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Triggering the Abscopal Effect: Is the Quality of the Radiation Important?
Accepted Manuscript Triggering the abscopal effect; is the quality of the radiation important? Frederik J. Vernimmen, FFRT, Jill T. Nicholson, MBBS PII:
S0360-3016(17)30474-1
DOI:
10.1016/j.ijrobp.2017.02.091
Reference:
ROB 24124
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 24 January 2017 Revised Date:
13 February 2017
Accepted Date: 17 February 2017
Please cite this article as: Vernimmen FJ, Nicholson JT, Triggering the abscopal effect; is the quality of the radiation important?, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/j.ijrobp.2017.02.091. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Triggering the abscopal effect; is the quality of the radiation important? Short title: Abscopal effect and high LET radiation Frederik J. Vernimmen,
RI PT
FFRT Cork University Hospital
SC
Jill T. Nicholson
M AN U
MBBS Cork University Hospital Corresponding author:
Cork University Hospital
TE D
Frederik Vernimmen
Wilton, Cork
AC C
Ireland
EP
Department of Radiation Oncology
[email protected] Tel: ++ 353-863522357
Fax: ++ 353-21-4921346 The authors declare no conflict of interest
ACCEPTED MANUSCRIPT
RI PT
New immunotherapy (IT) agents showing good efficacy in a number of clinical indications have created new research in applying these drugs in combination with radiation to make the treatment more immunogenic, and promote the triggering of an abscopal effect. Many
SC
questions still exist around the optimal combination of drug selection, pathology, timing, and radiation dose/schedule. With regard to radiation, a variety of total dose and dose per fraction
M AN U
schedules have been clinically investigated (1). These studies have used photon irradiation with little attention paid to other forms of radiation with different properties. The mechanism by which radiation and immunotherapy induce an abscopal effect is only beginning to be understood. An appropriate tumour suppressive environment and immune-
TE D
stimulating response must occur at the right time to elicit an abscopal response (2), which is the result of T-cell activation and proliferation. These circulating lymphocytes are highly
EP
sensitive to radiation, and protracted radiotherapy schedules, and the use of multiple treatment fields in IMRT with their associated large volume of “low dose bath” exacerbate
AC C
the lymphotoxicity
Immunotherapy phase I/II studies have used a variety of dose schedules, ranging from standard fractionated therapy to high dose single fractions (SBRT). No clear favourite schedule as yet has come to the forefront, but SBRT and hypo fractionation tend to produce a somewhat better abscopal effect (3, 4). Clinical trials in malignant melanoma have shown promising results (5).
ACCEPTED MANUSCRIPT The probability of cellular radiation damage depends not only on the absorbed dose, but also on the type of radiation, with various radiation modalities having different quality factors, now called a “radiation weighting factor”. Linear Energy Transfer (LET) is another way of describing the absorbed dose effects. Photons, electrons and protons are classified as low
RI PT
LET. Fast neutrons and heavy charged particles are high LET and they inflict more cellular damage per unit of dose (6), with the potential to increase the amounts of “immunogenic debris”. The biological basis for this is a dense clustering of Double Strand Breaks (DSBs)
SC
along the ion tracks with inefficient DSB repair (6). Both fast neutrons and carbon ions have similar radiobiological effects (RBE). Their physical characteristics are however different,
M AN U
with fast neutrons behaving like photons, and charged particles having a Bragg peak. Although protons are equally effective to photons with regard to the production of T cells mediated in tumour cell killing (7), protons delivered by pencil beam scanning (PBS) have an inherent advantage for triggering abscopal effects because of a lower integral dose and hence
TE D
less lymphotoxicity. Carbon ions offer the best of both worlds. Matsunaga et.al. (8) demonstrated that carbon ion treatment of the primary tumour resulted in a dramatic abscopal effect which was further significantly enhanced by combining it with immunotherapy.
EP
Ohkubo et.al. demonstrated a dramatic reduction in lung metastasis after Carbon ions
AC C
treatment. Here again the addition of immunotherapy significantly enhanced the abscopal effect further (9).
Very few carbon ion therapy centres exist, and use of neutron therapy has declined substantially (10). Nevertheless neutron therapy yielded better local control for some indications. No studies have explored the abscopal effects of neutrons, but they are potentially strong triggers for this. Their dose distribution disadvantage could be partially circumvented by the use of intensity modulated neutron therapy.
