bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib/II trial of lenvatinib plus pembrolizumab in advanced melanoma.
Authors: Taylor Matthew H. , Vogelzang Nicholas J. , Cohn Allen Lee , Stepan Daniel E. , Shumaker Robert Charles , Dutcus Corina E. , Guo Matthew , Schmidt Emmett V. , Rasco Drew W. 
Published: July 2019

15 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for first-line treatment of advanced melanoma (objective response rates [ORR], 21–34%). In preclinical studies, LEN decreased tumor-associated macrophage populations, increased CD8+ T cell infiltration, and augmented PD-1 inhibitor activity; thus, LEN is a rational combination partner for PEM. We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in solid tumors, focusing on advanced melanoma. Methods: In this multicenter, open-label study, patients (pts) with measurable, confirmed, metastatic melanoma and ECOG PS ≤1 received oral LEN (20 mg/day) + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. Tumor assessments were by investigator per immune-related RECIST (irRECIST). Phase 2 primary end point was ORR at 24 weeks (ORRWK24). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 14 (67%) were PD-L1+, 4 (19%) were PD-L1-; 3 (14%) not tested. 38% had ≥1 prior anticancer therapy. ORRWK24 was 47.6% (95% CI, 25.7–70.2). All pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 13 (62%) and 1 (5%; adrenal insufficiency) pts respectively. There were no fatal TRAEs. Most common any-grade TRAEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension (48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to TRAEs occurred in 13 (62%) and 10 (48%) pts, respectively. Conclusions: LEN + PEM was well-tolerated and had encouraging clinical activity. The combination may potentially improve on the antitumor activity of anti-PD-1 monotherapies, supporting further evaluation in advanced melanoma. Clinical trial information: NCT02501096. [Table: see text]
Infections in patients receiving immune checkpoint inhibitors.
Authors: Sae-Tia Sutthichai , Naidoo Jarushka , Mehta Seema 
Published: July 2019

155 Background: Immune checkpoint inhibitors (ICIs) - anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, avelumab), anti-CTLA-4 (ipilimumab) - have improved outcomes for several malignancies. ICIs may cause immune-related adverse events (irAEs), often treated with immunosuppression. The incidence of infections arising de novo during ICI therapy or from immunosuppression for irAEs is not well described. Methods: In- and outpatients receiving ICIs were referred for Infectious Diseases consultation between 6/2011-6/2018. Twenty-five were randomly selected for retrospective summarization of the spectrum of infections. Diagnosis of infection was made by the primary oncologist, based upon clinical/radiographic/laboratory data. Results: Solid tumor (24, 96%) and hematologic malignancies (1, 4%) were represented (Table). All 25 had infections. 15 (60%) were male; median age 58 years (29-97). 17 (68%) had irAEs: pneumonitis (10, 40%), thyroiditis (5, 20%), colitis (5, 20%), hepatitis (4, 16%), dermatitis (4, 16%) and myocarditis (1, 4%). 17 (68%) patients developed +1 irAE. 50% with pneumonitis were concurrently treated for pneumonia. Of the 25, 17 (72%) developed de novo infections on ICIs; whereas others were receiving systemic corticosteroids (7, 28%) or infliximab (1, 4%). Initial infections included pneumonia (13, 52%), bacteremia (3, 12%), sinusitis (2, 8%), wound infection (2, 8%), viral infections (HSV, CMV, HCV; 1, 4% each) and 1 (4%) each of empyema, UTI, peritonitis, osteomyelitis, and meningitis. 44% (11) developed a second infection within 60 days of the first. Conclusions: Patients receiving ICIs for cancer developed a myriad of infections, both de novo during ICI therapy, or consequent to immunosuppression for irAEs. Second infections are common, occurring in nearly half the patients. Awareness of this is vital for early diagnosis and appropriate management. Patients with suspected ICI-related infection. (n=25). [Table: see text]
A phase Ib/II trial of lenvatinib plus pembrolizumab in non-small cell lung cancer.
Authors: Brose Marcia S. , Vogelzang Nicholas J. , DiSimone Christopher , Jain Sharad K. , Richards Donald A. , Encarnacion Carlos A. , Rasco Drew W. , Shumaker Robert Charles , Dutcus Corina E. , Stepan Daniel E. , Guo Matthew , Schmidt Emmett V. , Taylor Matthew H. 
Published: July 2019

