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Multicenter Report on Toxicities of Concurrent Nivolumab and Radiation Therapy
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Volume 99 Number 2S Supplement 2017 Conclusion: Our data so far indicates that targeting gold nanoparticles to the nucleus results in the augmentation of radiation effects through increased formation of DNA double strand breaks. These results have set the stage for further studies in vivo, which are currently in progress. Author Disclosure: M.L. Aliru: None. K. Aziz: None. M. Bodd: None. K. Sanders: None. L.K. Mahadevan: None. N. Sahoo: Research Grant; NIH/ NCI, Varian Medical System. R.C. Tailor: None. S. Krishnan: Research Grant; Cancer Prevention and Research Institute of Texas, Celgene, DoD, Dunn Foundation, NIH. Royalty; Taylor and Francis Group; RTOG.
3368 Multicenter Report on Toxicities of Concurrent Nivolumab and Radiation Therapy N.P. Amin,1,2 A.M. Chhabra,3 P. Mohindra,3 C.B. Simone, II,3 and Z. Vujaskovic4; 1Department of Radiation Oncology, Upper Chesapeake Medical Center, Bel Air, MD, 2Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD, 3 University of Maryland Medical Center, Baltimore, MD, 4Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD Purpose/Objective(s): Combination immunotherapy (IT) and radiation therapy (RT) is an actively growing field of clinical investigation, yet there are limited data on safety and outcome optimization regarding RT dose, fractionation, and sequencing of RT with IT. This contributes to uncertainty when deciding to either 1) hold IT during palliative or definitive RT for fear of increased toxicities or immune-related adverse events (ir-AEs), or 2) deliver concurrent IT-RT with hopes of improved outcomes and abscopal effects. Nivolumab (NIVO), an anti-PD-1 monoclonal antibody, has been rapidly adopted in the clinic over the past 2 years. Preclinical studies have proposed a mechanism of synergistic effect of RT and PD-L/ PD-L1 axis (PDA) checkpoint inhibitors, and suggested that concurrent, but not sequential, blockade of the PDA with standard fractionated RT (2 Gy) generates effective antitumor immunity and potential for long-term tumor control. We reviewed our experience to assess the toxicity profile of concurrent NIVO-RT. Materials/Methods: A retrospective review of all consecutive patients (pts) who received NIVO and RT from 1/2015 to 2/2017 was conducted at 2 separate centers. Pts were grouped by sequencing of NIVO-RT: 1) Concurrent [C]: RT 14 days after NIVO, 2) Sequential [S]: RT 14 -19 days from prior & next NIVO, 3) Prior [P] Z RT 3 prior to initial NIVO infusion. Results: Out of a total of 165 pts who received NIVO, 23 pts (14%) with 30 treatment sites were identified who had P (nZ3), S (nZ5), or C (nZ15) NIVO-RT. Patient characteristics and RT details are summarized in the Table. With a median f/u of 102 (7-405) days, there was a range of local responses with no significant differences between sequencing cohorts: 5 CR, 6 PR, 2 stable, 7 progression, 3 pending assessment. Overall, 5 (22%) pts and 1 (4%) pt experienced grade 2 and 3 toxicities within 1 month of RT, respectively. Only pts in the concurrent cohort experienced new ir-AEs within 2 weeks of completing RT: G2 pancreatitis [33 Gy/3fx to left adrenal], G2 pneumonitis [30 Gy/5 fx to RLL, V20<10%]), and G3 colitis [30Gy/10 fx to T7-T9]. Interestingly, a patient with G2 nausea in the
S- cohort continued NIVO and developed G3 encephalopathy 5 months after WBRT. Conclusion: Concurrent NIVO-RT is generally well tolerated, however there may be an increased risk for G2 ir-AEs in non-extremity sites. It is unclear if total dose, dose/fx, or different sequencing of RT would reduce the frequency or intensity of these toxicities. Local response did not seem to be impacted by sequencing of therapy. Future prospective trials assessing fractionation and sequencing of RT with IT will help inform combined therapy recommendations. Author Disclosure: N.P. Amin: None. A.M. Chhabra: None. P. Mohindra: None. C.B. Simone: Annals of Palliative Medicine, Proton Collaborative Group (PCG). Z. Vujaskovic: None.
