bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimated clinical efficacy and radiographic response characteristics of PD1 inhibition in newly diagnosed and recurrent glioblastoma in clinical practice: A report from the iRANO Working Group.
Authors: Ellingson Benjamin M. , Huang Raymond Yi-kun , Villanueva-Meyer Javier , Lim-Fat Mary Jane , George Elizabeth , Iorgulescu Bryan , Young Geoffrey , Raymond Catalina , Oughourlian Talia , Schlossman Jacob , Gleason Tyler , Oberheim Bush Nancy Ann , Wen Patrick Y. , Cloughesy Timothy Francis , Chang Susan Marina , Reardon David A. , Weller Michael , Okada Hideho 
Published: May 2020

2521 Background: Despite concerns of immunotherapy-induced inflammatory response during PD1 inhibition, questions remain as to the true incidence of inflammatory response and potential clinical implications. The goals of the project were to use GBM patients pooled from academic centers to estimate radiographic PFS and OS, as well as determine the incidence of immunotherapy-induced inflammatory response. Methods: 152 patients with newly diagnosed (N = 57) or recurrent (N = 95) GBM treated with either nivolumab or pembrolizumab from Dana-Farber (N = 88), UCLA (N = 35) or UCSF (N = 29) were included in this study. Radiographic progression was defined by a 25% increase in bidirectional measurements according to RANO. Results: Median PFS and OS for newly diagnosed patients was 162 and 520 days, respectively, while median PFS and OS for recurrent patients was 72 and 225 days, respectively. No difference in OS was observed in recurrent patients treated with nivolumab vs. pembrolizumab (P = 0.58), but recurrent patients treated with nivolumab trended toward a longer PFS (P = 0.097). Of the recurrent patients with OS and PFS data available and radiographic progression, 95% of them progressed within 6 mos of starting treatment. Median post-progression survival (PPS) in recurrent patients with PFS < 6 mos was 151 days, while PPS for patients with PFS > 6 mos was 178 days (P = 0.51). In the 77 recurrent patients who progressed within 6 mos, 36.4% had an OS that was > 9 mos, while 63.6% had an OS < 9 mos, suggesting the majority of patients with “early progression” also died early and a minority of patients had what could be considered “immune-related inflammation”. Of the 81 recurrent patients with documented progression, only 2.5% showed stabilization within 3 mos of first progression, 30.9% died before the 3-month confirmation scan could be obtained, 24.7% showed continued tumor growth by 3 months, and 48.1% had no follow-up confirmatory imaging exams. Of the 70 patients who progressed within 6 mos and had documented death, 2.9% had disease stabilization, 31.4% died before the 3-month confirmation, and 75.7% had either documented tumor growth or had no follow-up confirmatory imaging exams. Conclusions: This study suggests immunotherapy-induced inflammation followed by a favorable PPS is uncommon in GBM. While patients treated with other types of immunotherapy may exhibit different imaging characteristics, these data provide an important basis to refine the iRANO criteria.
Response assessment and outcome of combining immunotherapy and radiosurgery for brain metastasis from malignant melanoma.
Authors: Le Rhun Emilie , Wolpert Fabian , Fialek Maud , Devos Patrick , Andratschke Nicolaus , Reyns Nicolas , Dummer Reinhard , Mortier Laurent , Weller Michael 
Published: May 2020

2532 Background: The evaluation of response in the context of treatment with stereotactic radiotherapy (SRT) or immune checkpoint inhibitors (ICI) or both, which represent major therapeutic options for patients with melanoma brain metastases, remains challenging due to potential tumor hemorrhage, pseudoprogression, and radionecrosis. Methods: We reviewed clinical and neuroimaging data of 62 melanoma patients, including 26 patients with BRAF-mutant tumors, with newly diagnosed brain metastases treated with immune checkpoint inhibitors (ICI) alone (n = 10, group 1), SRT alone or in combination with other systemic therapies (n = 20, group 2) or ICI plus SRT (n = 32, group 3). Response was assessed retrospectively using RECIST 1.1, RANO or iRANO criteria. Results: The MRI scans of 52 patients were available for central review. Patients received steroids at BM diagnosis in 10% in group 1, 60% in group 2 and 50% in group 3. Pseudoprogression was documented in 7 patients: 3 patients in group 2 (19%) and 4 patients (12%) in group 3. Radionecrosis was documented in 7 patients: 2 patients in group 2 (12%) and 5 patients (16%) in group 3. Patients treated with ICI alone had the worst outcome. Using RANO criteria by central review instead of local investigator assessment increased the rate of progressive disease (PD) as best response for the evaluation of SRT targets but not for the evaluation of the overall brain. Using complete RANO (including clinical assessment and steroid use) instead of RECIST criteria increased the rate of PD as best response, due to clinical deterioration noted in patients with MRI findings that did not qualify for PD. This pattern was seen in patients from all three groups. In contrast, the complete response (CR) rate was unaffected by the criteria used. More PD were also observed when comparing MRI only iRANO criteria versus complete iRANO criteria including clinical status and steroid use. Conclusions: Pseudoprogression is uncommon with ICI alone, suggesting that growing lesions in such patients should trigger an intervention. Pseudoprogression rates were similar after SRT alone or in combination with ICI. Response assessment criteria should be considered carefully when designing clinical studies for patients with brain metastases who receive SRT.