16 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is an approved monotherapy for previously treated patients (pts) with PD-L1 (+) (tumor proportion score ≥1%) metastatic non-small cell lung cancer (mNSCLC; objective response rate [ORR] 18%). We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in pts with solid tumors, focusing on the mNSCLC cohort. Methods: In this multicenter, open-label study (NCT02501096), pts with measurable, confirmed mNSCLC, ECOG PS ≤1, ≤ 2 prior systemic therapies (phase 2 only) received oral LEN (20 mg/day) and PEM (200 mg Q3W, IV). Pts were not preselected by PD-L1 status. The phase 2 primary end point was ORR at 24 weeks (ORRWK24) by investigator-assessed immune-related RECIST (irRECIST). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 9 (43%) PD-L1(+), 5 (24%) PD-L1(-), and 7 (33%) not tested. Pts were treatment-naïve (14%); or had 1 (33%), 2 (48%), or ≥3 (5%) prior lines of systemic therapy. ORRWK24 was 33.3% (95% CI, 14.6–57.0); other efficacy outcomes are summarized in the table. Grade 3 and 4 treatment-related adverse events (TRAEs) occurred in 48% and 5% (increased aspartate aminotransferase) of pts. There was 1 fatal TRAE (exsanguination; “possibly related” to study treatment). The most common grade 3 TRAEs were hypertension (24%), fatigue (14%), diarrhea (14%), proteinuria (10%), and arthralgia (10%). Conclusions: LEN + PEM showed promising clinical activity and a manageable safety profile in previously treated pts with mNSCLC who were not preselected for PD-L1 status. Further study is warranted.[Table: see text]
The SAINT: Initial results of a phase I/II study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.
Authors: Chawla Sant P. , Chua-Alcala Victoria S. , Kim Katherine , Assudani Nupur , Al-Shihabi Ahmad , Moradkhani Ania , Quon Doris , Wong Steven , Tseng William W. , Pollack Seth , Srikureja Amor M. , Jalas John , Jones Robin Lewis , Gordon Erlinda Maria 
Published: July 2019

22 Background: Sarcoma cells are most immunogenic at the onset of cancer. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To evaluate the safety of ipilimumab (I), a CTLA4 inhibitor, nivolumab (N), a PD-1 inhibitor, and escalating doses of trabectedin (T), a marine-derived natural alkaloid, in advanced soft tissue sarcomas (STS), (2) To investigate the BORR, DCR, PFS and OS, and (3) to correlate response with immune cell trafficking in the tumor microenvironment. Methods: This is an IRB-approved dose-seeking phase 1/2 study using defined doses of I (1 mg/kg IV q 12 weeks), N (3 mg/kg IV q 2 weeks) and escalating doses of T (1.0, 1.3, 1.5 mg/m2 IV q 3 weeks), employing “cohort of three” design, with a Phase 2 component using the MTD of T. Results: Phase 1 safety analysis: At Dose 1: Grade 3 treatment related adverse events (TRAEs): fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs: thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs: anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). At Phase 2, Grade 4 TRAEs: increased CK (n = 1); Grade 3 TRAEs: increased ALT (n = 4), anemia (n = 3) neutropenia (n = 1), portal cellulitis (n = 1). Efficacy analysis: Phase 1 (n = 9): At Dose 1: DCR 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1, rhabdomyosarcoma), DCR 60%, median PFS, > 42 weeks; median OS, > 47 weeks. Phase 2 (n = 16): PR (n = 3; 1 liposarcoma, 1 leiomyosarcoma, 1UPS); BORR 18.75%, DCR 87.5%, median PFS, > 19 weeks; median OS, > 26 weeks. Surgical resection was undertaken in 1 patient with SD after 4 cycles. The surgical specimen showed 80% necrosis and greater number (30%) of CD8+ killer T cells, 10% PD-L1+ cells in the TME compared to that of archived pre-treatment tumor. Conclusions: Taken together, these data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. The phase 2 part of the study is on-going. Clinical trial information: NCT03138161.
A novel humanized anti-CTLA-4 antibody compared to ipilimumab in preclinical studies.
Authors: Shi Qian , Liu YanLi , Yang Lan , Ma Hongli , Ma Wencui , Sun Ziyong 
Published: July 2019

