bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II study to evaluate the safety and clinical efficacy of atezolizumab (atezo; aPDL1) in combination with temozolomide (TMZ) and radiation in patients with newly diagnosed glioblastoma (GBM).
Authors: Weathers Shiao-Pei S. , Kamiya-Matsuoka Carlos , Harrison Rebecca A. , Liu Diane D. , Dervin Shannon , Yun Cindy , Loghin Monica Elena , Penas-Prado Marta , Majd Nazanin , Yung W. K. Alfred , O'Brien Barbara Jane , De Groot John Frederick
Published: May 2020

2511

Background: Immunotherapy strategies such as PD-1/PD-L1 inhibition may work synergistically with radiation, which is known to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety and clinical efficacy of concurrent atezo with radiation therapy and TMZ followed by adjuvant atezo and TMZ in patients with newly diagnosed GBM, unselected for MGMT status. Methods: Eligibility criteria included patients with newly diagnosed GBM age > 18 yrs who had undergone only surgery. The primary endpoint was safety in Phase I (n = 10) and OS in Phase II (n = 50). Secondary endpoints included progression free survival (PFS), overall response rate (ORR), and duration of response. All 60 patients were evaluated for efficacy. Correlative endpoints include profiling of tumor immune cell populations and peripheral blood for evaluation of circulating chemokines/cytokines. Results: 60 patients were enrolled. With median follow-up time of 16.7 months (data cutoff = 30 Dec 2019), 24 patients had died and 32 had progressed. Median OS was 17.1 months (95% CI: 13.9, not reached). Median PFS was 9.7 months (95% CI: 7.6-15). Median PFS in MGMT methylated patients (n = 18) was 16.7 months (95% CI: 7.85, not reached) and 7.9 months (95% CI: 6.70-12.4) in MGMT unmethylated patients (n = 33). Treatment-related adverse events with maximum CTCAE grade > 3 occurred in 33 patients; the most common were LFT elevation (n = 5) and lymphopenia (n = 23). To date, 17 of the enrolled 60 patients underwent re-resection post treatment with atezo. The matched paired tumor analysis of pre and post treatment tissue will provide valuable insights into mechanisms of anti-PD-L1 therapy resistance. Tumor immunocorrelative studies are pending. Conclusions: Concurrent use of atezo with radiation and TMZ was tolerable and demonstrated modest efficacy. Clinical trial information: NCT03174197 .
INO-5401 and INO-9012 delivered intramuscularly (IM) with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma (GBM): Interim results.
Authors: Reardon David A. , Brem Steven , Desai Arati Suvas , Bagley Stephen Joseph , Kurz Sylvia Christine , De La Fuente Macarena Ines , Nagpal Seema , Welch Mary Roberta , Hormigo Adilia , Carroll Nicholas , Bartra Sarah K , Campbell Patricia , Bhatt Kamalnayan , Lowy Israel , Boyer Jean , Kraynyak Kimberly , Morrow Matthew P , McMullan Trevor , Weiner David B. , Skolnik Jeffrey
Published: May 2020