Proteomic profiling to identify therapeutics targets in glioblastoma (GBM).
Authors: Thyparambil Sheeno P. , Liao Wei-Li , An Eunkyung , Bhalkikar Anuja , Heaton Robert , Sylvester Karl G. , Ling Xuefeng B. 
Published: May 2020

2555 Background: Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. Treatment at diagnosis is largely confined to surgery, radiation and temozolomide (TMZ) with median progression-free survival (PFS) of 7 months and median overall survival (mOS) of 15 months. GBM tumors recur in most cases and in patients with recurrent GBM, the mOS is 6.2 months. The lack of effective therapies underscores the importance of exploring other agents. We propose that quantitating therapy-associated protein biomarkers can improve treatment personalization for GBM. Methods: 97 FFPE GBM tissues were microdissected and solubilized for mass spectrometry-based proteomic analysis of therapy-associated protein biomarkers in our CLIA certified lab. We quantified protein levels of MGMT, hENT1, RRM1, TOPO1 and EGFR/TUBB3 (antibody target and payload resistance markers, respectively, for anti-EGFR ADCs) simultaneously. The multiplexed assay also quantified additional 24 clinically relevant proteins. Results: 43/57 patients were predicted to respond to TMZ based on undetectable levels of MGMT, confirming wide utility of this agent. 42/97(43%) patients were predicted to have gemcitabine sensitivity based on high expression of the response marker (hENT1 > 100 amol/ug) and low expression of the resistance marker (RRM1 < 700 amol/ug). 11/97(11%) patients expressed TOPO1 > 1350 amol/ug (75th percentile of all indications tested by author’s laboratory), suggesting likely response to irinotecan and topotecan. EGFR expression ranged from < 100 amol/ug to > 25000 amol/ug, including overexpression (> 1500 amol/ug) in 22%(21/97) of cases. While expression of EGFR(81/97, 84%) suggested likely response to anti-EGFR ADC, concurrent expression of TUBB3(78/81) may indicate resistance to several known payloads, such as taxanes and MMAE. Conjugation with another payload that targets sensitivity marker TOPO1 (68% expression) is a likely option. Proteomic analysis also revealed detectable levels of multiple RTKs (FGFR(4), AXL(20), IGF1R(10), MET overexpression(1), and HER2 overexpression(2)), indicating potential response to RTK inhibitors. Exploratory investigation in tumor vs TME using proteomics and metabolomics is ongoing. Conclusions: In this population of GBM patients, proteomic analysis identified protein targets of multiple approved and investigational therapies. Gemcitabine, which crosses the blood-brain barrier, may be considered as a salvage option after TMZ failure. Proteomic quantitation of EGFR and TUBB3 may improve patient selection for EGFR-targeting ADCs.
Clinical experience of ONC201 in patients with recurrent H3 K27M-mutant spinal cord glioma.
Authors: Kurz Sylvia Christine , Tarapore Rohinton , Odia Yazmin , Butowski Nicholas A. , Koschmann Carl Johannes , Aguilera Dolly , MacDonald Tobey J. , Lu Guangrong , Allen Joshua E. , Oster Wolfgang , Mehta Minesh P. , Chi Andrew S. , Wen Patrick Y. 
