Radiotherapy and immune checkpoints inhibitors for advanced melanoma

doi:10.1016/j.radonc.2016.06.003

Radiotherapy and Oncology

Volume 120, Issue 1, July 2016, Pages 1-12

https://doi.org/10.1016/j.radonc.2016.06.003 Get rights and content

Abstract

Introduction

The therapeutic landscape of metastatic melanoma drastically changed after the introduction of targeted therapies and immunotherapy, in particular immune checkpoints inhibitors (ICI). In recent years, positive effects on the immune system associated to radiotherapy (RT) were discovered, and radiation has been tested in combination with ICI in both pre-clinical and clinical studies (many of them still ongoing). We here summarize the rationale and the preliminary clinical results of this approach.

Materials and methods

In the first part of this review article, redacted with narrative non-systematic methodology, we describe the clinical results of immune checkpoints blockade in melanoma as well as the biological basis for the combination of ICI with RT; in the second part, we systematically review scientific publications reporting on the clinical results of the combination of ICI and RT for advanced melanoma.

Results

The biological and mechanistic rationale behind the combination of ICI and radiation is well supported by several preclinical findings. Retrospective observational series and few prospective trials support the potential synergistic effect between radiation and ICI for metastatic melanoma.

Conclusion

RT may potentiate anti-melanoma activity of ICI by enhancing response on both target and non-target lesions. Several prospective trials are ongoing with the aim of further exploring this combination in the clinical setting, hopefully confirming initial observations and opening a new therapeutic window for advanced melanoma patients.

Section snippets

Materials and methods

A narrative methodology was used for selecting and reporting studies on the clinical use of ICI for advanced melanoma, and for describing the biological and mechanistic basis of the combination of radiation and ICI. A systematic review was then performed according to validated guidelines [18], [19] for selecting clinical studies reporting on the combination of RT and ICI for advanced melanoma. For this second part, we searched for English-language full length articles published from January

Conclusions

Both preclinical models and clinical data showed that RT to one or few melanoma metastases might trigger and/or enhance the so-called abscopal effect. This effect is amplified in melanoma when combining RT with ICI such as anti-CTLA-4 or anti-PD-1/anti-PD-L1 antibodies, or the concomitant/sequential combination of both. Recent discoveries led to a better understanding of the mechanisms underlying this effect, and clinical data from retrospective observational studies and few prospective studies

Conflict of interest statement

The Authors declare no conflict of interest with the material included in this review article.

Acknowledgements

The Authors would like to thank Pierluigi Fresia for his precious assistance in preparing the Figures.

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To improve the results of ICI in MM, future alternative or additional treatment strategies aimed at enhancing the immunogenicity of MM may be of interest. For example, combined radiotherapy and ICI bear the potential to create a synergistic anti-tumour response. [36,37] In addition, the use of oncolytic viruses has been shown a promising treatment modality in MM.
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Systematic reviewRadiotherapy and immune checkpoints inhibitors for advanced melanoma

Abstract

Introduction

Materials and methods

Results

Conclusion

Section snippets

Materials and methods

Conclusions

Conflict of interest statement

Acknowledgements

Cell

Int J Radiat Oncol Biol Phys

Radiother Oncol

Cancer Treat Rev

Adv Immunol

Lancet Oncol

Lancet Oncol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Mol Ther

Radiother Oncol

Lancet Oncol

Blood

Lancet Oncol

Cancer Cell

Transl Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Eur J Cancer

Cancer Cell

Int J Radiat Oncol Biol Phys

Natural innate and adaptive immunity to cancer

Ann Rev Immunol

The three Es of cancer immunoediting

Annu Rev Immunol

Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma

J Clin Oncol

Metastatic melanoma treatment: combining old and new therapies

Crit Rev Oncol Hematol

The convergence of radiation and immunogenic cell death signaling pathways

Front Oncol

Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and RT

Nat Med

The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation

Radiat Res

An interesting case of possible abscopal effect in malignant melanoma

Br J Radiol

Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer

Clin Cancer Res

Immunologic correlates of the abscopal effect in a patient with melanoma

N Engl J Med

Abscopal effects of RT on advanced melanoma patients who progressed after ipilimumab immunotherapy

Oncoimmunology

Concurrent RT and ipilimumab immunotherapy for patients with melanoma

Cancer Immunol Res

Exploiting the stress response to radiation to sensitize poorly immunogenic tumours to anti-CLA-4 treatment

Oncoimmunology

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

Nature

New concepts and insights into the role of radiation therapy in extracranial metastatic disease

Expert Rev Anticancer Ther

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Ann Intern Med

Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients

J Clin Oncol

Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma

Cochrane Database Syst Rev

Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials

J Clin Oncol

The blockade of immune checkpoints in cancer immunotherapy

Nat Rev

Improved survival with ipilimumab in patients with metastatic melanoma

N Engl J Med

Systematic review
Radiotherapy and immune checkpoints inhibitors for advanced melanoma