2514

Background: Novel T cell-enabling therapies, in combination with checkpoint inhibition, may improve OS in GBM. INO-5401 (synthetic DNA plasmids encoding for hTERT, WT-1 and PSMA), plus INO-9012 (synthetic DNA plasmid encoding IL-12), with the PD-1 checkpoint inhibitor cemiplimab, is given to patients with newly-diagnosed GBM to evaluate tolerability, efficacy and immunogenicity of the combination. Methods: Phase I/II, single arm, 2 cohort study (A: MGMT unmethylated, B: MGMT methylated). The primary endpoint is safety; efficacy and immunogenicity are secondary. Nine mg INO-5401 plus 1 mg INO-9012 (every 3 weeks for 4 doses, then Q9W) is given with EP by CELLECTRA 2000 with cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over 3 weeks. TMZ is given with radiation (all patients), followed by maintenance (Cohort B only). Results: Fifty two subjects were enrolled: 32 in Cohort A; 20 in Cohort B. 35% women and 90% white. Median age 60 years (range 19-78 years). Common Grade ≥3 AEs reported were: platelet count decreased (11.5%), tumor inflammation (7.7%), seizure (7.7%), ALT increased (7.7%), lymphocyte count decreased (7.7.%). One Grade 5 unrelated event of urosepsis was reported. Of 69 SAEs reported there was only 1 related to the combination therapy, Grade 1 pyrexia. 48% of subjects reported irAEs, most frequently ALT increased (9.6%), AST increased (7.7%), diarrhea (7.7%), pyrexia (7.7%) and tumor inflammation (7.7%). 71% of the reported SAEs and irAEs occurred within the first 12 weeks of treatment. OS at 12 months was 84.4% (95% CI 67.2, 94.7) in Cohort A; Cohort B will be presented at ASCO. ELISpot assessments demonstrated T cell responses to INO-5401. Flow cytometry demonstrated evidence of activated INO-5401-specific CD8+T cells with lytic potential (CD38+Prf+GrzA+) when compared with baseline, post-treatment in the majority of patients assayed. Conclusions: INO-5401 + INO-9012 in combination with cemiplimab and RT/TMZ has an acceptable safety profile, is immunogenic and may show a survival advantage in patients with newly-diagnosed GBM. OS18 data will be presented later this year. Clinical trial information: NCT03491683 .
Superior therapy response predictions for patients with glioblastoma (GBM) using Cellworks Singula: MyCare-009-03.
Authors: Wen Patrick Y. , Watson Drew , Kapoor Shweta , Alam Aftab , Alam Aktar , Lala Deepak Anil , Sahu Diwyanshu , Agrawal Ashish , Basu Kabya , Ganesh Naga , Pampana Anusha , Grover Himanshu , Mundkur Nirjhar , Kumar Chandan , Mohapatra Subrat , Raman Rahul K , Elangovan Preethi , Patil Mamatha , Birajdar Shivgonda , Ahluwalia Manmeet Singh
Published: May 2020

2519

Background: Despite using cytogenetic and molecular-risk stratification and precision medicine, the current overall outcome of GBM patients remains relatively poor. Therapy selection is often based on information considering only a single aberration and ignoring other patient-specific omics data which could potentially enable more effective treatment selection. The Cellworks Singula™ report predicts response for physician prescribed therapies (PPT) using the novel Cellworks Omics Biology Model (CBM) to simulate downstream molecular effects of cell signaling, drugs, and radiation on patient-specific in silico diseased cells. We test the hypothesis that Singula is a superior predictor of progression-free survival (PFS) and overall survival (OS) compared to PPT. Methods: Singula’s ability to predict response was evaluated in an independent, randomly selected, retrospective cohort of 109 GBM patients aged 17 to 83 years treated with PPT. Patient omics data was available from TCGA. Singula uses PubMed to generate protein interaction network activated and inactivated disease pathways. We simulated PPT for each patient and calculated the quantitative drug effect on a composite GBM disease inhibition score based on specific phenotypes while blinded to clinical response. Univariate and multivariate proportional hazards (PH) regression analyses were performed to determine if Singula provides predictive information for PFS and OS, respectively, above and beyond age and PPT. Results: In univariate analyses, Singula was a significant predictor of both PFS (HR = 4.130, p < 0.000) and OS (HR = 2.418, p < 0.0001). In multivariate PH regression analyses, Singula (HR = 4.033, p < 0.0001) remained an independent predictor of PFS after adjustment for PPT (p = 0.1453) and patient age (p = 0.4273). Singula (HR = 1.852, p = 0.0070) was also a significant independent predictor of OS after adjustment for PPT (p = 0.4127) and patient age (p = 0.0003). Results indicate that Singula is a superior predictor of both PFS and OS compared to PPT. Singula provided alternative therapy selections for 29 of 52 disease progressors detected by Cellworks. Conclusions: Singula is a superior predictor of PFS and OS in GBM patients compared to PPT. Singula can identify non-responders to PPT and provide alternative therapy selections.
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 .
In vitro and in vivo characterization of MDNA11: A long-acting “beta-only” IL-2 superkine in syngeneic mice tumor models and nonhuman primates.
Authors: Rafei Moutih , To Minh , Merchant Fahar , Merchant Nina
Published: May 2020

