Browsing by Author "Fecci, Peter"
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Item Open Access Creation of Non-Contact Device for Use in Metastatic Melanoma Margin Identification in ex vivo Mouse Brain.(Proceedings of SPIE--the International Society for Optical Engineering, 2022-01) Tucker, Matthew; Lacayo, Matthew; Joseph, Suzanna; Ross, Weston; Chongsathidkiet, Pakawat; Fecci, Peter; Codd, Patrick JBecause contemporary intraoperative tumor detection modalities, such as intraoperative MRI, are not ubiquitously available and can disrupt surgical workflow, there is an imperative for an accessible diagnostic device that can meet the surgeon's needs in identifying tissue types. The objective of this paper is to determine the efficacy of a novel non-contact tumor detection device for metastatic melanoma boundary identification in a tissue-mimicking phantom, evaluate the identification of metastatic melanoma boundaries in ex vivo mouse brain tissue, and find the error associated with identifying this boundary. To validate the spatial and fluorescence resolution of the device, tissue-mimicking phantoms were created with modifiable optical properties. Phantom tissue provided ground truth measurements for fluorophore concentration differences with respect to spatial dimensions. Modeling metastatic disease, ex vivo melanoma brain metastases were evaluated to detect differences in fluorescence between healthy and neoplastic tissue. This analysis includes determining required-to-observe fluorescence differences in tissue. H&E staining confirmed tumor presence in mouse tissue samples. The device detected a difference in normalized average fluorescence intensity in all three phantoms. There were differences in fluorescence with the presence and absence of melanin. The estimated tumor boundary of all tissue phantoms was within 0.30 mm of the ground truth tumor boundary for all boundaries. Likewise, when applied to the melanoma-bearing brains from ex vivo mice, a difference in normalized fluorescence intensity was successfully detected. The potential prediction window for the tumor boundary location is less than 1.5 mm for all ex vivo mouse brain tumors boundaries. We present a non-contact, laser-induced fluorescence device that can identify tumor boundaries based on changes in laser-induced fluorescence emission intensity. The device can identify phantom ground truth tumor boundaries within 0.30 mm using instantaneous rate of change of normalized fluorescence emission intensity and can detect endogenous fluorescence differences in melanoma brain metastases in ex vivo mouse tissue.Item Open Access CTIM-10. REPRODUCIBILITY OF CLINICAL TRIALS USING CMV-TARGETED DENDRITIC CELL VACCINES IN PATIENTS WITH GLIOBLASTOMA(Neuro-Oncology, 2021-11-12) Batich, Kristen; Mitchell, Duane; Healy, Patrick; Herndon, James; Broadwater, Gloria; Michael, Gunn; Huang, Min-Nung; Hotchkiss, Kelly; Sanchez-Perez, Luis; Nair, Smita; Congdon, Kendra; Norberg, Pam; Weinhold, Kent; Archer, Gary; Reap, Elizabeth; Xie, Weihua; Shipes, Steven; Albrecht, Emily; Peters, Katherine; Randazzo, Dina; Johnson, Margaret; Landi, Daniel; Desjardins, Annick; Friedman, Henry; Vlahovic, Gordana; Reardon, David; Vredenburgh, James; Bigner, Darell; Khasraw, Mustafa; McLendon, Roger; Thompson, Eric; Cook, Steven; Fecci, Peter; Codd, Patrick; Floyd, Scott; Reitman, Zachary; Kirkpatrick, John; Friedman, Allan; Ashley, David M; Sampson, JohnAbstract INTRODUCTION Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. METHODS To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with primary GBM. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. RESULTS Our initial study was the phase II ATTAC study (NCT00639639; total n=12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning (P=0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR=0.820, P=0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n=24, unpulsed DC n=19; 24h, P=0.031 and 48h, P=0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td (P=0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%). CONCLUSION We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM.Item Open Access Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy.(International journal of radiation oncology, biology, physics, 2018-03) Yoon, Suk W; Tsvankin, Vadim; Shrock, Zachary; Meng, Boyu; Zhang, Xiaofeng; Dewhirst, Mark; Fecci, Peter; Adamson, Justus; Oldham, MarkThis work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo-therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions.In vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation.Luminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA-treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P << .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present.This work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam.Item Open Access Investigating the Dynamics of T cell Exhaustion in Glioblastoma and Other Solid Tumors(2024) Waibl Polania, JessicaWhile terminally exhausted T cells (Tex_term) retain important anti-tumor cytotoxic function, it is the relative preservation of renewable, stem-like progenitor exhaustion (Tex_prog) that better indicates immunotherapeutic responsivity. Therefore, elucidating the requirements for progression from Tex_prog to Tex_term takes on clinical significance, where the cellular interactions in a tumor microenvironment (TME) governing such progression remain poorly established. Employing glioblastoma (GBM) and other solid tumors as models of severe exhaustion, we provide a detailed characterization of the progression from Tex_prog to Tex_term within the TME, where we observe a striking and disproportionate loss of Tex_prog over time. We find exhaustion concentrated within tumor-specific T cell subsets, with cognate antigenic exposure requisite for acquisition of the Tex_term phenotype. However, we identify tumor-associated macrophages (TAM), and not tumor cells, as the source of antigenic exposure governing the Tex_prog to Tex_term transition. Using cell – cell interaction analysis, we additionally highlight candidate receptor–ligand communications that may be specifically mediating the progression to Tex_term within the TME.
Item Open Access Racial disparities in inpatient clinical presentation, treatment, and outcomes in brain metastasis(Neuro-Oncology Practice, 2022) McCray, Edwin; Waguia, Romaric; de la Garza Ramos, Rafael; Price, Meghan J; Williamson, Theresa; Dalton, Tara; Sciubba, Daniel M; Yassari, Reza; Goodwin, Andrea N; Fecci, Peter; Johnson, Margaret O; Chaichana, Kaisorn; Goodwin, C RoryAbstract Background Few studies have assessed the impact of race on short-term patient outcomes in the brain metastasis population. The goal of this study is to evaluate the association of race with inpatient clinical presentation, treatment, in-hospital complications, and in-hospital mortality rates for patients with brain metastases (BM). Method Using data collected from the National Inpatient Sample between 2004 and 2014, we retrospectively identified adult patients with a primary diagnosis of BM. Outcomes included nonroutine discharge, prolonged length of stay (pLOS), in-hospital complications, and mortality. Results Minority (Black, Hispanic/other) patients were less likely to receive surgical intervention compared to White patients (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.66–0.74, p < 0.001; OR 0.88; 95% CI 0.84–0.93, p < 0.001). Black patients were more likely to develop an in-hospital complication than White patients (OR 1.35, 95% CI 1.28–1.41, p < 0.001). Additionally, minority patients were more likely to experience pLOS than White patients (OR 1.48; 95% CI 1.41–1.57, p < 0.001; OR 1.34; 95% CI 1.27–1.42, p < 0.001). Black patients were more likely to experience a nonroutine discharge (OR 1.25; 95% CI 1.19–1.31, p < 0.001) and higher in-hospital mortality than White (OR 1.13; 95% CI 1.03–1.23, p = 0.008). Conclusion Our analysis demonstrated that race is associated with disparate short-term outcomes in patients with BM. More efforts are needed to address these disparities, provide equitable care, and allow for similar outcomes regardless of care.Item Open Access Single fraction stereotactic radiosurgery for multiple brain metastases.