect was observed after partial irradiation with a single dose of 10 Gy in the 67NR model. CONCLUSIONS:In these models, radiation controls tumor growth both directly through cell killing and indirectly through immune activation. This outcome raises the possibility that this effect could be induced in the clinic.

SUBMITTER: Markovsky E

PROVIDER: S-EPMC6764416 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models.

Markovsky Ela E Budhu Sadna S Samstein Robert M RM Li Hongyan H Russell James J Zhang Zhigang Z Drill Esther E Bodden Chloe C Chen Qing Q Powell Simon N SN Merghoub Taha T Wolchok Jedd D JD Humm John J Deasy Joseph O JO Haimovitz-Friedman Adriana A

International journal of radiation oncology, biology, physics 20181018 3

<h4>Purpose</h4>This study examined tumor growth delay resulting from partial irradiation in preclinical mouse models.<h4>Methods and materials</h4>We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2 × 2 cm collimator on a microirradiator. Radiation response was modulated by treatment with anti-CD8 and anti-intercellular adhesion molecule (anti-ICAM) antibodies. Similar experiments were performe ...[more]

PMID: 30342090

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Project description:Background: Delivery of radiotherapeutic dose to recurrent head and neck cancer (HNC) is primarily limited by locoregional toxicity in conventional radiotherapy. As such, HNC patients stand to benefit from the conformal targeting of primary and remnant disease achievable with radiopharmaceutical therapies. In this study, the authors investigated the tumor targeting capacity of 131I-CLR1404 (iopofosine I-131) in various HNC xenograft mouse models and the impact of partial volume correction (PVC) on theranostic dosimetry based on 124I-CLR1404 (CLR 124) positron emission tomography (PET)/computed tomography (CT) imaging. Methods: Mice bearing flank tumor xenograft models of HNC (six murine cell line and six human patient derived) were intravenously administered 6.5-9.1 MBq of CLR 124 and imaged five times over the course of 6 d using microPET/CT. In vivo tumor uptake of CLR 124 was assessed and PVC for 124I was applied using a novel preclinical phantom. Using subject-specific theranostic dosimetry estimations for iopofosine I-131 based on CLR 124 imaging, a discrete radiation dose escalation study (2, 4, 6, and 8 Gy) was performed to evaluate tumor growth response to iopofosine I-131 relative to a single fraction of external beam radiation therapy (6 Gy). Results: PET imaging demonstrated consistent tumor selective uptake and retention of CLR 124 across all HNC xenograft models. Peak uptake of 4.4% ± 0.8% and 4.2% ± 0.4% was observed in squamous cell carcinoma-22B and UW-13, respectively. PVC application increased uptake measures by 47%-188% and reduced absolute differences between in vivo and ex vivo uptake measurements from 3.3% to 1.0 percent injected activity per gram. Tumor dosimetry averaged over all HNC models was 0.85 ± 0.27 Gy/MBq (1.58 ± 0.46 Gy/MBq with PVC). Therapeutic iopofosine I-131 studies demonstrated a variable, but linear relationship between iopofosine I-131 radiation dose and tumor growth delay (p < 0.05). Conclusions: Iopofosine I-131 demonstrated tumoricidal capacity in preclinical HNC tumor models and the theranostic pairing with CLR 124 presents a promising new treatment approach for personalizing administration of iopofosine I-131.

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An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models.

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An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models.

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