3036

Background: Use of IL-2 (Proleukin) remains limited due to its short half-life, toxicity, and its ability to preferentially activate Tregs resulting in unwanted immune suppression. Approaches to reduce binding to CD25 (IL2α), such as pegylation techniques, also results in reduced affinity to CD122 (IL2β). To bypass these limitations, we engineered MDNA11, an IL-2 Superkine containing core mutations to diminish binding to CD25 while increasing affinity to CD122. To increase half-life, MDNA11 was fused to an albumin scaffold, which is known to allow accumulation at the tumor site. Methods: MDNA11 was evaluated using in vitro and in vivo studies that included: IL-2 signaling in human PBMCs, Biacore binding analyses, PK studies in mice, and efficacy studies in syngeneic tumor models with or without immune checkpoint inhibitors (ICIs). In addition, dose-range finding studies in cynomolgus monkeys (NHP) were performed to characterize the safety and PK/PD profiles of MDNA11. Results: MDNA11 displayed enhanced STAT5 signaling in human NK and naïve CD8 T-cells with diminished Treg activity. In mice, the terminal half-life of MDNA11 was 24-fold longer than IL-2. As a result, MDNA11 triggered effective tumor growth control, as monotherapy or in combination with ICI, in multiple tumor models in spite of q1wk dosing for two weeks. MDNA11 administration to mice with pre-established CT26 colon cancer resulted in tumor-free animals and induced strong memory response and protection against subsequent re-challenges. MDNA11 also inhibited the growth of B16F10 melanomas, which translated into a durable increase in tumor infiltrating CD8 T-cells. When tested in NHP, MDNA11 led to increased circulating CD8 T-cells lasting for almost 14 days with limited effects on Tregs and eosinophils (the latter being a source of IL-5 causing vascular leak syndrome). High doses resulted in mild side effects that were transient and reversible even following repeated dosing. Conclusions: The long-acting MDNA11 Superkine has superior potency over IL-2 at activating naïve CD8 T-cells and NK cells, while exhibiting diminished Treg activation. This molecule potently inhibited tumor growth and induced durable regression and long-term memory response. Studies in NHP showed prolonged proliferation of immune effector cells lasting almost two weeks post-MDNA11 administration. The sum of these data underscores the potency of MDNA11 to trigger the host’s immune response to control or eradicate established tumors.
Novel biomarker panel based on cellular and soluble checkpoint proteins for PD-1/PD-L1 blockade treatment efficacy.
Authors: Nagai Hiroki , Ganepola Ganepola A.P. , Lee Jin , Kirshner Eli , Wood Kevin C. , Rakowski Thomas J. , Suh Jason , Teplinsky Eleonora , Insinga Alysha , Rutledge John R , Chang David H
Published: May 2020

3045

Background: Although anti-PD-1/PD-L1 therapy has become one of the standard treatments for advanced cancers, its low treatment efficacy (10-30%) has remained a major issue. We sought to perform a detailed immune profiling of cells and soluble proteins in order to characterize key regulators and signaling molecules and identify therapeutic targets and biomarkers that may improve treatment efficacy and diagnosis. Methods: This observational study enrolled 49 advanced cancer patients treated with PD-1/PD-L1 blockade monotherapy. Treatment response was assessed by RECIST 1.1. PBMC and plasma samples were collected at baseline and every 6 weeks following initial treatment. Immune profiling of PBMC was done by multi-parametric flow cytometer, and t-SNE analysis was used to identify key immune subtypes. Soluble proteins were evaluated by LUMINEX assays. Cut-off values were determined by ROC curve analysis. Results: Three unique subtypes of immune cells were identified. The population of CD11c+HLA-DRlowCD80+CD86− CD274+ cells (regDC) at baseline was significantly higher in patients with progressive disease (PD, n=28) than in patients showing clinical benefit (non-PD, n=21; p=0.030). The higher regDC population also correlated with higher levels of IL-8, IL-10, CXCL1, CXCL5, and CXCL11 in plasma. The population of CD4+CD25+CD62L+ T cells (Treg) was also higher in PD patients (p<0.001). A unique subtype of CD4+CD28− T cell, however, was higher in non-PD patients (p<0.001). For the soluble proteins, the levels of sLAG-3 and sGITR in plasma correlated with better clinical outcome in low regDC patients (p=0.004 and 0.044, respectively). The combined biomarker panel (cellular and protein markers) yields high sensitivity (90.5 %) and specificity (82.1 %) for predicting treatment efficacy. Disease control rate (DCR) and median progression free survival (PFS) are shown in the Table. Conclusions: To our knowledge, this pilot study is the first to detect three immune cell subtypes, regDC, Treg and CD4+CD28− cells, associated with clinical outcome in the treatment of PD-1/PD-L1 blockade. Profiling of immune cell subtypes and soluble immune checkpoint proteins can serve to identify therapeutic targets and biomarkers for treatment efficacy. We will report the data with further enrollment. [Table: see text]
Clinical value of noninvasive biomarkers reflecting a collagen-rich stroma in metastatic melanoma patients treated with anti-PD1 therapy.
Authors: Jensen Christina , Hurkmans Daan , Koolen Stijn L.W. , Karsdal Morten A. , Mathijssen Ron H.J. , Willumsen Nicholas
Published: May 2020

