Deep abscopal response to radiotherapy and anti-PD-1 in an oligometastatic melanoma patient with unfavorable pretreatment immune signature

Tsubasa Watanabe,Anca-Ligia Grosu,Nicolas Ehrat,Simone Gaedicke,Frank Meiss,Dagmar Von Bubnoff,Amir Abdollahi,Annette Schmitt-Graeff,Ren Luo,Jessica C Hassel,Elke Firat,Corinne Heinrich,Gabriele Niedermann,Jutta Scholber,Gabriele Multhoff

doi:10.1007/s00262-020-02587-8

Abstract

Radiotherapy can elicit abscopal effects in non-irradiated metastases, particularly under immune checkpoint blockade (ICB). We report on two elderly patients with oligometastatic melanoma treated with anti-PD-1 and stereotactic body radiation therapy (SBRT). Before treatment, patient 1 showed strong tumor infiltration with exhausted CD8+ T cells and high expression of T cell-attracting chemokines. This patient rapidly mounted a complete response, now ongoing for more than 4.5 years. Patient 2 exhibited low CD8+ T cell infiltration and high expression of immunosuppressive arginase. After the first SBRT, his non-irradiated metastases did not regress and new metastases occurred although neoepitope-specific and differentiation antigen-specific CD8+ T cells were detected in the blood. A second SBRT after 10 months on anti-PD-1 induced a radiologic complete response correlating with an increase in activated PD-1-expressing CD8 T cells. Apart from a new lung lesion, which was also irradiated, this deep abscopal response lasted for more than 2.5 years. However, thereafter, his disease progressed and the activated PD-1-expressing CD8 T cells dropped. Our data suggest that oligometastatic patients, where a large proportion of the tumor mass can be irradiated, are good candidates to improve ICB responses by RT, even in the case of an unfavorable pretreatment immune signature, after progression on anti-PD-1, and despite advanced age. Besides repeated irradiation, T cell epitope-based immunotherapies (e.g., vaccination) may prolong antitumor responses even in patients with unfavorable pretreatment immune signature.

Highlights

The standard of care for metastatic melanoma is immune checkpoint blockade (ICB) or targeted therapy [1]
Since only three body regions were affected, with a limited number of macroscopic metastases, the patient was treated with potentially curative stereotactic body radiation therapy (SBRT) to the three liver lesions (Fig. 1b, c, e)
Since only one organ showed a limited number of macroscopic metastases, potentially curative SBRT (3 fractions of 15 Gy every other day) was delivered to the two largest lesions located close together in a non-central liver region

Summary

Introduction

The standard of care for metastatic melanoma is immune checkpoint blockade (ICB) or targeted therapy [1]. In the absence of brain metastases, pembrolizumab and nivolumab monotherapy yield durable responses in approx. 30–40% of patients; the complete response (CR) rate is approx. Extended author information available on the last page of the article [2, 3]. Preclinical work has shown that localized RT can induce CD8+ T cells, which contribute to the control of the irradiated tumor and sometimes elicit abscopal effects in non-irradiated metastases, when combined with ICB [4,5,6,7]. It is not fully clear how to best induce an RT-mediated abscopal response and whether pretreatment biomarkers can predict which patients respond to combined RT/ICB

Methods

Results

Conclusion