Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model

被引:81
作者
Kosinsky, Yuri [1 ]
Dovedi, Simon J. [2 ]
Peskov, Kirill [1 ]
Voronova, Veronika [1 ]
Chu, Lulu [3 ]
Tomkinson, Helen [4 ]
Al-Huniti, Nidal [3 ]
Stanski, Donald R. [5 ]
Helmlinger, Gabriel [3 ]
机构
[1] M&S Decis, Moscow, Russia
[2] MedImmune, Oncol Res, Cambridge, England
[3] AstraZeneca, Early Clin Dev, IMED Biotech Unit, 35 Gatehouse Dr, Waltham, MA 02451 USA
[4] AstraZeneca, Early Clin Dev, IMED Biotech Unit, Cambridge, England
[5] AstraZeneca, Early Clin Dev, IMED Biotech Unit, Gaithersburg, MD USA
关键词
Radiation therapy; Immuno-oncology (IO); Checkpoint inhibitors; PD-1; PD-L1; Quantitative systems pharmacology; CT26; tumors; Cancer immunity cycle; Immuno-activation; Immuno-suppression; Dose sequencing and scheduling; LINEAR-QUADRATIC MODEL; MELANOMA BRAIN METASTASES; CANCER-IMMUNOTHERAPY; CHECKPOINT BLOCKADE; MATHEMATICAL-MODEL; ANTITUMOR IMMUNITY; TUMOR-GROWTH; T-CELLS; RADIOTHERAPY; THERAPY;
D O I
10.1186/s40425-018-0327-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. We here present a model-based analysis of tumor size dynamics and immune markers, which integrates experimental data from multiple studies and provides a validated simulation framework predictive of biomarkers and anti-tumor response rates, for untested dosing sequences and schedules of combined radiation (RT) and anti PD-(L) 1 therapies. Methods: A quantitative systems pharmacology model, which includes key elements of the cancer immunity cycle and the tumor microenvironment, tumor growth, as well as dose-exposure-target modulation features, was developed to reproduce experimental data of CT26 tumor size dynamics upon administration of RT and/or a pharmacological IO treatment such as an anti-PD-L1 agent. Variability in individual tumor size dynamics was taken into account using a mixed-effects model at the level of tumor-infiltrating T cell influx. Results: The model allowed for a detailed quantitative understanding of the synergistic kinetic effects underlying immune cell interactions as linked to tumor size modulation, under these treatments. The model showed that the ability of T cells to infiltrate tumor tissue is a primary determinant of variability in individual tumor size dynamics and tumor response. The model was further used as an in silico evaluation tool to quantitatively predict, prospectively, untested treatment combination schedules and sequences. We demonstrate that anti-PD-L1 administration prior to, or concurrently with RT reveal further synergistic effects, which, according to the model, may materialize due to more favorable dynamics between RT-induced immuno-modulation and reduced immuno-suppression of T cells through anti-PD-L1. Conclusions: This study provides quantitative mechanistic explanations of the links between RT and anti-tumor immune responses, and describes how optimized combinations and schedules of immunomodulation and radiation may tip the immune balance in favor of the host, sufficiently to lead to tumor shrinkage or rejection.
引用
收藏
页数:15
相关论文
共 48 条
[1]   Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy [J].
Ahmed, K. A. ;
Stallworth, D. G. ;
Kim, Y. ;
Johnstone, P. A. S. ;
Harrison, L. B. ;
Caudell, J. J. ;
Yu, H. H. M. ;
Etame, A. B. ;
Weber, J. S. ;
Gibney, G. T. .
ANNALS OF ONCOLOGY, 2016, 27 (03) :434-441
[2]   The mathematics of cancer: integrating quantitative models [J].
Altrock, Philipp M. ;
Liu, Lin L. ;
Michor, Franziska .
NATURE REVIEWS CANCER, 2015, 15 (12) :730-745
[3]   Cellular responses to DNA double-strand breaks after low-dose γ-irradiation [J].
Asaithamby, Aroumougame ;
Chen, David J. .
NUCLEIC ACIDS RESEARCH, 2009, 37 (12) :3912-3923
[4]   Computational oncology - mathematical modelling of drug regimens for precision medicine [J].
Barbolosi, Dominique ;
Ciccolini, Joseph ;
Lacarelle, Bruno ;
Barlesi, Fabrice ;
Andre, Nicolas .
NATURE REVIEWS CLINICAL ONCOLOGY, 2016, 13 (04) :242-254
[5]   The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence [J].
Barker, Holly E. ;
Paget, James T. E. ;
Khan, Aadil A. ;
Harrington, Kevin J. .
NATURE REVIEWS CANCER, 2015, 15 (07) :409-425
[6]   Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway [J].
Boussiotis, Vassiliki A. .
NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (18) :1767-1778
[7]   The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction [J].
Brenner, David J. .
SEMINARS IN RADIATION ONCOLOGY, 2008, 18 (04) :234-239
[8]   The linear-quadratic model and most other common radiobiological models result in similar predictions of time-dose relationships [J].
Brenner, DJ ;
Hlatky, LR ;
Hahnfeldt, PJ ;
Huang, Y ;
Sachs, RK .
RADIATION RESEARCH, 1998, 150 (01) :83-91
[9]   Oncology Meets Immunology: The Cancer-Immunity Cycle [J].
Chen, Daniel S. ;
Mellman, Ira .
IMMUNITY, 2013, 39 (01) :1-10
[10]   Role of Local Radiation Therapy in Cancer Immunotherapy [J].
Demaria, Sandra ;
Golden, Encouse B. ;
Formenti, Silvia C. .
JAMA ONCOLOGY, 2015, 1 (09) :1325-1332