Most oncology providers and staff agree that obtaining social risk information is important for patient care. Developing clinic-based solutions that integrate social risk screening and referral workflows within the oncology setting is imperative to reduce cancer health disparities. Future efforts that leverage the use of electronic health records to conduct social risk screening and streamline referrals to community-based resources in oncology may improve cancer health equity.

Our results are consistent with our hypothesis that equal access care diminishes the impacts of living within a disadvantaged neighborhood. Future research should investigate the interaction between health care access and social and demographic factors.

Purpose/Objective(s) The use of radical prostatectomy (RP) for men with high-risk prostate cancer (PC) is increasing. RP is often utilized as a component of multi-modality therapy, as a method to intensify treatment. Many patients who undergo RP will subsequently require radiation therapy (RT), exposing patients to side effects from both treatments. While the side effects of RT and RP have been directly compared in previous studies, there is limited data comparing side effects of primary RT with those of patients undergoing RP and RT (RP/RT). We hypothesize that patients undergoing RP/RT for high-risk PC will experience significantly higher side effects than those undergoing primary RT. Materials/Methods We used the Surveillance Epidemiology and End Results (SEER) database with Medicare insurance claims to identify patients 66 years or older with primary high-risk PC who underwent RP, RT, or both between January 1, 2004 and December 31, 2013. High-risk PC was defined as disease meeting one or more of the following criteria: stage ≥ T3a, grade group ≥ 4, PSA >20. Outcomes of interest included treatment for urinary incontinence, urethral stricture, erectile dysfunction (ED), proctitis and cystitis at least 1 year after completion of primary prostate cancer treatment, which were captured using diagnosis and procedure codes. Rates of these endpoints were compared using cumulative incidence functions as well as cox proportional hazard models. Patients who were lost to follow up or died were censored at the time of their last encounter. Results The cohort included 17,649 patients, of which 15,399 were treated with primary RT (87.25%) and 2,250 were treated with RP/RT (12.75%). On multivariable analysis, compared to primary RT, RP/RT was associated with an increased risk of incontinence therapy [HR 1.907 (1.679-2.166)], stricture therapy [HR 1.865 (95% CI: 1.589-2.190)] and ED therapy [HR 2.869 (95% CI: 2.046-4.023)] after treatment for prostate cancer. Rates of therapy for cystitis or proctitis were not significantly different between these two groups. Conclusion For men with high-risk PC, treatment with RP/RT was associated with increased utilization of incontinence therapy, stricture therapy, and ED therapy after completion of prostate cancer treatment. With multiple curative treatment options and long duration of survival after treatment, the side effect profile of treatment is a major factor in determining the most appropriate course of treatment for an individual patient. Patients considering primary RP as a component of multimodality therapy for high-risk PC should be informed about the increased risk of side effects. Clinical trials are required to better evaluate this treatment paradigm.

Purpose/Objective(s) Objective response rates to PD-1 blockade in human papillomavirus (HPV) mediated Head and Neck Squamous cell carcinoma (HNSCC) are low and resistance mechanisms are unclear. HPV oncogenes are known to modulate immune responses; however, the role that they play in limiting responses to PD-1 blockade is poorly understood. Here we investigated HPV oncogenes and uncovered a novel mechanism by which HPV E5 suppresses immune responses and diminishes the activity of PD-1 blockade in HNSCC. Materials/Methods Human cell lines were engineered to express HPV E5 and RNAseq was performed to elucidate E5 mediated alterations in transcriptome. MHC class I pull downs and tandem MS/MS was performed to characterize the immunopeptidome and investigate the effect of HPV E5 on the repertoire of presented tumor antigens. Syngeneic murine models were used to dissect molecular mechanisms by which E5 modulates antigen presentation and IFN signaling pathways. Finally, a curated database of tumor RNAseq from 35 HPV-positive HNSCC patients was analyzed to determine the impact of E5 on HLA expression and patient outcomes. Results RNAseq revealed dramatic downregulation of antigen processing and type I interferon pathways in E5-expressing human cell lines. Immunopeptidome analysis revealed that E5-expressing cells have a significantly restricted antigen repertoire, indicating that E5 may help HPV mediated tumors escape from host immune surveillance. Remarkably, syngeneic murine tumors expressing HPV E5 were rendered entirely resistant to PD-1 blockade compared to responding parental lines without E5 expression. Mechanistically HPV E5 was demonstrated to suppress phosphorylation of IRF3 and type I interferon production, while directly binding MHC and preventing translocation to the cell surface. Ultimately, we observed a striking improvement in disease free survival (DFS) and overall survival (OS) in patients with low E5 and high HLA expression [Median DFS 50mo in E5 high/HLA-A low versus not reached in E5 low/HLA-A high; p=0.039]. Conclusion Our findings establish HPV E5 as a mediator of resistance to PD-1 checkpoint blockade via inhibition of HLA expression and IFN response pathways. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV E5-mediated immunosuppression which can be exploited to improve response rates to PD-1 checkpoint blockade. Objective response rates to PD-1 blockade in human papillomavirus (HPV) mediated Head and Neck Squamous cell carcinoma (HNSCC) are low and resistance mechanisms are unclear. HPV oncogenes are known to modulate immune responses; however, the role that they play in limiting responses to PD-1 blockade is poorly understood. Here we investigated HPV oncogenes and uncovered a novel mechanism by which HPV E5 suppresses immune responses and diminishes the activity of PD-1 blockade in HNSCC. Human cell lines were engineered to express HPV E5 and RNAseq was performed to elucidate E5 mediated alterations in transcriptome. MHC class I pull downs and tandem MS/MS was performed to characterize the immunopeptidome and investigate the effect of HPV E5 on the repertoire of presented tumor antigens. Syngeneic murine models were used to dissect molecular mechanisms by which E5 modulates antigen presentation and IFN signaling pathways. Finally, a curated database of tumor RNAseq from 35 HPV-positive HNSCC patients was analyzed to determine the impact of E5 on HLA expression and patient outcomes. RNAseq revealed dramatic downregulation of antigen processing and type I interferon pathways in E5-expressing human cell lines. Immunopeptidome analysis revealed that E5-expressing cells have a significantly restricted antigen repertoire, indicating that E5 may help HPV mediated tumors escape from host immune surveillance. Remarkably, syngeneic murine tumors expressing HPV E5 were rendered entirely resistant to PD-1 blockade compared to responding parental lines without E5 expression. Mechanistically HPV E5 was demonstrated to suppress phosphorylation of IRF3 and type I interferon production, while directly binding MHC and preventing translocation to the cell surface. Ultimately, we observed a striking improvement in disease free survival (DFS) and overall survival (OS) in patients with low E5 and high HLA expression [Median DFS 50mo in E5 high/HLA-A low versus not reached in E5 low/HLA-A high; p=0.039]. Our findings establish HPV E5 as a mediator of resistance to PD-1 checkpoint blockade via inhibition of HLA expression and IFN response pathways. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV E5-mediated immunosuppression which can be exploited to improve response rates to PD-1 checkpoint blockade.

