Page 203 - 2014 Printable Abstract Book
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vascular and neurogenic injuries following irradiation of only the NVB or PB, and after irradiation of all
three sites (prostate, NVB and PB) with varying doses of radiation. Materials/Methods: In the first study,
dogs were treated with 50 Gy to the prostate, NVB and PB, NVB and PB, NVB only or PB only, via 5-fraction
SBRT. In a second study, the prostate, NVB and PB of dogs were treated with 50, 40 or 30 Gy in 5 fractions.
Electrophysiologic studies of the pudendal nerve and bulbospongiosus muscles, as well as MRI and
ultrasound studies of pelvic perfusion were performed before and after SBRT. Results of these bioassays
were correlated with histopathologic changes. Results: SBRT caused slowing of the systolic rise time,
which corresponded to changes in arterial patency. Furthermore, a dose-dependent alteration in the
response of the internal pudendal artery to vasoactive drugs was observed, wherein SBRT caused a
paradoxical response to papaverine, which slowed the systolic rise time after 40 and 50 Gy. The
neurofilament content of penile nerves decreased in a dose-dependent fashion after irradiation, and was
more profound when only the PB was irradiated than when only the NVB was irradiated. These findings
are coincident with slowing of motor nerve conduction velocities in the pudendal nerve after SBRT.
Conclusions: This is the first known report in which prostatic irradiation was shown to cause morphologic
arterial damage that was coincident with altered internal pudendal areterial tone, and in which decreased
motor function in the pudendal nerve was attributed to axonal degeneration and loss. Further
investigation of the roles that internal pudendal arterial dysfunction and pudendal nerve damage play in
RI-ED is warranted.
(PS3-24) Combining checkpoint blockade with radiation therapy results in tumor and immunological
responses in an autochthonous mouse model of lung cancer. Amanda Walker; Chris Nirschle; Katriana
Nugent; Hailun Wang; Timothy Harris; Reem Malek; Russell Hales; John Wong; Charles Drake; Phuoc T.
Tran, MD, PhD; Johns Hopkins Medicine, Baltimore, MD
Blockade of the PD-1 pathway has shown promising clinical results in non-small cell lung cancer
(NSCLC). Radiation therapy (RT) has been shown to increase antigen presentation and promote a pro-
inflammatory microenvironment. We hypothesized that the combination of α-PD-L1 and RT would
enhance tumor response in an autochthonous NSCLC mouse model. Given the complimentary roles of
CTLA-4 and PD-1 pathways in the immune response, we also examined the effects of α-CTLA-4, α-PD-L1
and RT. KrasG12D-/Twist1 NSCLC transgenic mice were stratified into treatment groups: (1) control, (2) α-
PD-L1, (3) α-PD-L1 + α-CTLA-4, (4) RT + isotype, (5) RT+ α-PD-L1, and (6) RT + α-PD-L1+ α-CTLA-4. Image-
guided RT (15 Gy x 1) was delivered to the right hemithorax. Mice were sacrificed after treatment to
confirm tumor burden and to quantify immune infiltrate in the tumor and draining lymph nodes.
Checkpoint blockade alone (α-PD-L1 or α-PD-L1 + α-CTLA-4) or RT alone decreased the rate of tumor
progression compared to isotype control (p <0.05). The only animals demonstrating complete-durable
responses at week 3 and beyond were treated with both checkpoint blockade and RT. Both antibodies +
RT led to an average 60% decrease in tumor size at week 3 (p<0.01) and 80% decrease in tumor size at
week 6 (p=0.01). There was also decreased tumor growth in the contralateral unirradiated hemithorax in
mice treated with checkpoint blockade and RT providing some evidence for an abscopal effect (p=0.01).
Post treatment, we found an increase in CD8 effector cells (CD8+/IFNγ+) in the lungs of treated mice, and
did not find an increase in regulatory T cells (CD4+/Foxp3+) or activated CD4 T cells (CD4+/IFNγ+). This
increase in cytotoxic T cells was seen in both the irradiated and unirradiated lungs with the greatest
change after treatment with combined RT plus α-PD-L1 and α-CTLA4 antibodies (p<0.05). The combination
of checkpoint blockade and RT in a model of NSCLC improved local tumor response in the irradiated lung
201 | P a g e
three sites (prostate, NVB and PB) with varying doses of radiation. Materials/Methods: In the first study,
dogs were treated with 50 Gy to the prostate, NVB and PB, NVB and PB, NVB only or PB only, via 5-fraction
SBRT. In a second study, the prostate, NVB and PB of dogs were treated with 50, 40 or 30 Gy in 5 fractions.
