Ruff, Michael W.

6526 Background: In the current literature, the association between social determinants of health (SDH) and head & neck-nervous system cancer (HNNsC) is limited by the narrow scope of SDH assessed and the broad classifications of HNNsC. Our study utilizes the CDC-Social Vulnerability Index (SVI) to assess both the individual and collective impact of four social determinant themes on various HNNsC in US adults. Methods: This study utilized the SEER database to evaluate 116,373 adult patients from 1975-2017 who presented with HNNsC. Patients were assigned SVI scores based on county-of-residence at the time of diagnosis, encompassing total-SVI score and 4 sub-scores of socioeconomic status, minority-language status, household composition, and housing-transportation. Using these scores, univariate linear regressions were used to assess patient care (months of follow-up) and prognosis (months of survival). Results: As total-SVI score increased, decreases in months of follow-up (MOF) and months of survival (MOS) were observed for many HNNsC tumors (p less than 0.001) when comparing the lowest to highest vulnerability cohorts. There was a decrease ranging from 3.55-36.6% in the MOF, with the largest decreases occurring in embryonal, anaplastic oligodendroglioma, and anaplastic ependymoma tumor types, with the largest sub-score contribution coming from socioeconomic status for these three disease classes. Similarly, there was a decrease ranging from 6.90-45.81% in the MOS, with the largest decreases occurring in anaplastic ependymoma, anaplastic astrocytoma, and pilocytic astrocytoma tumor types with the largest sub-score contribution coming from socioeconomic status for these three disease classes. Increases in vulnerability within SDH themes contributed significantly to these total-SVI trends in MOF and MOS, with each social determinant impacting different disease classes to varying extents. Socioeconomic status was the most impactful sub-score for MOF in nine of fourteen disease classes, followed by housing-transportation and household composition, each leading the impact of two of fourteen disease classes, and minority-language status leading the impact of one of fourteen disease classes. Similarly, socioeconomic status was the most impactful sub-score for MOS in eight of fourteen disease classes, followed by housing-transportation leading the impact of three of fourteen disease classes, household composition leading the impact of two of fourteen disease classes, and minority-language status leading the impact of one of fourteen disease classes. Conclusions: The results of this study show that with increasing social vulnerability, there is a significant decrease in both the care (follow-up) and the prognosis (survival) of US adults with HNNsC and highlight which SDH contributes more to disparities.

3109 Background: WSD0922-Fu is an oral, central nervous system (CNS)-penetrant, small molecule, ATP non-competitive, reversible EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). We report initial results of a first-in-human phase 1 dose-escalation trial (NCT04197934) in patients with EGFR aberrant recurrent HGA and NSCLC. Methods: Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR mutant and/or EGFR amplified HGA were enrolled. WSD0922-Fu was orally administered, and dose escalated in cohorts based on a standard 3+3 design to determine the maximum tolerated dose (MTD). Toxicities were graded per CTCAE v5.0 and preliminary efficacy was based on modified RANO criteria or RECIST 1.1 as appropriate. Results: 25 patients (17 HGA, 8 NSCLC) were enrolled and treated in six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles). The median age was 57 years (range 39-75 years). 24% were female and 36% were ECOG 0. For patients with HGA, all patients were previously treated with radiation and temozolomide; the median number of prior lines of systemic therapy was 1 (range 1-4). For patients with NSCLC, all patients were previously treated with an EGFR inhibitor (prior osimertinib 88%); the median number of prior lines of systemic therapy was 1.5 (range 1-6). The median duration of exposure to WSD0922-Fu among all patients was 54 days (range 2-258 days). The most common (≥25%) treatment-related adverse events included fatigue (68%), acneiform rash (68%), diarrhea (52%), nausea (48%) and pruritis (28%). The frequency of severe AEs was dose dependent. The most common Grade 3+ AEs (≥10%) included lymphopenia (16%), acneiform rash (12%), headache (12%) and diarrhea (12%). The MTD was defined as 160 mg twice daily. At Cycle 1 Day 15 for patients treated at this dose level, the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h; range 6.2-78.7 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Oral clearance at steady state was inversely related with dose, suggesting either inhibition or saturation of clearance processes. Among patients treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients with NSCLC demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses (intracranial and extracranial). Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Conclusions: The MTD for WSD0922-Fu monotherapy is 160 mg BID. Preliminary efficacy was observed in patients with osimertinib-resistant NSCLC and EGFRvIII mutant HGA. Enrollment to expansion cohorts is ongoing. Clinical trial information: NCT04197934 .