Published: May 2020

2563 Background: High-grade gliomas of the spinal cord are a rare and understudied entity, representing < 5% of all spinal cord tumors. Reported median survival times range from 10-16 months. Up to 53% of tumors harbor the H3 K27M mutation, which is associated with an unfavorable prognosis. Postsurgical treatment often includes radiation ± temozolomide, although the role of chemotherapy has not been conclusively established. At recurrence, there are no effective therapies and most clinical studies exclude patients with spinal cord tumors. We report our clinical experience with ONC201, a small molecule DRD2 antagonist and caseinolytic protease P agonist, in patients with recurrent H3 K27M-mutant diffuse gliomas of the spinal cord (scDG). Methods: Adults and children with recurrent H3 K27M-mutant scDG received ONC201 in two Phase II clinical trials enrolling adult recurrent H3 K27M-mutant glioma patients (NCT02525692; NCT03295396) and in one Phase I clinical trial enrolling pediatric patients (NCT03416530). Adult patients received ONC201 at the RP2D dose of 625 mg weekly and pediatric patients received the RP2D of 625 mg weekly, scaled by body weight. All patients began ONC201 as a single agent until disease progression. Five patients continued ONC201 combined with bevacizumab beyond progression. Results: As of January 15, 2020, 12 evaluable patients (adult n = 8, pediatric n = 4) received ONC201. The median age was 20.9 (range: 7-72) years. The median follow-up time for the single agent ONC201 group was 5.4 (range 1.3-9.7) months while that of the combination group is 7.4 (range 6.2-25.1) months. The median number of ONC201 doses was 10 (range: 5-39) for the ONC201 single agent group and 34 (range: 21-100) for the combination group. Five of 7 patients remain alive in the ONC201 single agent group while 3 of 5 patients remain alive in the combination group. Three patients in the ONC201 single agent group and 2 patients in the combination group continue on treatment. There were no drug-related toxicities requiring dose reduction or discontinuation. Conclusions: Treatment with ONC201 alone or combined with bevacizumab is well tolerated in patients with recurrent H3 K27M-mutant scDG and a subset of patients experiences prolonged survival that exceeds historical outcomes. Clinical trial information: NCT02525692; NCT03295396; NCT03416530 .
Oral DNA vaccination targeting VEGFR2 combined with anti-PDL1 avelumab in patients with progressive glioblastoma: Safety run-in results—NCT03750071.
Authors: Wick Wolfgang , Wick Antje , Chinot Olivier L. , Van Den Bent Martin J. , De Vos Filip Yves Francine Leon , Mansour Marc , Podola Lilli , Lubenau Heinz , Platten Michael 
Published: May 2020

3001 Background: VEGFR2 overexpression in glioblastoma serves as a target for VEGFR2 primed T cells using VXM01 DNA vaccine encoding for VEGFR2. VXM01 is delivered in a bacterial Ty21a carrier suitable for oral administration. A previous phase I/II study in 14 patients with progressive glioblastoma showed that detection of VEGFR2 specific T cells as well as altered intra-tumoral immunity is correlated with prolonged overall survival, one partial response was reported with VXM01 alone. Three patients received nivolumab in addition to VXM01, which resulted in one complete and one partial clinical response. Based on these findings, a trial combining VXM01 and avelumab was designed. Methods: A multicentre, open-label phase I/II study ( EudraCT 2017-003076-31) in progressive glioblastoma includes 30 patients (24 non-resectable, 6 resectable) previously treated with temozolomide/radiotherapy. VXM01 is administered on day 1, 3, 5, 7 followed by boostings q4w. Avelumab 800mg is given intravenously q2w. Treatment continues up to week 48 followed by a 2 year observation period. The safety run-in phase of dose groups treated with VXM01 106 or 107 CFU plus avelumab was completed with 9 patients. Safety evaluation by the Data Safety Monitoring Board was performed after 3 and 9 patients treated for at least 5 weeks. Endpoints include safety and tolerability, objective response rate (ORR), clinical response using immune-response assessment in Neurooncology criteria (iRANO), and immunological assays like ELISpot, FACS, TCR-sequencing and tumor stainings. Results: No treatment-related toxicities were observed. Three partial responses with tumor reductions of 58, 81 and 95% to baseline were reported in 9 patients according to iRANO. Two of these patients are progression-free > 6 months. Significant VEGFR2 specific T cell responses were measured in several patients, and pre-existing intra-tumoral T cells are positively associated with the effectiveness of the immunotherapy combination. Conclusions: VXM01 in combination with avelumab was safe and produces detectable peripheral VEGFR-2 specific immune responses. Three patients had an objective response. Clinical trial information: NCT03750071 .