Craniospinal irradiation (CSI) is an important treatment modality for medulloblastoma and other brain tumors that can spread through the cerebrospinal fluid. The exit dose associated with traditional photon CSI has the potential to cause significant acute and late toxicities. Proton CSI allows for the sparing of structures beyond the target volume. Vertebral-body-sparing (VBS) proton CSI does not include the vertebral body in the target volume, further sparing adjacent bone marrow and tissues immediately anterior to the vertebral body. This retrospective review compares the acute side effect profiles of photon and VBS proton CSI. Pediatric patients treated with CSI between 2008 and 2018 were included in this single institution study. Patients were treated with a CSI dose of 23.4-39.6 Gy followed by boosts to the posterior fossa. Proton patients were treated with VBS technique. Photon patients were treated with posterior beams or VMAT. Chemotherapy varied per patient depending on protocol. Medical records were reviewed for acute toxicities which were graded according to CTCAE v4.03. DFS was evaluated using Kaplan-Meier, toxicity rates were compared using Fisher's exact test. A total of 38 patients were included. The median age at treatment was 7.5 years (range 2-16). Median follow up time was 20.5 months. 13 patients were treated with photon CSI and 25 with VBS proton CSI. The 2 year DFS was 81.3% for VBS proton CSI and 61.5% for photon CSI (p=0.18). Rates of acute GI toxicity ≥ Grade 2 were significantly lower in the VBS proton CSI group (6, 24% vs 10, 76.5% p=0.0045). Rates of nausea ≥ Grade 2 were also lower (6, 24.0% vs 8, 61.5% p=0.0353). No patients treated with VBS proton CSI had esophagitis, while 38% were symptomatic in the photon CSI group (0, 0% vs 5, 38.4% p=0.0026 for any Grade esophagitis). Detailed serial labs were available for 10 photon CSI patients and 23 in VBS proton CSI. Acute hematologic toxicity ≥ Grade 2 was present in 82% of the VBS proton CSI patients and 100% of the photon CSI (p=0.2890). Anemia requiring pRBC transfusions occurred at significantly lower rates in VBS proton CSI patients (5, 21.7% vs 6, 60.0% p=0.0494). Leukopenia ≥ Grade 2 was not significantly different between the groups (17, 73.9% vs 7, 70.0% p=0.2890). Grade 4 lymphopenia occurred significantly less in the VBS proton CSI group (7, 33.3% vs 7, 77.8% p=0.0457), with lymphopenia data available in 21 and 9 patients, respectively. There were no grade 5 toxicities of any type and no treatment delays due to acute toxicities. VBS proton CSI was associated with less acute toxicity than photon CSI. This supports the presumed dosimetric benefits of sparing structures beyond the thecal sac. Further research is warranted to determine late toxicity benefits from this treatment approach.

