Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

doi:10.3389/fphar.2019.00511

. 2019 May 14:10:511.

doi: 10.3389/fphar.2019.00511. eCollection 2019.

Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

Maike Trommer^{1

2

3}, Sin Yuin Yeo^{2

4}, Thorsten Persigehl^{3

4}, Anne Bunck^{3

4}, Holger Grüll^{2

4}, Max Schlaak^{2

5}, Sebastian Theurich^{2

6

7}, Michael von Bergwelt-Baildon^{2

6}, Janis Morgenthaler^{1

3}, Jan M Herter^{1

3

8}, Eren Celik^{1

3}, Simone Marnitz^{1

2

3}, Christian Baues^{1

2

3}

Affiliations

¹ Faculty of Medicine and University Hospital Cologne, Department of Radiation Oncology and Cyberknife Center, University of Cologne, Cologne, Germany.
² Faculty of Medicine and University Hospital Cologne, Radio Immune-Oncology Consortium, University of Cologne, Cologne, Germany.
³ Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology (CIO Köln Bonn), University of Cologne, Cologne, Germany.
⁴ Faculty of Medicine and University Hospital Cologne, Department of Diagnostic and Interventional Radiology, University of Cologne, Cologne, Germany.
⁵ Department of Dermatology and Allergology, Ludwig-Maximilians University Munich, Munich, Germany.
⁶ Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.
⁷ Gene Center, Cancer- and Immunometabolism Research Group, Ludwig-Maximilians University Munich, Munich, Germany.
⁸ Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

PMID: 31156434
PMCID: PMC6530339
DOI: 10.3389/fphar.2019.00511

Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

Maike Trommer et al. Front Pharmacol. 2019.

. 2019 May 14:10:511.

doi: 10.3389/fphar.2019.00511. eCollection 2019.

Authors

Affiliations

¹ Faculty of Medicine and University Hospital Cologne, Department of Radiation Oncology and Cyberknife Center, University of Cologne, Cologne, Germany.
² Faculty of Medicine and University Hospital Cologne, Radio Immune-Oncology Consortium, University of Cologne, Cologne, Germany.
³ Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology (CIO Köln Bonn), University of Cologne, Cologne, Germany.
⁴ Faculty of Medicine and University Hospital Cologne, Department of Diagnostic and Interventional Radiology, University of Cologne, Cologne, Germany.
⁵ Department of Dermatology and Allergology, Ludwig-Maximilians University Munich, Munich, Germany.
⁶ Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.
⁷ Gene Center, Cancer- and Immunometabolism Research Group, Ludwig-Maximilians University Munich, Munich, Germany.
⁸ Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

PMID: 31156434
PMCID: PMC6530339
DOI: 10.3389/fphar.2019.00511

Erratum in

Corrigendum: Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition.
Trommer M, Yeo SY, Persigehl T, Bunck A, Grüll H, Schlaak M, Theurich S, von Bergwelt-Baildon M, Morgenthaler J, Herter JM, Celik E, Marnitz S, Baues C. Trommer M, et al. Front Pharmacol. 2020 Jan 31;10:1615. doi: 10.3389/fphar.2019.01615. eCollection 2019. Front Pharmacol. 2020. PMID: 32082149 Free PMC article.

Abstract

Immune checkpoint inhibition (ICI) targeting the programmed death receptor 1 (PD-1) has shown promising results in the fight against cancer. Systemic anti-tumor reactions due to radiation therapy (RT) can lead to regression of non-irradiated lesions (NiLs), termed "abscopal effect" (AbE). Combination of both treatments can enhance this effect. The aim of this study was to evaluate AbEs during anti-PD-1 therapy and irradiation. We screened 168 patients receiving pembrolizumab or nivolumab at our center. Inclusion criteria were start of RT within 1 month after the first or last application of pembrolizumab (2 mg/kg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks) and at least one metastasis outside the irradiation field. We estimated the total dose during ICI for each patient using the linear quadratic (LQ) model expressed as 2 Gy equivalent dose (EQD2) using α/β of 10 Gy. Radiological images were required showing progression or no change in NiLs before and regression after completion of RT(s). Images must have been acquired at least 4 weeks after the onset of ICI or RT. The surface areas of the longest diameters of the short- and long-axes of NiLs were measured. One hundred twenty-six out of 168 (75%) patients received ICI and RT. Fifty-three percent (67/126) were treated simultaneously, and 24 of these (36%) were eligible for lesion analysis. AbE was observed in 29% (7/24). One to six lesions (mean = 3 ± 2) in each AbE patient were analyzed. Patients were diagnosed with malignant melanoma (MM) (n = 3), non-small cell lung cancer (NSCLC) (n = 3), and renal cell carcinoma (RCC) (n = 1). They were irradiated once (n = 1), twice (n = 2), or three times (n = 4) with an average total EQD2 of 120.0 ± 37.7 Gy. Eighty-two percent of RTs of AbE patients were applied with high single doses. MM patients received pembrolizumab, NSCLC, and RCC patients received nivolumab for an average duration of 45 ± 35 weeks. We demonstrate that 29% of the analyzed patients showed AbE. Strict inclusion criteria were applied to distinguish the effects of AbE from the systemic effect of ICI. Our data suggest the clinical existence of systemic effects of irradiation under ICI and could contribute to the development of a broader range of cancer treatments.