32 Background: The efficacy of ipilimumab as a single agent and in combination for the treatment of melanoma and other malignancies has validated the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) blockade in immunotherapy. Clinical trials that include anti-CTLA-4 in a combination design have gained traction. However, ipilimumab is the only anti-CTLA-4 antibody therapeutic approved worldwide. Therefore, novel anti-CTLA-4 therapeutics that may overcome the shortcomings of ipilimumab to fulfill the unmet medical needs is desperately desired. Methods: Mouse hybridoma cells were screened, cloned, and lead antibodies were humanized to obtain candidates with high activity in blocking CTLA-4/CD80 interaction. The resulting lead antibody was further characterized with in vitro binding and blocking assays, as well as mixed lymphocyte reaction assay. A humanized CTLA-4-B6 mouse model was used to evaluate the in vivo tumor growth inhibition activity of the antibody. Results: CBT-509, a novel IgG1 humanized monoclonal antibody against CTLA-4 was obtained. EC50 of CBT-509 binding with CTLA-4 and IC50 of CBT-509 blocking CTLA4/CD80 interaction were comparable to ipilimumab. CBT-509 binds to a distinct epitope, and has a high affinity with CTLA-4 (KD = 2.73E-10 M), more than 4-fold stronger than ipilimumab (KD = 1.21E-9 M). Compared with ipilimumab, CBT-509 was more active in mixed lymphocyte reaction, suggesting that it is more potent in human T-cell activation. Importantly, the efficacy of CBT-509 in killing tumor cells in vivo is much stronger than that of ipilimumab. In a MC38 murine colorectal cancer model under huCTLA-4 B6 mice background, CBT-509 eradicated tumors in 7 of 8 mice at a dose of 3 mg/kg, while ipilimumab eradicated tumors in 4 of 8 mice at the same dosage. Conclusions: Taken together, CBT-509 demonstrated an improvement over ipilimumab. Future efforts will focus on developing molecules that can further improve the efficacy and safety of anti-CTLA-4 based therapeutics.
Assessment of PD-1 expression in human resting and activated natural killer cells and murine tumor models.
Authors: Judge Sean J. , Dunai Cordelia , Sturgill Ian R. , Stoffel Kevin M. , Murphy William J. , Canter Robert J. 
Published: July 2019

36 Background: Blockade of the PD-1/PD-L1/2 axis has revolutionized cancer therapy. Although reinvigorated PD-1+ T cells are the main effectors in the response to checkpoint blockade, the contribution of Natural Killer (NK) cells to PD-1/PD-L1 inhibition is under debate. While PD-1 has been identified on NK cells, this appears to be restricted to small populations under limited conditions. We sought to evaluate the extent of PD-1 expression in mouse and human resting and activated NK cells. Methods: Human NK cells were isolated from healthy donor PBMCs and cancer patients. Ex vivo activation and proliferation techniques included recombinant human cytokine and feeder line co-culture. Murine NK cells were isolated from splenocytes, and PBMCs from wild type and immunodeficient mice. We assessed NK cell surface markers and intracellular cytokine by flow cytometry, and gene expression by quantitative RT-PCR. Results: Over 21-days of ex vivo expansion, expression of PD-1 or PD-L1 on human NK cells was < 1% at all time points, while TIGIT+ expression increased to > 85%. Conversely, ConA stimulation of T cells increased PD-1 expression with no change in TIGIT expression. QRT-PCR demonstrated absent PD-1 expression in purified NK cells compared to a 5-fold increase in PD-1 gene expression in ConA stimulated PBMCs. PD-1/PD-L1 was also < 1% in the NK92 cell line and < 2.5% in peripheral CD56+CD3- NK cells from patients with soft tissue sarcoma (STS). NK cells from digested freshly resected STS show variable PD-1 ( < 10%) and minimal PD-L1 ( < 1%) expression with a small, but measurable population of intra-tumoral NK cells (1% of immune cells). In vivo mouse studies showed < 5% PD-1+ NK cells in spleen and tumor of CT26 tumor-bearing mice, while PD-L1+ NK cells increased in frequency from spleen (5-35%) to tumor (40-95%) in both wild type BALB/C and SCID mice. Conclusions: In contrast to prior studies, we did not observe a substantial PD-1+ population on human or murine NK cells after multiple activation strategies compared to T cells. Contrary to its application in T cells, our data suggest that PD-1 is not a useful marker for NK cell exhaustion/dysfunction. PD-L1 on NK cells may represent an important link between NK and T cell immunotherapy.
Targeted tumor-derived cellular immunotherapy in advanced breast cancer patients induces initial immune responses and tumor regression.
Authors: Sunkari Vivekananda , Williams William , Peoples George , Graeve Sanne , Wiseman Charles , Lacher Markus 
Published: July 2019

