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HPV-related OPSCC occurs in younger patients, has a significantly better prognosis, and is most often caused by HPV subtype 16. There is a 90% overall survival for HPV+/p16+ OPSCC (40% for HPV-/p16- OPSCC), which can be cured with multimodality care. For patients with R/M disease, treatment with pembrolizumab (P) +/- chemotherapy is palliative, with a median OS of approximately 12 months for patients with PD-L1 combined positive score (cps) >1 treated with pembrolizumab (P) alone. Heterologous prime boost with DNA priming followed by vaccinia-based boosting against HPV16 viral antigens will be studied using the priming of pBI-11 DNA [pNGVL4a DNA construct encoding HPV16 E7(detox)/ HPV18 E7(detox)/HPV16 E6(detox)/HPV18 E6(detox) fusion protein linked to mycobacteria tuberculosis heat shock protein 70] followed by boosting of TA-HPV (recombinant vaccinia-human papillomavirus (denoted TA-HPV) derived from the Wyeth strain of vaccinia which carries modified E6 and E7 genes from HPV types 16 and 18). This study is approved by the Vanderbilt University IRB and is open (NCT NCT05799144). Additional sites will include the University of Michigan, Mayo Clinic Scottsdale and Mount Sinai Medical Center Miami Beach Patients with R/M, HPV positive OPSCC without prior therapy for R/M disease, without contraindications to immunotherapy and with a PD-L1 cps > 1 will be screened. There is a 6 patient safety run-in. Treatment with pBI-11 vaccine (2 IM injections on weeks 1 and 4) plus one IM administration of TA-HPV on week 7 will be given in combination with P IV on weeks 1, 4, and 7). Following restaging, all patients will continue (including those with PD) with 3 more cycles of P followed by restaging. The primary clinical outcome is RR to addition of vaccine in the 50% of predicted P non-responders (NR) who proceed to Part II (ie conversion to responders). All responders will continue to receive P until progression. Approximately 54 patients with be enrolled. Two research tumor biopsies and blood draws will be obtained pre- and on treatment (week7-9). Tumor tissue cores will be utilized for immunohistochemical and molecular tests (e.g., expression of immune cell and viral markers, TCR sequencing and total transcripts). Blood with be tested for HPV16/18 E6, E7 antibodies and vaccinia virus neutralizing antibodies; proliferative responses of peripheral blood lymphocytes to stimulation by HPV16/18 E6 and E7; HPV16/18 E6- and E7-Specific T cells; and HPV DNA in plasma. 2 patients enrolled. Accrual ongoing. [ABSTRACT FROM AUTHOR]

Radiation immunodynamics, or the understanding of immune markers over a fractionated course of radiotherapy (RT), is a critical intermediate step in developing personalized RT approaches, including Immune-guided Radiotherapy (IM-GRT). Peripheral-origin myeloid cells are a major component of the glioblastoma (GBM) tumor microenvironment. The effect of adjuvant chemoradiation (CRT) on programmed death-ligand 1 (PD-L1)-expressing suppressive myeloid cells is unknown. We hypothesize that PD-L1+ monocytes increase from baseline in the peripheral blood of patients with GBM undergoing CRT. Tumor and peripheral blood were collected from a prospective, single-institution, biospecimen protocol of newly diagnosed GBM participants undergoing CRT. A neuropathologist selected regions of interest within baseline formalin-fixed, paraffin-embedded tissue for digital spatial profiling. Expression for PD-L1 on CD163+ regions of interest is quantified relative to isotype and presented as fold change. Flow cytometry was performed on peripheral blood immune cells at seven time points in relation to CRT: one prior to start, five weekly during, and one month after completion. Flow cytometry data are expressed as percent frequency (%fx) of CD14+ monocytes. Correlative studies focusing on plasma analytes, metabolic proteins, and bulk RNA sequencing were also performed. Relationships between PD-L1 and overall survival (OS) or progression-free survival (PFS) were assessed by Cox model. "Survivors" were alive 2 years after diagnosis. A total of 15 cases with baseline PD-L1 assessment are included. Digital spatial profiling (n=10) of tumor identified PD-L1 expression within regions of interest with CD163+ myeloid cells is increased in non-survivors compared to survivors (log2FC=0.28; padj<0.05). The median %fx of peripheral blood CD14+ PD-L1+ cells at the pre-CRT baseline is 39.2% among survivors and 16.0% among non-survivors, and not associated with OS (HR=0.98, p=0.36) or PFS (HR=0.99, p=0.7). Comparing to baseline, the %fx of CD14+PD-L1+ cells at week 4 during CRT decreases (median fold change 0.49, range 0.08-0.92) in survivors but increases (median fold change 1.86, range 0.31-4.32) in non-survivors. Such a mid-CRT change (in terms of fold change) is significantly associated with OS (HR=2.21, p=0.008) but not PFS (HR=1.33, p=0.17). One month after CRT, the median %fx is 4.9% in survivors and 19.7% in non-survivors, and not associated with OS (HR=1.04, p=0.11) or PFS (HR=1.02, p=0.33). This is the first study to demonstrate changes in peripheral CD14+PD-L1+ myeloid cells over the course of CRT and to associate these changes with survival outcome. Dynamic biomarker assessments, like radiation immunodynamics, may identify patients who would benefit from immune adjuvants while undergoing CRT in neuro-oncology and other disease sites. [ABSTRACT FROM AUTHOR]