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Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy.

ABSTRACT: Purpose: In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB).Experimental Design: We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN.Results: Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T cells as well as FoxP3+ regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1.Conclusions: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. Clin Cancer Res; 24(20); 5058-71. ©2018 AACR.

SUBMITTER: Marciscano AE

PROVIDER: S-EPMC6532976 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy.

Marciscano Ariel E AE Ghasemzadeh Ali A Nirschl Thomas R TR Theodros Debebe D Kochel Christina M CM Francica Brian J BJ Muroyama Yuki Y Anders Robert A RA Sharabi Andrew B AB Velarde Esteban E Mao Wendy W Chaudhary Kunal R KR Chaimowitz Matthew G MG Wong John J Selby Mark J MJ Thudium Kent B KB Korman Alan J AJ Ulmert David D Thorek Daniel L J DLJ DeWeese Theodore L TL Drake Charles G CG

Clinical cancer research : an official journal of the American Association for Cancer Research 20180613 20

<b>Purpose:</b> In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB).<b>Experimental Design:</b> We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiot ...[more]

PMID: 29898992

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Project description:PurposeWe evaluate the feasibility of the elective nodal irradiation strategy in stereotactic body radiotherapy (SBRT) for pancreatic cancer.MethodsThree simultaneous integrated boost (SIB)-SBRT plans (Boost1, Boost2, and Boost3) were retrospectively generated for each of 20 different patients. Boost1 delivered 33 and 25 Gy to PTV1 and PTV2, respectively. Boost2 delivered 40, 33, and 25 Gy to boostCTV, PTV1, and PTV2, respectively. Boost3 delivered 33 and 25 Gy to PTV1 and PTV3, respectively. PTV1 covered the initial standard SBRT plan (InitPlan) gross tumor volume (GTV). PTV2 covered CTVgeom which was created by a 10-mm expansion (15 mm posterior) of GTV. PTV3 covered CTVprop which included elective nodal regions. The boostCTV included GTV as well as involved vasculature. The planning feasibility in each scenario and dose-volume histograms (DVHs) were analyzed and compared with the InitPlan (delivered 33 Gy only to PTV1) by paired t-test. Next, a novel DVH prediction model was developed and its performance was evaluated according to the prediction accuracy (AC) of planning violations. Then, the model was used to simulate the impacts of GTV-to-organs at risk (OAR) distance and gastrointestinal (GI) OAR volume variations on planning feasibility.ResultsSignificant dose increases were observed in GI-OARs in SIB-SBRT plans when compared with InitPlan. All dose constraints were met in 63% of cases in InitPlan, Boost1, and Boost2, whereas Boost3 developed DVH violations in all cases. Utilizing previous patient anatomy, the novel DVH prediction model achieved a high AC in the prediction of violations for GI-OARs; the positive predictive value, negative predictive value, and AC were 66%, 90%, and 84%, respectively. Experiments with the model demonstrated that the larger proximity volume of GI-OAR at the shorter distance substantially impacted on planning violations.ConclusionsSIB-SBRT plan with geometrically defined prophylactic areas can be dosimetrically feasible, but including all nodal areas with 25 Gy in five fractions appears to be unrealistic.

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Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy.

Publications

Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy.

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