3049

Background: Poor response to anti-PD1/PD-L1 remains a clinical challenge in a subgroup of patients with metastatic melanoma. Recent evidence strongly suggests that these poor responses are associated with TGF-β signaling and CD8+ T-cell excluded tumors characterized by a collagen-rich peritumoral stroma that blocks the interaction between T cells and tumor cells. In the pursuit of identifying non-invasive biomarkers associated with a T-cell excluded phenotype and predict resistance/response to immune checkpoint inhibitor therapy, we evaluated the association between blood-based biomarkers measuring type III collagen formation and cross-linking and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. Methods: 107 patients with metastatic melanoma who started anti-PD1 monotherapy between May 2016 – March 2019 entered in a prospective real-life study (nivolumab n = 62, pembrolizumab n = 45). Type III collagen formation (PRO-C3) and type III collagen formation and cross-linking (PC3X) were measured with ELISAs in pre-treatment serum. Biomarker levels were associated to Disease Control Rate (according to RECIST v.1.1) by Mann-Whitney test and correlated to survival outcomes by Kaplan-Meier and Cox regression analyses. Results: PRO-C3 was significantly elevated in patients with progressive disease compared to the combined group of patients with complete response, partial response and stable disease (p = 0.046). High PRO-C3 and PC3X ( > 75th percentile) prior to treatment were significantly associated with poor overall survival (PRO-C3: HR = 2.4, p = 0.008; PC3X: HR = 2.2, p = 0.019) and progression free survival (PRO-C3: HR = 1.91, p = 0.016; PC3X: HR = 1.94, p = 0.013). The median overall survival was 417 and 511 days in biomarker high patients compared to 1269 and 1269 days in biomarker low patients, for PRO-C3 and PC3X, respectively. Conclusions: Biomarkers quantified in a pre-treatment liquid biopsy reflecting excessive collagen formation and cross-linking were associated with poor response and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. This supports an association between collagen formation and resistance to anti-PD1 therapy. Furthermore, if validated, these non-invasive collagen biomarkers may have potential for guiding patient stratification for immune checkpoint inhibitor therapy and combination therapies. Clinical trial information: NTR7015 .
Rechallenging with immune checkpoint inhibition after a treatment-limiting immune-related adverse event.
Authors: O'Neal Richard Lee , Roberts Kandice , Hao Zhonglin , Arnold Susanne M.
Published: May 2020