TPS2085 Background: Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) remains at only 30 weeks for recurrent GBM (rGBM) patients, emphasizing the need for novel treatments. GBM tumors are immunologically ‘cold,’ in that they have an immune-suppressive microenvironment with a low number of tumor-infiltrating lymphocytes (TIL). Interleukin 7 (IL-7) plays a key role in T cell development and survival. The physiological level of IL-7 increases to stimulate T cell expansion in lymphopenic condition. Previous studies have shown that lymphopenic GBM patients have shorter survival. However, their IL-7 levels are unexpectedly low. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. Further, we recently completed a Phase I study which showed that NT-I7 is safe, well- tolerated, and increased absolute lymphocyte counts (ALC) in newly diagnosed GBM patients. Phase II dosing was determined through this Phase I study reaching maximum tolerated dose. Thus, we hypothesized that NT-I7 may reverse GBM-associated immune suppression and potentiate the effect of an immune checkpoint inhibitor, leading to an increase in TILs and improved survival. Our preliminary data suggests that combining NT-I7 with pembrolizumab, an anti-PD-1 antibody, improves survival in murine glioma models. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. Methods: This is an open-label single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. Key eligibility criteria include candidates willing to undergo clinically indicated resection or biopsy, age ≥ 18 years, Karnofsky performance status ≥ 70, and dexamethasone dose > 2 mg/day ≤ 2 days prior to registration. The primary endpoint is a 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets, T cell effector function, cytokine analysis, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened on 1/20/2023. Two of the planned 30 patients had been enrolled by submission on 2/14/2023. Clinical trial information: NCT05465954 .

2002 Background: Elderly patients with glioblastoma have a poor prognosis with phase III trials reporting median overall survival (OS) and global time to deterioration of 6–9 and 1.2 months respectively. 18F-DOPA (3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. Proton beam therapy (PBT) can spare more healthy tissue that may improve quality of life for this patient population. With improved targeting of disease along with dosimetric advantages of PBT, this phase II trial tested whether hypofractionated PBT can offer both improved survival and quality of life. Methods: Patients with newly diagnosed glioblastoma aged ≥65 years without contraindications to 18F-DOPA were eligible. Target volumes were defined by PET (tumor/normal brain SUV ≥2.0) and MRI areas of contrast enhancement including surgical cavity. Patients received dose escalated hypofractionated PBT of 35-40 GyE to PET/MRI over 5-10 treatments with 10 mm margin. Patients received concurrent/adjuvant temozolomide. With an alpha of 0.1, 18 of 39 patients would be required to be alive at 12 months for the study to be considered a success. Kaplan-Meier/Cox regression analysis was performed for progression free survival (PFS) and OS. Toxicities were evaluated with CTCAE v4.0. Patients completed EORTC BN20, QLQ-C30, and MMSE questionnaires. Time to deterioration, defined as a 10-point decrease in the score of the function domain or 10-point increase in score of symptom domain, was evaluated. Results: Between 5/2019-6/2021, 43 patients were enrolled, with 4 patients withdrawing due to progression/insurance denial prior to beginning protocol therapy. The median age was 70.2 yrs. and median follow-up was 12.5 months. MGMT methylation was present in 13 (33%). Tumors were multifocal in 10 (26%) and unifocal in 29 (74%). The primary endpoint was met with median PFS/OS was 6.5/12.9 months for all patients and for MGMT methylated patients 11.9/29.8 months respectively. Grade 3 baseline adjusted treatment related adverse events included 1 (3%) confusion, 2 (5%) fatigue, and 1 (3%) seizure. There were no grade 4/5 events. Multivariate analysis revealed MGMT unmethylated, ECOG 2 and biopsy only patients had worse survival. PET volume was more predictive than MRI volume for OS with PET volume>26 cc having a hazard ratio of 3.7. The median time to global deterioration per QLC-C30 was 6.3 months. Conclusions: This phase II trial incorporating 18F-DOPA PET-guided dose escalated hypofractionated proton beam treatment for elderly patients with glioblastoma met its primary endpoint for improved OS and patient reported quality of life compared to historical controls. Further investigation is warranted. Clinical trial information: NCT03778294 .