Keywords: PD-1; abscopal effect; advanced cancer disease; combination treatment; immune checkpoint inhibition; radio-immunotherapy; radiotherapy.

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Figures

**Figure 1**
Patient 1 (Table 2B) presenting AbE in the lung. CT scans show the analyzed lesion (yellow arrows) before **(A)**, 10 **(B)**, 27 **(C)**, and 50 weeks **(D)** after the induction of pembrolizumab. **(E)** The change in the lesion surface area with respect to the administration of IT (duration = 24 weeks, gray shaded area) and concurrent RT (red lines and area) of cerebral metastases with 1 × 20 Gy (1 week after 1st IT) and 25 × 2 Gy (23 weeks after 1st IT).

**Figure 2**
Patient 2 (Table 2B) presenting AbE a soft tissue metastasis in the perirenal region. CT scans show the analyzed lesion (yellow arrows) before **(A)**, and 10 **(B)**, 23 **(C)**, 37 **(D)**, and 47 weeks **(E)** after the induction of pembrolizumab. **(F)** The change in the lesion surface area with respect to the administration of IT (duration = 31 weeks, gray shaded area) and concurrent RT (red shaded areas) of the whole brain with 20 × 2 Gy (1 week after 1st IT) and of bone metastases in the left popliteal fossa and lower left leg 18 × 3 Gy (27 weeks after 1st IT) together with SRS of cerebral metastases with 1 × 20 Gy (29 weeks after 1st IT, blue line).

**Figure 3**
Patient 4 (Table 2B) presenting AbE in the suprarenal gland. CT images show the analyzed lesion (yellow arrows) before **(A)** and 3 **(B)**, 12 **(C)**, and 21 weeks **(D)** after the induction of nivolumab. **(E)** The change in the lesion surface area with respect to the administration of IT (duration = 7 weeks, gray shaded area) and RT (red shaded areas) of brain metastases with 3 × 9 Gy and 1 × 20 Gy (3 weeks after IT induction), and RT of bone metastases 10 × 3 Gy of the right femur, left sacrum and ischium (3, 12, and 21 weeks after induction of IT).

See this image and copyright information in PMC

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References

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[1] Abuodeh Y., Venkat P., Kim S. (2016). Systematic review of case reports on the abscopal effect. Curr. Probl. Cancer 40, 25–37. 10.1016/j.currproblcancer.2015.10.001 - DOI - PubMed

[2] Abuodeh Y., Venkat P., Kim S. (2016). Systematic review of case reports on the abscopal effect. Curr. Probl. Cancer 40, 25–37. 10.1016/j.currproblcancer.2015.10.001 - DOI - PubMed

[3] Alexandrov L. B., Nik-Zainal S., Wedge D. C., Aparicio S. A. J. R, Behjati S., Biankin A. V., et al. . (2013). Signatures of mutational processes in human cancer. Nature 500, 415–421. 10.1038/nature12477 - DOI - PMC - PubMed

[4] Alexandrov L. B., Nik-Zainal S., Wedge D. C., Aparicio S. A. J. R, Behjati S., Biankin A. V., et al. . (2013). Signatures of mutational processes in human cancer. Nature 500, 415–421. 10.1038/nature12477 - DOI - PMC - PubMed

[5] Andrews J. R. (1978). The Radiobiology of Human Cancer Radiotherapy. Baltimore, MD: University Park Press.

[6] Andrews J. R. (1978). The Radiobiology of Human Cancer Radiotherapy. Baltimore, MD: University Park Press.

[7] Bang A., Wilhite T. J., Pike L. R. G., Cagney D. N., Aizer A. A., Taylor A., et al. . (2017). Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 98, 344–351. 10.1016/j.ijrobp.2017.02.003 - DOI - PubMed

[8] Bang A., Wilhite T. J., Pike L. R. G., Cagney D. N., Aizer A. A., Taylor A., et al. . (2017). Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 98, 344–351. 10.1016/j.ijrobp.2017.02.003 - DOI - PubMed

[9] Barker H. E., Paget J. T. E., Khan A. A., Harrington K. J. (2015). The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425. 10.1038/nrc3958 - DOI - PMC - PubMed

[10] Barker H. E., Paget J. T. E., Khan A. A., Harrington K. J. (2015). The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425. 10.1038/nrc3958 - DOI - PMC - PubMed

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Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

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Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

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