3369 CCAAT Box, Not CArG Motifs, Identify Surviving as a Highly Potent Radiation Inducible Promoter W.O. Arafat1,2 and G. Naoum3; 1University of Alexandria, Alexandria, Egypt, 2Alexandria comprehensive cancer center, Alexandria, alexandria, Egypt, 3Alexandria Comprehensive Cancer Center, alexandria, Egypt Purpose/Objective(s): Radiogenetic therapy is a novel approach in the treatment of cancer, which employs genetic modification to alter the sensitivity of tumor cells to the effect of applied radiation. Some previous studies concluded that CArG motifs are the elements responsible for radiation mediated transcription regulation, while other concluded that CCAAT box consensus are present in low frequencies in radioresponsive genes in comparison to normal genes. Using bioinformatics we aim to detect mechanism of radiation mediated transcription regulation in the context of glioblastoma adenoviral gene therapy. Materials/Methods: The effect of radiation was tested on 6 different inhouse promoters (iNOS, FLT-1, DR5, Cox-2, VEGF, and survivin) where levels of mRNA expression of these promoters were assessed using Quantitative RTPCR in D54 MG cells before and after radiation exposure. Recombinant Ad/reporter genes driven by 7 different promoters; CMV, VEGF, FLT-1, DR5, iNOS, cox-2 and Survivin were constructed. Glioma cell lines were infected with different Multiplicity of infection of the (promoter) Ad or CMV Ad. Cells were then exposed to a range of radiation (0-12Gy) at single fraction. Fluorescent Microscopy, Luc assay and X-gal staining was used to detect the level of expression of related genes. A time course experiment was carried out to look for effect of time of radiation on gene expression. These promoters were screened for the presence CArG motifs and CCAAT box consensus using NCBI Blast bioinformatics software. Results: Radiotherapy increase the expression of gene expression by1.75fold in DR5, 2-fold in VEGF and 0 fold Flt-1 after 2 hr of radiation. Most importantly Cells treated with RT and Ad Luc driven by Survivin promoter showed 5-fold increase in expression after 2 Gy of radiation in compare to non-irradiated cells. RNA analysis was done and has shown increase copy no. of corresponding genes in level range from 2 fold for VEGF 3 fold for iNOS and as expected 30 fold more for Survivin. Using NCBI BLAST software, none of CArG motifs were found in the different 6 promoters. Survivin with the best response to radiation had the lowest number of CCAAT box (nZ2) while iNOS with the lowest response to radiation had the highest number of CCAAT (nZ14) with other promoters having different numbers of CCAAT ranging between these two values.
Abstract 3368 Patients
NZ23
Sites of RT
Cycles of NIVO Age Gender M/F Primary Cancer Lung Renal GI HN Melanoma
6 (1-33) 60 (43-82) 13/10
Central thorax/Abd Extremity CW/Axilla Brain HN
11 5 3 2 2
NZ30 9 6 6 6 3
STD RT
#
> STD RT
#
30 /10 (3) 20/5 (4) 8/1 (8) 20/10 (2) 50/25 (2)
10 6 5 1 1
24/3 (8) 33/3 (11) 30/5 (6) 30/10 +12Gy GRID 20/5 +12Gy GRID+ hyperthermia 57.5/23 (2.5) + Hyperthermia
2 1 1 1 1 1
Volume 99 Number 2S Supplement 2017 Conclusion: Our data so far indicates that targeting gold nanoparticles to the nucleus results in the augmentation of radiation effects through increased formation of DNA double strand breaks. These results have set the stage for further studies in vivo, which are currently in progress. Author Disclosure: M.L. Aliru: None. K. Aziz: None. M. Bodd: None. K. Sanders: None. L.K. Mahadevan: None. N. Sahoo: Research Grant; NIH/ NCI, Varian Medical System. R.C. Tailor: None. S. Krishnan: Research Grant; Cancer Prevention and Research Institute of Texas, Celgene, DoD, Dunn Foundation, NIH. Royalty; Taylor and Francis Group; RTOG.
3368 Multicenter Report on Toxicities of Concurrent Nivolumab and Radiation Therapy N.P. Amin,1,2 A.M. Chhabra,3 P. Mohindra,3 C.B. Simone, II,3 and Z. Vujaskovic4; 1Department of Radiation Oncology, Upper Chesapeake Medical Center, Bel Air, MD, 2Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD, 3 University of Maryland Medical Center, Baltimore, MD, 4Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD Purpose/Objective(s): Combination immunotherapy (IT) and radiation therapy (RT) is an actively growing field of clinical investigation, yet there are limited data on safety and outcome optimization regarding RT dose, fractionation, and sequencing of RT with IT. This contributes to uncertainty when deciding to either 1) hold IT during palliative or definitive RT for fear of increased toxicities or immune-related adverse events (ir-AEs), or 2) deliver concurrent IT-RT with hopes of improved outcomes and abscopal effects. Nivolumab (NIVO), an anti-PD-1 monoclonal antibody, has been rapidly adopted in the clinic over the past 2 years. Preclinical studies have proposed a mechanism of synergistic effect of RT and PD-L/ PD-L1 axis (PDA) checkpoint inhibitors, and suggested that concurrent, but not sequential, blockade of the PDA with standard fractionated RT (2 Gy) generates effective antitumor immunity