3053

Background: Immune checkpoint inhibition (ICI) with cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), or programmed death ligand-1 (PD-L1) blockade can be associated with the development of immune related adverse events (irAE), many of which can be treatment-limiting. Due to an absence of randomized controlled trials, the current approach in regards to ICI discontinuation versus rechallenging remains controversial. Methods: We assessed all patients who had received ICI at a single academic institution from 5/2015 to 1/2019, identifying those who had delays in their treatment. Retrospective chart review was performed to determine type of ICI, type and grade of irAE, treatment of irAE, and recurrence and grades of irAE if ICI was resumed, as well as to assess overall survival (OS). Results: 562 patients received ICI (lung cancer [232, 41%], melanoma [66, 12%], kidney cancer [43, 8%], bladder cancer [27, 5%], and other cancers [194, 34.5%]) from 5/2015 – 1/2019. Of these, 121 (22%) had a treatment-limiting irAE (most commonly dermatitis [24%], colitis [17%], pneumonitis [14%], and hepatitis [12%]). Of the patients who had ICI held, 80/121 (66%) were eventually rechallenged, while 41/121 (34%) discontinued permanently. When rechallenged with ICI, 47/80 (59%) had no further treatment-limiting irAEs, 16/80 (20%) had a recurrence of the same irAE, and 17/80 (21%) developed a different irAE. Of those who were rechallenged, only 17/80 (21%) ultimately had to discontinue because of a second irAE. At a median follow up time of 12.1 months, median OS was not reached in those patients who experienced a treatment limiting irAE and was 8.1 months in those who did not (hazard ratio [HR] for death, 0.33; 95% CI 0.23 – 0.48; p < 0.001). At 12 months from initiation of ICI, 77.0% of patients who had a treatment-limiting irAE were alive, compared to 39.6% of those who did not have an event. Restarting ICI after a treatment-limiting irAE was not associated with a change in OS (HR 0.66 [95% CI 0.27 – 1.66], p = 0.38). Conclusions: Patients who discontinued ICI secondary to irAEs had relatively low rates of recurrent toxicity when rechallenged with treatment. These patients were just as likely to develop a new toxicity as a recurrence of the original irAE, and relatively few had to discontinue permanently. Development of a treatment-limiting irAE was associated with improved OS compared to those who did not. This study suggests that rechallenging with ICI may be safe in selected patients, though this did not have an impact on OS.
Characteristics and outcomes of real-world (RW) patients (pts) with microsatellite instability-high (MSI-H) solid tumors treated with pembrolizumab monotherapy (P) after FDA approval.
Authors: Snow Tamara , Swaminathan Akshay , Snider Jeremy , Schrock Alexa Betzig , Li Gerald , Alexander Brian Michael , Singal Gaurav , Castellanos Emily , McCusker Margaret Elizabeth
Published: May 2020

3060

Background: The first tumor-agnostic, biomarker-based FDA approval in oncology was P in May 2017 for pts with MSI-H or mismatch repair (MMR) deficient tumors. 1 yr overall survival (OS) was >70% for colorectal cancer (CRC) and >60% for non-CRC in P-treated MSI-H clinical trial pts (Le 2019; Marabelle 2019). As tumor-agnostic therapies are a new paradigm, it is important to assess their use and effectiveness in routine clinical practice. We examined characteristics and outcomes of RW pts with MSI-H solid tumors who received P after May 2017. Methods: Pts with MSI-H solid tumors who received P after May 2017 were selected from the Flatiron Health-Foundation Medicine (FH-FMI) clinico-genomic database, a nationwide de-identified EHR-derived database linked to comprehensive genomic profiling (CGP) data. Pts with 2+ visits in the FH network from 01/2011-09/2019 with CGP prior to P use were included. Clinical characteristics were assessed at first P use. Time to treatment discontinuation (TTD) and OS from first P use were estimated with Kaplan-Meier analyses of all pts and the largest tumor types. Results: 33,395 pts had a solid tumor tested for MSI by CGP, of which 557 (1.7%) were MSI-H (median age 68 yrs; 34% male). 129 MSI-H pts across 33 tumor types received first P after May 2017. CRC (N=36) and Endometrial cancer (N=39) were most common. 52 pts (40%) had a concurrent MMR alteration (MLH1, MSH2, MSH6 or PMS2); median TMB was 32.2 mut/mb (IQR 20.9-47.5). Median number of therapies prior to P was 1; median time from CGP to first P use was 3 mos. Table shows OS and TTD. Conclusions: In this RW study, P use was observed across 33 MSI-H tumor types. Median OS exceeded 1 yr across all pts and in CRC, Endometrial, and Other cohorts. 1 yr OS rate was consistent with P trial outcomes. Further study should evaluate whether effectiveness differs across diseases, MSI testing method, or other genomic attributes to improve treatment selection. [Table: see text]
Assessing the effect of immunosuppressive agents for immune-related adverse event management on tumor response.
Authors: Reid Pankti , Olson Daniel , Gajewski Thomas
Published: May 2020