ACCEPTED MANUSCRIPT Proton therapy is rapidly becoming more available worldwide. This should allow for research on the immunogenic effects of protons, by exploiting their lower integral dose. Studies on the immunogenicity of irradiation have many variables. Protons and high LET
RI PT
radiation carry a lot of promise in the quest to enhance the abscopal effect, which in itself reflects a strong systemic immunogenic response. References:
SC
1. Kang J, Demaria \s, Formenti A: Current clinical trials testing the combination of
immunotherapy with radiotherapy. Journal for Immunotherapy of Cancer Sep 2016; 4:51:1-
M AN U
20
2. John NG, Tong Daj, Radiation Therapy and the abscopal effect; a concept comes of age.
TE D
Annals of Translational Medicine March 2016; 4(6): 118
3. Demaria S, Formenti SC: Radiation as an immunological adjuvant: current evidence on
AC C
EP
dose and fractionation. Frontiers in Oncology 2012 2: article 153
4. Popp I, Grosu AL, Niedermann G, et al: Immune modulation by hypofractionated stereotactic radiation therapy: Therapeutic implications. Radiother Oncol 120(2):185-94
5. Chandra R.A., Wilhite T.J., Balboni T.A. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab Oncolimmunology May 2015; 4:11
ACCEPTED MANUSCRIPT
6. Lorat Y, Timm S, Jakob B, et al: Clustered double-strand breaks in heterochromatine perturb DNA repair after high linear energy transfer irradiation. Radiother Oncol. 2016;
RI PT
121(1):154-161
7. Gameiro SR, Malamas AS, Bernstein MB, et al. Tumor cells surviving exposure to proton
SC
or photon radiation share a common immunogenic modulation signature, rendering them
M AN U
more sensitive to T cell-mediated killing. Int J Rad Oncol Biol Phys. 2016; 95 (1): 120-130
8. Matsunaga A, Ueda Y, Yamada S, et al. Carbon-ion beam treatment induces systemic antitumor immunity against Murine Squamous Cell Carcinoma. Cancer August 2010; 3740-
TE D
3748
EP
9. Ohkubo Y, Iwakawa M, Seino K-I, et al. Combining carbon ion radiotherapy and local
injection of ∝-Galactosylceramide-pulsed dendritic cells inhibits lung metastasis in an In
AC C
Vivo murine model. Int. J. Rad Onc. Biol. Phys 2010; 78: 1524-1531
10. Specht H.M., Neff T., Reuschel W, Wagner F.M. Paving the road for modern particle
therapy – What can we learn from the experience gained with fast neutron therapy in Munich; Frontiers in Oncology 2015; vol 5, 262
S0360-3016(17)30474-1
DOI:
10.1016/j.ijrobp.2017.02.091
Reference:
ROB 24124
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 24 January 2017 Revised Date:
13 February 2017
Accepted Date: 17 February 2017
Please cite this article as: Vernimmen FJ, Nicholson JT, Triggering the abscopal effect; is the quality of the radiation important?, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/j.ijrobp.2017.02.091. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Triggering the abscopal effect; is the quality of the radiation important? Short title: Abscopal effect and high LET radiation Frederik J. Vernimmen,
RI PT
FFRT Cork University Hospital
SC
Jill T. Nicholson
M AN U
MBBS Cork University Hospital Corresponding author:
Cork University Hospital
TE D
Frederik Vernimmen
Wilton, Cork
AC C
Ireland
EP
Department of Radiation Oncology
[email protected] Tel: ++ 353-863522357
Fax: ++ 353-21-4921346 The authors declare no conflict of interest
ACCEPTED MANUSCRIPT
RI PT
New immunotherapy (IT) agents showing good efficacy in a number of clinical indications have created new research in applying these drugs in combination with radiation to make the treatment more immunogenic, and promote the triggering of an abscopal effect. Many
SC
questions still exist around the optimal combination of drug selection, pathology, timing, and radiation dose/schedule. With regard to radiation, a variety of total dose and dose per fraction
M AN U
schedules have been clinically investigated (1). These studies have used photon irradiation with little attention paid to other forms of radiation with different properties. The mechanism by which radiation and immunotherapy induce an abscopal effect is only beginning to be understood. An appropriate tumour suppressive environment and immune-
TE D
stimulating response must occur at the right time to elicit an abscopal response (2), which is the result of T-cell activation and proliferation. These circulating lymphocytes are highly
EP
sensitive to radiation, and protracted radiotherapy schedules, and the use of multiple treatment fields in IMRT with their associated large volume of “low dose bath” exacerbate
AC C
the lymphotoxicity
Immunotherapy phase I/II studies have used a variety of dose schedules, ranging from standard fractionated therapy to high dose single fractions (SBRT). No clear favourite schedule as yet has come to the forefront, but SBRT and hypo fractionation tend to produce a somewhat better abscopal effect (3, 4). Clinical trials in malignant melanoma have shown promising results (5).