and potential for long-term tumor control. We reviewed our experience to assess the toxicity profile of concurrent NIVO-RT. Materials/Methods: A retrospective review of all consecutive patients (pts) who received NIVO and RT from 1/2015 to 2/2017 was conducted at 2 separate centers. Pts were grouped by sequencing of NIVO-RT: 1) Concurrent [C]: RT 14 days after NIVO, 2) Sequential [S]: RT 14 -19 days from prior & next NIVO, 3) Prior [P] Z RT 3 prior to initial NIVO infusion. Results: Out of a total of 165 pts who received NIVO, 23 pts (14%) with 30 treatment sites were identified who had P (nZ3), S (nZ5), or C (nZ15) NIVO-RT. Patient characteristics and RT details are summarized in the Table. With a median f/u of 102 (7-405) days, there was a range of local responses with no significant differences between sequencing cohorts: 5 CR, 6 PR, 2 stable, 7 progression, 3 pending assessment. Overall, 5 (22%) pts and 1 (4%) pt experienced grade 2 and 3 toxicities within 1 month of RT, respectively. Only pts in the concurrent cohort experienced new ir-AEs within 2 weeks of completing RT: G2 pancreatitis [33 Gy/3fx to left adrenal], G2 pneumonitis [30 Gy/5 fx to RLL, V20<10%]), and G3 colitis [30Gy/10 fx to T7-T9]. Interestingly, a patient with G2 nausea in the
S- cohort continued NIVO and developed G3 encephalopathy 5 months after WBRT. Conclusion: Concurrent NIVO-RT is generally well tolerated, however there may be an increased risk for G2 ir-AEs in non-extremity sites. It is unclear if total dose, dose/fx, or different sequencing of RT would reduce the frequency or intensity of these toxicities. Local response did not seem to be impacted by sequencing of therapy. Future prospective trials assessing fractionation and sequencing of RT with IT will help inform combined therapy recommendations. Author Disclosure: N.P. Amin: None. A.M. Chhabra: None. P. Mohindra: None. C.B. Simone: Annals of Palliative Medicine, Proton Collaborative Group (PCG). Z. Vujaskovic: None.
3369 CCAAT Box, Not CArG Motifs, Identify Surviving as a Highly Potent Radiation Inducible Promoter W.O. Arafat1,2 and G. Naoum3; 1University of Alexandria, Alexandria, Egypt, 2Alexandria comprehensive cancer center, Alexandria, alexandria, Egypt, 3Alexandria Comprehensive Cancer Center, alexandria, Egypt Purpose/Objective(s): Radiogenetic therapy is a novel approach in the treatment of cancer, which employs genetic modification to alter the sensitivity of tumor cells to the effect of applied radiation. Some previous studies concluded that CArG motifs are the elements responsible for radiation mediated transcription regulation, while other concluded that CCAAT box consensus are present in low frequencies in radioresponsive genes in comparison to normal genes. Using bioinformatics we aim to detect mechanism of radiation mediated transcription regulation in the context of glioblastoma adenoviral gene therapy. Materials/Methods: The effect of radiation was tested on 6 different inhouse promoters (iNOS, FLT-1, DR5, Cox-2, VEGF, and survivin) where levels of mRNA expression of these promoters were assessed using Quantitative RTPCR in D54 MG cells before and after radiation exposure. Recombinant Ad/reporter genes driven by 7 different promoters; CMV, VEGF, FLT-1, DR5, iNOS, cox-2 and Survivin were constructed. Glioma cell lines were infected with different Multiplicity of infection of the (promoter) Ad or CMV Ad. Cells were then exposed to a range of radiation (0-12Gy) at single fraction. Fluorescent Microscopy, Luc assay and X-gal staining was used to detect the level of expression of related genes. A time course experiment was carried out to look for effect of time of radiation on gene expression. These promoters were screened for the presence CArG motifs and CCAAT box consensus using NCBI Blast bioinformatics software. Results: Radiotherapy increase the expression of gene expression by1.75fold in DR5, 2-fold in VEGF and 0 fold Flt-1 after 2 hr of radiation. Most importantly Cells treated with RT and Ad Luc driven by Survivin promoter showed 5-fold increase in expression after 2 Gy of radiation in compare to non-irradiated cells. RNA analysis was done and has shown increase copy no. of corresponding genes in level range from 2 fold for VEGF 3 fold for iNOS and as expected 30 fold more for Survivin. Using NCBI BLAST software, none of CArG motifs were found in the different 6 promoters. Survivin with the best response to radiation had the lowest number of CCAAT box (nZ2) while iNOS with the lowest response to radiation had the highest number of CCAAT (nZ14) with other promoters having different numbers of CCAAT ranging between these two values.
Abstract 3368 Patients
NZ23
Sites of RT
Cycles of NIVO Age Gender M/F Primary Cancer Lung Renal GI HN Melanoma
6 (1-33) 60 (43-82) 13/10
Central thorax/Abd Extremity CW/Axilla Brain HN
11 5 3 2 2
NZ30 9 6 6 6 3
STD RT
#
> STD RT
#
30 /10 (3) 20/5 (4) 8/1 (8) 20/10 (2) 50/25 (2)
10 6 5 1 1
24/3 (8) 33/3 (11) 30/5 (6) 30/10 +12Gy GRID 20/5 +12Gy GRID+ hyperthermia 57.5/23 (2.5) + Hyperthermia
2 1 1 1 1 1