Anti-PD-1 checkpoint blockade immunotherapy (CBI) was recently approved for recurrent or metastatic cisplatin refractory Head and Neck Squamous Cell Carcinoma (HNSCC); however, response rates remain low. Multiple pre-clinical studies and emerging clinical studies have described synergistic interactions between radiation (RT) and CBI. We previously defined the role of RT in enhancing T-cell activation and proliferation via antigen cross-presentation in the draining lymph node (DLN) when combined with anti-PD-1 CBI. However, the ability for RT to enhance local control and anti-tumor immune responses when combined with anti-PD-L1 CBI in HPV specific HNSCC models is understudied. Here we used novel flank and orthotopic HNSCC tumor models including AT-84 expressing HPV E7 to study the effects of RT+CBI. Focused RT (8-12Gyx1) was delivered to AT84-E7 flank tumors and orthotopic tongue tumors via the JL Shepard CS-137. Cohorts of C3H or B6 mice received either no treatment or three IP injections of 200ug anti-PD-L1 Ab immediately before, and at 3 and 6 days post RT. Tumor diameter was measured every 2 to 3 days using electronic caliper and reported as volume using the formula (m1 x m22)/2. Cell surface markers and development of antigen-specific immune responses were analyzed in tumor draining lymph node (DLN) and matched tumor infiltrating lymphocytes (TIL) by flow cytometry on BD FACSAria II. RT + anti-PD-L1 CBI resulted in a statistically significant improvement in local tumor control compared to RT alone in our HNSCC orthotopic tumor models (RT 16.5 +/- 8.9 mm3 vs RT + CBI 1.2 +/- 0.6 mm3, p<0.001). RT + CBI also significantly increased CD8+ and CD4+ activated T-cells in the TIL population (CD8: RT 2.3 +/- 0.7% vs RT + IT 4.1 +/- 1.2%, p < 0.05; CD4: RT 0.7 +/- 0.3% vs RT + IT 4.1 +/- 2.2%, p< 0.05). Additionally, RT + CBI enhanced IFNg production and development of antigen specific anti-tumor immunity in the DLN compared to RT or CBI alone. Mechanistically we observed significant changes in cell adhesion molecules including ICAM-1 and VCAM-1 which may contribute to enhanced T-cell infiltration. Response rates to single agent CBI remain low in HNSCC and combinatorial strategies are required to improve outcomes. Here we used novel HPV specific flank and orthotopic HNSCC models and observed that RT + anti-PD-L1 CBI results in a significant improvement in local control and development of anti-tumor immune responses compared to RT or CBI alone. These findings indicate that combination RT + CBI could be an effective therapy for HPV positive head and neck cancer, and provide additional rationale for clinical trials in this space.

Checkpoint blockade immunotherapy (CBI) targeting the PD-1 and CTLA-4 pathways is revolutionizing oncology. However, objective response rates for single agent CBI in solid malignancies remain low and combinatorial strategies are required to improve outcomes. Our group has pioneered the use of radiation (RT) and stereotactic body radiation therapy (SBRT) in combination with anti-PD-1 CBI. We previously demonstrated in tumor models that RT+ CBI can enhance antigen specific immune responses and improve local and systemic tumor control. Nevertheless, the clinical benefit of SBRT+CBI remains unclear. Our primary objective was to conduct a clinical trial to test the hypothesis that SBRT + CBI increases objective response rates (ORR) compared to CBI alone. Here we present an interim analysis. We designed and opened an investigator initiated Phase II study (ClinicalTrials.gov NCT02843165) which randomizes patients (1:1) with advanced metastatic disease to receive investigators choice of anti-PD-1/PD-L1 CBI versus anti-PD-1/PD-L1 CBI combined with concurrent SBRT. SBRT was started 1-21 days after C1D1 of CBI and was prescribed at 9.5Gy x 3 fractions delivered to 1-3 non-CNS tumor foci consecutively or every other day. The study is powered to detect a 33% relative improvement in ORR with a total anticipated enrollment of 146. Safety and Toxicity was analyzed prospectively for all patients using CTCAE 4.0. ORR are measured from unirradiated tumors using RECIST 1.1 criteria. Three research blood draws are obtained to analyze immune correlates. We performed an interim analysis of safety and toxicity among all patients and between treatment groups. We have enrolled a total of 35 patients at this time. There were a total of 126 CTCAE toxicity events observed with 67 (53.2%) Low grade (CTCAE 1-2), and 59 (46.8%) High grade (CTCAE 3-5) events with a mean followup of 5.1 months. The most common toxicities were fatigue, nausea, pain, and rash. The most common SBRT treatment sites were lung, liver, adrenal gland, and soft tissue. Experimental treatment attributions are as follows: 18 events (14.3%) Unrelated, 44 events (34.9%) Unlikely, 48 events (38.1%) Possible, and 13 events (10.3%) Probable or Definite. There were 7 (5.5%) high grade events attributed as probably or definitely related to study: one grade 4 fatigue, one grade 3 weight loss, one grade 3 rash, and two grade 3 electrolyte abnormalities, and two grade 3 acute kidney injury. When comparing between CBI and CBI+SBRT treatment groups there was no significant difference in any grade of toxicity at this time. Our interim analysis suggests that SBRT to lung, liver, adrenal and soft tissues prescribed at 9.5Gy x 3 fractions combined with concurrent anti-PD-1/PD-L1 CBI appears to be safe and well tolerated in patients with advanced metastatic disease. Continued analysis of safety and toxicity, ORR, and immune correlates between randomized treatment groups is ongoing.