3066

Background: High grade immune-related adverse events (irAEs) to cancer immune checkpoint inhibitors (ICI) require considerable immunosuppression (IS) with high-dose steroids and steroid-sparing IS (SSIS) for steroid-dependent cases. T lymphocyte-specific IS has generally been avoided or used with significant caution due to the fear that these agents may negatively impact ICI efficacy. We sought to determine whether T cell-specific IS agents, such as calcineurin inhibitors (CNIs), have an adverse effect on tumor control when compared to other immunomodulatory drugs (IMDs). Methods: We retrospectively analyzed clinical annotations of adult patients treated with ICIs for malignancy from 1/1/2000-12/31/2019, highlighting patients who were managed with SSIS, specifically those most commonly used for autoimmune disease therapy. Topical IS use was excluded. Patients were categorized as tumor responders or non-responders, and irAEs were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Progression-free survival (PFS) was assessed via Kaplan-Meier curve. Results: 1331 unique individuals were prescribed ≥1 ICIs, with 526 prescribed systemic steroids (39.5%) and 90 (6.8%) patients prescribed SSIS agents, 25 patients with >1 SSIS: mycophenolate (39), methotrexate (26), leflunomide (5), azathioprine (3), rituximab (24), tocilizumab (3), infliximab (8), etanercept (1), adalimumab (1), golimumab (1) and CNIs (18): cyclosporine, tacrolimus. IMDs hydroxychloroquine (6) and sulfasalazine (5) were also prescribed. The objective response rate was 50.0% in the CNI group compared to 45.5% in the IMD cohort and 45.4% in the irAE group (CTCAE grade matched) with steroids alone without any SSIS. Median PFS were compared between CNI cohort (5.4 months, range 1.3-34 months) to IMD (1.1 months, range 0.4-6.4, p=0.02) and steroid alone (2.4 months, range 0.69-17.7, p=0.48). Multiple regression analysis identified irAE presence as an independent correlates to tumor response (p=0.02). Conclusions: T cell-specific IS should not be excluded from irAE treatment algorithm as we observed that PFS was comparable to immunomodulators and similar efficacy was observed compared to steroids alone. Rapid identification and management of irAEs can help mitigate morbidity but there are virtually no reliable clinical trials to guide irAE management with SSIS. These findings support the need for larger, prospective evaluation of immunosuppression use for high grade irAE therapy.
Checkpoint inhibitor treatment-related cutaneous adverse events in skin of color patients at Memorial Sloan Kettering Cancer Center.
Authors: Geisler Amaris , Barrios M.S Dulce M. , Noor Sarah J. , Lacouture Mario E.
Published: May 2020

3076

Background: The advent of immune checkpoint inhibitors (CPIs) for the management of advanced malignancies has led to unintended consequences of nonspecific immune activation. Cutaneous immune related adverse events (irCAEs) are the most common and first to manifest, on average within 3.6 weeks of treatment initiation. irCAEs may require CPI treatment dose reduction or discontinuation and negatively impact patient quality of life. There is substantial variability in the reporting of these toxicities and inadequate reporting in skin of color patients (SOC), who are often underrepresented in oncology clinical trials. The purpose of this study is to characterize irCAEs in SOC cancer patients. Methods: A single center retrospective analysis of electronic medical records from 2009-2020 was conducted. SOC was defined as African American, Hispanic, Native American/Pacific Islander, or Asian. irCAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Of 1459 SOC patients that presented to our institution and received CPIs during the study period, 175 (12%) presented to dermatology for irCAEs [African American (56, 32%); Asian (98, 56%); Hispanic (20,11%); Native American (1, 0.5%)]. Patients’ toxicities were stratified by CPI mechanism: anti-PD-1/L1 (139, 79%), combination of anti-PD-1/L1 plus anti-CTLA-4 (29, 17%), and anti-CTLA-4 therapy (7, 4%). Of 376 irCAEs, pruritus (62, 16%), xerosis (42, 11%), maculopapular rash (40, 11%), and cutaneous hyperpigmentation (36, 10%) were most frequently diagnosed. There were 86 (23%) grade 1, 93 (25%) grade 2, and 18 (5%) grade 3 events. Average time from CPI-treatment initiation to irCAE onset was 6.5 months (SD 7.9). Fifteen (9%) patients required CPI dose reduction or discontinuation due to skin toxicity. Topical corticosteroids (133, 76%) were the most frequently used treatment for all irCAEs. Conclusions: Our findings suggest that irCAEs occur frequently in SOC cancer patients. Furthermore, a 6.5-month delay in time to diagnosis highlights a need for increased surveillance of these cutaneous toxicities in darkly pigmented skin. Generally, SOC patients present unique diagnostic and management challenges due to differences in skin biology and propensity toward hyperpigmentation; however, in SOC cancer patients, the mechanisms of oncologic immunotherapy must be considered in developing successful treatment strategies and management of dermatologic health in this population.