Interim subgroup analysis for response by PD-L1 status of CLASSICAL-Lung, a phase Ib/II study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.
Authors: Shafique Michael Rahman , Fisher Terrence Lee , Evans Elizabeth E. , Leonard John E. , Pastore Desa Rae Electa , Mallow Crystal L. , Smith Ernest , Schröder Andreas , Chin Kevin M. , Beck Joseph Thaddeus , Baumgart Megan Ann , Govindan Ramaswamy , Gabrail Nashat Y. , Sanborn Rachel E. , Spira Alexander I. , Seetharamu Nagashree , Lou Yanyan , Mansfield Aaron Scott , Goldman Jonathan Wade , Zauderer Maurice 
Published: May 2020

3011 Background: Antibody blockade of semaphorin 4D (SEMA4D, CD100) promotes tumoral dendritic cell and CD8+ T cell infiltration and reduces function and recruitment of immunosuppressive myeloid cells. Importantly, these mechanisms to overcome immune exclusion and suppression have been shown to complement immune checkpoint therapies in preclinical models. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple T cell activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This phase 1b/2, single arm, first-in-human study is designed to evaluate the safety, tolerability and efficacy of pepinemab with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) pts and pts whose tumors progressed following immunotherapy (IOF). Results: Among 21 evaluable ION pts, 5 experienced partial response (PR), 3 pts had clinical benefit ≥ 1 year, and the disease control rate (DCR) is 81%. Pts enrolled in this study were observed to have lower PD-L1 expression relative to prior single agent studies (likely due to approval of pembrolizumab for first line therapy). We, therefore, performed subgroup analysis for response by PD-L1 status. The objective tumor response (ORR) in the PD-L1 negative and low population ( < 80% TPS by Dako 73-10 assay) appears to be approximately 2-2.5 fold greater with combination therapy than with historical single agent immune checkpoint controls. Notably, 97% of pts who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Among 29 evaluable IOF pts, the combination resulted in 59% DCR, including 2 PR and 7 patients with durable clinical benefit of ≥ 23 weeks. Biomarker analysis of pre- and on-treatment biopsies confirmed increased CD8+ T cell density correlating with response. Surprisingly, analysis of myeloid-derived suppressor cells (MDSCs) revealed a relative paucity of these cells in pretreatment NSCLC biopsies as compared to other cancer indications such as HNSCC. Conclusions: This trial is nearing completion with only 5 of 62 subjects remaining on study. Preliminary data suggest the combination is well tolerated and shows signs of increased antitumor activity, particularly in PD-L1 negative or low tumors. Updated clinical response data and immunophenotypic analyses will be presented. Clinical trial information: NCT03268057 .
CD56bright/CD16bright NK-cell adoptive immunotherapy in patients with concurrent CNS disease and relapsed or refractory (R/R) AML.