ACCEPTED MANUSCRIPT The probability of cellular radiation damage depends not only on the absorbed dose, but also on the type of radiation, with various radiation modalities having different quality factors, now called a “radiation weighting factor”. Linear Energy Transfer (LET) is another way of describing the absorbed dose effects. Photons, electrons and protons are classified as low
RI PT
LET. Fast neutrons and heavy charged particles are high LET and they inflict more cellular damage per unit of dose (6), with the potential to increase the amounts of “immunogenic debris”. The biological basis for this is a dense clustering of Double Strand Breaks (DSBs)
SC
along the ion tracks with inefficient DSB repair (6). Both fast neutrons and carbon ions have similar radiobiological effects (RBE). Their physical characteristics are however different,
M AN U
with fast neutrons behaving like photons, and charged particles having a Bragg peak. Although protons are equally effective to photons with regard to the production of T cells mediated in tumour cell killing (7), protons delivered by pencil beam scanning (PBS) have an inherent advantage for triggering abscopal effects because of a lower integral dose and hence
TE D
less lymphotoxicity. Carbon ions offer the best of both worlds. Matsunaga et.al. (8) demonstrated that carbon ion treatment of the primary tumour resulted in a dramatic abscopal effect which was further significantly enhanced by combining it with immunotherapy.
EP
Ohkubo et.al. demonstrated a dramatic reduction in lung metastasis after Carbon ions
AC C
treatment. Here again the addition of immunotherapy significantly enhanced the abscopal effect further (9).
Very few carbon ion therapy centres exist, and use of neutron therapy has declined substantially (10). Nevertheless neutron therapy yielded better local control for some indications. No studies have explored the abscopal effects of neutrons, but they are potentially strong triggers for this. Their dose distribution disadvantage could be partially circumvented by the use of intensity modulated neutron therapy.
ACCEPTED MANUSCRIPT Proton therapy is rapidly becoming more available worldwide. This should allow for research on the immunogenic effects of protons, by exploiting their lower integral dose. Studies on the immunogenicity of irradiation have many variables. Protons and high LET
RI PT
radiation carry a lot of promise in the quest to enhance the abscopal effect, which in itself reflects a strong systemic immunogenic response. References:
SC
1. Kang J, Demaria \s, Formenti A: Current clinical trials testing the combination of
immunotherapy with radiotherapy. Journal for Immunotherapy of Cancer Sep 2016; 4:51:1-
M AN U
20
2. John NG, Tong Daj, Radiation Therapy and the abscopal effect; a concept comes of age.
TE D
Annals of Translational Medicine March 2016; 4(6): 118
3. Demaria S, Formenti SC: Radiation as an immunological adjuvant: current evidence on
AC C
EP
dose and fractionation. Frontiers in Oncology 2012 2: article 153
4. Popp I, Grosu AL, Niedermann G, et al: Immune modulation by hypofractionated stereotactic radiation therapy: Therapeutic implications. Radiother Oncol 120(2):185-94
5. Chandra R.A., Wilhite T.J., Balboni T.A. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab Oncolimmunology May 2015; 4:11
ACCEPTED MANUSCRIPT
6. Lorat Y, Timm S, Jakob B, et al: Clustered double-strand breaks in heterochromatine perturb DNA repair after high linear energy transfer irradiation. Radiother Oncol. 2016;
RI PT
121(1):154-161
7. Gameiro SR, Malamas AS, Bernstein MB, et al. Tumor cells surviving exposure to proton
SC
or photon radiation share a common immunogenic modulation signature, rendering them
M AN U
more sensitive to T cell-mediated killing. Int J Rad Oncol Biol Phys. 2016; 95 (1): 120-130
8. Matsunaga A, Ueda Y, Yamada S, et al. Carbon-ion beam treatment induces systemic antitumor immunity against Murine Squamous Cell Carcinoma. Cancer August 2010; 3740-
TE D
3748
EP
9. Ohkubo Y, Iwakawa M, Seino K-I, et al. Combining carbon ion radiotherapy and local
injection of ∝-Galactosylceramide-pulsed dendritic cells inhibits lung metastasis in an In
AC C
Vivo murine model. Int. J. Rad Onc. Biol. Phys 2010; 78: 1524-1531
10. Specht H.M., Neff T., Reuschel W, Wagner F.M. Paving the road for modern particle
therapy – What can we learn from the experience gained with fast neutron therapy in Munich; Frontiers in Oncology 2015; vol 5, 262