Abstract CD19 directed chimeric antigen receptor T (CART19) cell therapy has resulted in remarkable outcomes in B cell malignancies and was FDA approved in multiple indications. However, durable remissions are limited to 40% of treated patients. Inhibitory myeloid cells in tumor microenvironment have been found to suppress T cell expansion and contribute to failure of CART19 cell therapy. In this study, we aimed to unravel the interactions between monocytes, CART19 cells and tumor cells to understand how monocytes-CART19 cell interactions impact CART19 cell effector functions and clinical outcomes. Two sets of experiments were conducted, 1) use of healthy CART19 cells, CD19+ tumor cells, and healthy monocytes; 2) use of brexu-cel products from ZUMA-2 clinical trial treating mantle cell lymphoma (MCL), patient-matched monocytes and circulating MCL tumor cells (n = 11; 6 durable responders, 2 relapsed after initial response and 3 non-responders). CD28 costimulated CART19 (CART19-28ζ) cells generated in the lab from healthy donors were co-cultured with donor freshly isolated monocytes in the presence of Jeko-1 cells (a CD19+ MCL cell line). CART19 antigen specific proliferation was not inhibited by freshly isolated monocytes. When monocytes were co-cultured with CART19 and tumor cells, higher levels of eotaxin, GRO, MCP-3 and IL-7 were detected. When CART19 cells were co-cultured with the CD19+ JeKo-1 cells in the presence of ex vivo M2 polarized macrophages, CART19 antigen specific proliferation was inhibited (p=0.0045). Transwell experiments demonstrate that M2-induced CART19 inhibition is not contact dependent. Cytokine profile analysis indicated increased level of IL-1ra, IP-10 and MCP-1 and decreased level of IL-17A, sCD40L, IL-9 and MIP-1α when M2 macrophages were co-cultured with CART19 and tumor cells compared to co-cultures of tumor cells and CART19. Then we conducted ex vivo co-cultures of brexu-cel products, autologous monocytes and circulating MCL tumor cells from MCL patients (ZUMA-2) collected prior to CART19 cell infusion. Here we observed trends of elevation of IL-13 and IL-5 and reduction of GRO, MCP-3, MIP-1β and IL-8 in non-responders, compared to responders (durable responses or relapsed patients). Our results support that monocyte- and macrophage-dependent cytokine release could modulate CART19 effector and trafficking functions, and thus CART19 clinical outcomes. This warrants further investigation around strategies to improve durable responses to CART cell therapy. Citation Format: Kun Yun, Reona Leo Sakemura, Michelle J. Cox, Truc Huynh, Claudia Manriquez-Roman, Olivia Sirpilla, Carli M. Stewart, James H. Girsch, Ekene J. Ogbodo, Ismail Can, Brooke Kimball, Lionel A. Kankeu Fonkoua, Mehrdad Hefazi, Michael W. Ruff, Elizabeth L. Siegler, Mike Mattie, Sao-Mai Nguyen-Mau, Simone Filosto, Saad S. Kenderian. Impact of immunosuppressive monocytes on CART19 cell effector functions and outcomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4082.