Authors: Silla Lucia , Paz Alessandra , Filho Vicente Odone , Hamerschlak Nelson , Bittencourt Rosane , Lee Dean Anthony 
Published: May 2020

3025 Background: Patients (pts) with R/R AML and concurrent CNS disease rarely respond to chemotherapy and have a dismal prognosis. Adoptive immunotherapy (AI) with haploidentical ex vivo-activated/expanded NK cells shows promise in R/R AML, but it is unknown whether the blood–brain barrier (BBB) represents an obstacle to this approach. Here we present data from 4 pts with CNS disease from a phase 1 study of 13 pts receiving NK AI for R/R AML (NCT02809092). Methods: Double bright (CD56bright/16bright) activated NK cells (DBNK) were expanded from haploidentical family donors on feeder cells expressing membrane-bound IL-21. DBNK were infused thrice weekly for six doses 3–7 days after fludarabine, cytarabine, and G-CSF (FLAG). Pts received doses ranging from 106 to 107 DBNK/kg/infusion. CNS responses at day 30 were assessed using Response Assessment in Neuro-Oncology criteria. RNA sequencing was used to compare gene expression in DBNK vs unexpanded NK cells. Results: Demographics of the 4 pts with CNS disease are shown (Table). All pts had received a prior stem cell transplant and were heavily pretreated (median 6 prior treatments), and 1 had primary refractory disease. All pts completed 6 NK-cell infusions without dose-limiting toxicities. No cytokine storm syndrome was reported. Other toxicities were manageable, including CNS hypertension symptoms. Imaging studies showed inflammation localized to disease sites. All 4 pts showed a response (Table), with complete, long-lasting resolution of CNS lesions documented in pts #1 & #5, almost complete resolution of bone and nerve root leukemic infiltration in pt #4, and a 50% reduction of CNS chloromas in pt #6. Responses were durable, lasting up to 7 months. DBNK showed upregulation of homing receptors associated with CNS trafficking. Conclusions: Multiple infusions of ex vivo IL-21-expanded DBNK were tolerable and demonstrated unprecedented CNS responses in patients with R/R AML. These data support effectiveness of DBNK across the BBB. Clinical trial information: NCT02809092 . [Table: see text]
A prospective phase I trial of dendritic cell-based cryoimmunotherapy in metastatic castration-resistant prostate cancer.
Authors: Thomsen Liv Cecilie Vestrheim , Honoré Alfred , Reisæter Lars Anders , Almås Bjarte , Førde Kristina , Kristoffersen Einar Kleboe , Melve Guro Kristin , Biermann Martin , Helle Svein Inge , Azeem Waqas , Halvorsen Ole Johan , Akslen Lars , Bahn Duke , Pantel Klaus , Riethdorf Sabine , Ragde Haakon , Gjertsen Bjørn T. , Øyan Anne Margrete , Kalland Karl-Henning , Beisland Christian 
Published: May 2020

3029 Background: Dendritic cell (DC)-based cryoimmunotherapy (CryoIT) was used to treat metastatic castration-resistant prostate cancer in a Phase I clinical trial. Primary objective was safety of treatment. Secondarily, clinical, radiological and immunological treatment responses were investigated. Methods: In 18 patients cryoablation by a freeze-thaw process under general anesthesia was performed, followed by intratumoral autologous immature DC injection. In the last 9 patients checkpoint inhibition of either CTLA-4 or PD-1 was added. Subjects had minimum 46 weeks follow-up. Adverse events (AEs) and blood analyses were registered at all visits. Disease progression was determined by three imaging modalities according to (i)RECISTv1.1 and progression-free survival (PFS) by Kaplan-Meier method. Circulating tumor cells (CTC/7.5 mL, CellSearch) and ultradeep T-cell receptor (TCR) b-chain sequences (TCRSafe) were enumerated. Patients were separated by CTC into none (n=10), 1-4 (n=4) and ≥ 5 (n=4). Health related quality of life (HRQoL) measured by EORTC-QLQ C30 questionnaire were answered at inclusion, and 10, 22 and 46 weeks post CryoIT. Scores were calculated according to the EORTC manual. Results: Subjects progressing within 22 weeks had higher PSA (p=0.03). AE profile of the total cohort (n=18) was comparable with interim reports (n=13); of 20 possible DC-related AEs one was severe (urinary retention) and 19 mild-to-moderate, and spread independent of treatment regime. Maximum tolerated dose of DC was not reached. By 46 weeks, imaging showed 6 patients partial response or stable disease. Median PFS was 150 days in total cohort. Pretreatment CTC counts ≥5 indicated higher progression rates and recurring CTC. Ultradeep TCR-sequencing showed more prevalent and higher expressed (>5-fold) new TCR clonotypes at 2-6 weeks in men without progression. Participants reported high and stable HRQoL scores throughout the study. However, presence of CTC was associated with worse HRQoL scores at week 10 (p=0.031) and 22 (p=0.005). Conclusions: DC treatment seems safe and well tolerated, also combined with checkpoint inhibitors. Effect is indicated in subjects with moderate pre-treatment PSA levels. Immune responses are suggested by higher number of novel TCR clonotypes in men with non-progressive disease. Clinical trial information: NCT02423928 .