(Adv Radiat Oncol, 2017-10) Limon, Dror; McSherry, Frances; Herndon, James; Sampson, John; Fecci, Peter; Adamson, Justus; Wang, Zhiheng; Yin, Fang-Fang; Floyd, Scott; Kirkpatrick, John; Kim, Grace JIntroduction: Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM. Methods and materials: All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ≥4 BM were included in this institutional review board-approved, retrospective, single-institution study. Patients were treated with linear accelerator-based image guided SRS. Results: A total of 59 patients with ≥4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8 cc (range, 0.7-28.8 cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20 Gy. The median of the mean dose to the total PTV was 19.5 Gy. Although the number of treated lesions (4-5 vs ≥6) did not influence survival, better survival was noted for a total PTV <10 cc versus ≥10 cc (7.1 vs 4.2 months, respectively; P = .0001). A mean dose of ≥19 Gy to the entire PTV was also associated with increased survival (6.6 vs 5.0 months, respectively; P = .0172). Patients receiving a dose of >12 Gy to ≥10 cc of normal brain had worse survival (5.1 vs 8.6 months, respectively; P = .0028). Conclusion: In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12 Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.Item Embargo TNFR2 Is a Novel Marker of Exhaustion and TNFR2 Blockade Improves Subcutaneous Tumor Control(2024) Hoyt-Miggelbrink, Alexandra MarinaCD8+ T cells have potent anti-tumor responses. However, continuous stimulation by tumor cells causes these cells differentiate down an exhaustion pathway. This differentiation negatively impacts CD8+ T cell function and response to immunotherapies. One potential factor that influences the progression along this pathway is tumor necrosis factor (TNF). Using multiple tumor models and a chronic viral infection model, we determined that the TNF receptor (TNFR2) is significantly upregulated in tumor- infiltrating CD8+ T cells and CD8+ T cells in the spleen of virus-infected mice. Furthermore, TNFR2 correlated with other canonical markers of exhaustion. We identified that upregulation of TNFR2 was associated with loss of progenitor-like functions and acquisition of functions resembling terminally exhausted cells. To investigate the role of TNFR2 in this transition, we employed TNFR2 KO mice. While the frequency of the progenitor and terminally exhaustion populations were similar, the exhaustion- associated transcription factor TOX was significantly decreased in TNFR2 KO T cells. We demonstrate that the loss of TNFR2 is sufficient to increase effector functions of CD8+ T cells in tumor-draining lymph nodes, but not in the tumor. Loss of TNFR2 resulted in a CD8-mediated reduction in tumor growth in various subcutaneous tumor models. Finally, treatment with a TNFR2 antagonist in combination with an immune checkpoint inhibitor (aPD1) resulted in decreased tumor growth. Together, these data suggest that TNFR2 is a novel marker of exhaustion and blockade could be utilized as a novel treatment strategy.
Item Open Access X-Ray Psoralen Activated Cancer Therapy (X-PACT).(PLoS One, 2016) Oldham, Mark; Yoon, Paul; Fathi, Zak; Beyer, Wayne F; Adamson, Justus; Liu, Leihua; Alcorta, David; Xia, Wenle; Osada, Takuya; Liu, Congxiao; Yang, Xiao Y; Dodd, Rebecca D; Herndon, James E; Meng, Boyu; Kirsch, David G; Lyerly, H Kim; Dewhirst, Mark W; Fecci, Peter; Walder, Harold; Spector, Neil LThis work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of solid cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with current application to proliferative disease and extracorporeal photopheresis (ECP) of cutaneous T Cell Lymphoma. An immunogenic role for light-activated psoralen has been reported, contributing to long-term clinical responses. Psoralen therapies have to-date been limited to superficial or extracorporeal scenarios due to the requirement for psoralen activation by UVA light, which has limited penetration in tissue. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and re-radiate (phosphoresce) at UV wavelengths. The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry in combination with complimentary assays, and the in-vivo mouse study. In an in-vitro study, we show that X-PACT induces significant tumor cell apoptosis and cytotoxicity, unlike psoralen or phosphor alone (p<0.0001). We also show that apoptosis increases as doses of phosphor, psoralen, or radiation increase. Finally, in an in-vivo pilot study of BALBc mice with syngeneic 4T1 tumors, we show that the rate of tumor growth is slower with X-PACT than with saline or AMT + X-ray (p<0.0001). Overall these studies demonstrate a potential therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. In summary, X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation are delivered to a specific tumor site to generate UVA light which in-turn unleashes both short- and potentially long-term antitumor activity of photo-active therapeutics like psoralen.