Abstract BACKGROUND Interpretation of serial magnetic resonance imaging (MRI) for glioblastoma following radiation therapy (RT) is complicated by difficulty differentiating tumor from treatment-related changes, even using updated RANO criteria. The incorporation of novel imaging such as 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET/CT to post-treatment serial imaging may improve prognostication and better facilitate future treatment decisions. METHODS The secondary analysis of a recent phase II prospective clinical trial of 18F-DOPA PET/CT-directed dose-escalated RT included patients with IDH-wildtype, MGMT-unmethylated glioblastoma who underwent post-treatment serial 18F-DOPA PET/CT surveillance. Quantitative features were extracted from pre-RT and post-RT serial PET/CT images, and robust prognostic features were selected using an in-house workflow. Both an automated machine learning (ML) algorithm and an interpretable ML algorithm were utilized to correlate surveillance PET image features with subsequent survival of greater than 12 months versus less than 12 months from the surveillance timepoint. Changes from pre-RT to post-RT PET/CT (delta model) were also assessed for association with post-RT survival and validated with a separate cohort. RESULTS Thirty-five patients with IDH-wildtype, MGMT-unmethylated glioblastoma who had at least one available (range: 1-14) post-treatment 18F-DOPA PET/CT were included. Twenty-four were used for model training, while 11 were used for validation. Ultimately, a five-feature post-RT model utilizing two shape, two texture, and one first-order radiomic feature was selected. For the delta model, five texture, two shape, and one first order radiomic feature were selected. The models show 90% accuracy in predicting survival < 12 months post-surveillance on the training set, and 68%-73% accuracy (AUC 0.64-0.73) for the validation cohort. Delta features were significantly associated with overall survival (p < 0.05). CONCLUSIONS Post-RT serial 18F-DOPA PET/CT imaging can help distinguish true tumor progression in patients with glioblastoma using a radiomics model. Tumor response evaluated for changes from pre-RT to post-RT 18F-DOPA PET/CT also predicted subsequent overall survival.

Abstract INTRODUCTION Medulloblastomas (MB) are embryonal tumors arising in the cerebellum, predominantly affecting pediatric patients. Recognition of molecularly defined subgroups has advanced management. Factors influencing the prognosis and management of adult MB patients remain poorly understood. METHODS We retrospectively reviewed our experience with adult (> 18 years at initial diagnosis) MB patients, diagnosed between 1992-2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (Log-rank test assessing for group differences) were performed for univariate survival analysis with cox regression used for multivariate (subgroup, age, gender, disseminated disease, extent of resection) analyses. RESULTS Our cohort included 76 adult MB patients (62% male), with a median age of 31.7 years (range: 18-66) at diagnosis, and median follow-up of 7.7 years (range: 0.6-26.9). 58 patients had sufficient tissue for molecular characterization by immunohistochemistry and corresponded to the SHH-activated (n=37; 64%), non-WNT/non-SHH (n=12; 21%), WNT-activated (n=9; 15%) subgroups. At initial diagnosis, all patients underwent radiotherapy, with 97% (n=66) receiving craniospinal irradiation with a boost either to the posterior fossa (75%) or tumor bed (22%); and underwent gross total resection (n=51; 67%) and chemotherapy (n=56; 75%). Median overall survival (OS) for the whole cohort was 14.8 years (93% 2-year OS; 86% 5-year OS; 64% 10-year OS) and was longer for younger patients (< 30: > 15.4 years, > 30: 9.9 years; Log-rank p< 0.001). No significant OS difference was identified by MB molecular subgroup (SHH, TP53-wt: 14 years, WNT: 11.4 years, non-WNT/non-SHH: > 14.8 years; Log-rank p=0.1167) or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses. DISCUSSION We report one of the largest retrospective cohorts in adult MB patients with molecular subtyping. Survival and molecular subgroup frequencies were similar to previous reports. Survival was longer for younger patients and was not significantly different by MB molecular subgroup or extent of resection.