Electrophysiologic studies of the pudendal nerve and bulbospongiosus muscles, as well as MRI and
ultrasound studies of pelvic perfusion were performed before and after SBRT. Results of these bioassays
were correlated with histopathologic changes. Results: SBRT caused slowing of the systolic rise time,
which corresponded to changes in arterial patency. Furthermore, a dose-dependent alteration in the
response of the internal pudendal artery to vasoactive drugs was observed, wherein SBRT caused a
paradoxical response to papaverine, which slowed the systolic rise time after 40 and 50 Gy. The
neurofilament content of penile nerves decreased in a dose-dependent fashion after irradiation, and was
more profound when only the PB was irradiated than when only the NVB was irradiated. These findings
are coincident with slowing of motor nerve conduction velocities in the pudendal nerve after SBRT.
Conclusions: This is the first known report in which prostatic irradiation was shown to cause morphologic
arterial damage that was coincident with altered internal pudendal areterial tone, and in which decreased
motor function in the pudendal nerve was attributed to axonal degeneration and loss. Further
investigation of the roles that internal pudendal arterial dysfunction and pudendal nerve damage play in
RI-ED is warranted.
(PS3-24) Combining checkpoint blockade with radiation therapy results in tumor and immunological
responses in an autochthonous mouse model of lung cancer. Amanda Walker; Chris Nirschle; Katriana
Nugent; Hailun Wang; Timothy Harris; Reem Malek; Russell Hales; John Wong; Charles Drake; Phuoc T.
Tran, MD, PhD; Johns Hopkins Medicine, Baltimore, MD
Blockade of the PD-1 pathway has shown promising clinical results in non-small cell lung cancer
(NSCLC). Radiation therapy (RT) has been shown to increase antigen presentation and promote a pro-
inflammatory microenvironment. We hypothesized that the combination of α-PD-L1 and RT would
enhance tumor response in an autochthonous NSCLC mouse model. Given the complimentary roles of
CTLA-4 and PD-1 pathways in the immune response, we also examined the effects of α-CTLA-4, α-PD-L1
and RT. KrasG12D-/Twist1 NSCLC transgenic mice were stratified into treatment groups: (1) control, (2) α-
PD-L1, (3) α-PD-L1 + α-CTLA-4, (4) RT + isotype, (5) RT+ α-PD-L1, and (6) RT + α-PD-L1+ α-CTLA-4. Image-
guided RT (15 Gy x 1) was delivered to the right hemithorax. Mice were sacrificed after treatment to
confirm tumor burden and to quantify immune infiltrate in the tumor and draining lymph nodes.
Checkpoint blockade alone (α-PD-L1 or α-PD-L1 + α-CTLA-4) or RT alone decreased the rate of tumor
progression compared to isotype control (p <0.05). The only animals demonstrating complete-durable
responses at week 3 and beyond were treated with both checkpoint blockade and RT. Both antibodies +
RT led to an average 60% decrease in tumor size at week 3 (p<0.01) and 80% decrease in tumor size at
week 6 (p=0.01). There was also decreased tumor growth in the contralateral unirradiated hemithorax in
mice treated with checkpoint blockade and RT providing some evidence for an abscopal effect (p=0.01).
Post treatment, we found an increase in CD8 effector cells (CD8+/IFNγ+) in the lungs of treated mice, and
did not find an increase in regulatory T cells (CD4+/Foxp3+) or activated CD4 T cells (CD4+/IFNγ+). This
increase in cytotoxic T cells was seen in both the irradiated and unirradiated lungs with the greatest
change after treatment with combined RT plus α-PD-L1 and α-CTLA4 antibodies (p<0.05). The combination
of checkpoint blockade and RT in a model of NSCLC improved local tumor response in the irradiated lung
201 | P a g e