6 Background: SV-BR-1-GM is a GM-CSF secreting breast cancer cell line which also expresses HLA class I & II antigens. In a previous clinical trial, a partial response of widely metastatic breast cancer was seen in a patient who allele-matched SV-BR-1-GM at HLA-DRB3. Here we report regression of metastatic breast cancer and efficacy analysis with immunologic correlates in subjects of a Phase I/IIa trial of SV-BR-1-GM in patients with advanced breast cancer. Methods: 24 patients with recurrent and/or metastatic breast cancer refractory to standard therapies have been dosed with SV-BR-1-GM in a Phase I/IIa trial. Patients who have undergone at least one cycle of SV-BR-1-GM therapy were analyzed. Patients first received low-dose cyclophosphamide, then intradermal injection of SV-BR-1-GM (20-40x106 cells/four sites) with interferon-α injected into inoculation sites (10,000 IU/site) ~2 & 4 days subsequently. Immunologic responses were measured by delayed type hypersensitivity (DTH) after inoculation and IgG titers of antibodies against SV-BR-1 were measured in sera samples collected prior to and after the first dose of SV-BR-1-GM by flow cytometry. Results: 24 patients have been inoculated with SV-BR-1-GM cells with no unexpected adverse events. None of the patients exhibited immediate hypersensitivity to SV-BR-1. DTH response was recorded in 18 subjects till date, of these, 61% exhibited DTH to cell inoculations. The patient with the most marked DTH response, 01-002, also had a clinical response with regression of multiple lung metastases. Two other patients had evidence of tumor regression (tumor regression is matched SV-BR-1-GM at least at one HLA allele). Sera samples from 6 patients were evaluated and found to contain anti-SV-BR-1 antibodies. Conclusions: SV-BR-1-GM in this regimen appears to be safe and well-tolerated. Initial analysis of SV-BR-1-GM showed significant DTH and antibody responses. HLA matching improves the response rate and is being evaluated as a predictor of response. Clinical trial information: NCT03066947.
PD-1 blockade after PD-(L)1 inhibitors in head and neck cancer: Role of immunotherapy rechallenge.
Authors: Cabezas-Camarero Santiago , Pérez-Segura Pedro 
Published: July 2019

69 Background: Immunotherapy (IO) has shown to improve survival in recurrent or metastatic (R/M) squamous cell cancer of the head and neck (SCCHN) with a better toxicity profile than chemotherapy (CT). An increased objective response rate (ORR) to CT has been shown after PD(L)1 blockade in SCCHN and other solid tumors. However, there are no data regarding the safety and efficacy of PD(L)1 rechallenge in SCCHN. Methods: Retrospective study of patients with R/M SCCHN treated with PD-1 inhibitors after an overt clinical and radiological progression to PD(L)1 blockade. Post-IO CT regimens, overall survival (OS), objective response rates (ORR) and percentage of tumor reduction (PTR) with post-IO CT and toxicity of IO rechallenge were recorded. Results: Eight patients treated between October 2016 and October 2018, were included. All patients received the first IO (1st-IO) treatment within clinical trials (anti-PDL1: 7; anti-PD1: 1), and received rescue cetuximab-based CT at progression (PD) (ERBITAX: 7; EXTREME: 1). ORR to post-IO 1st rescue CT (1RCT): 7 partial responses (PR), 1 stable disease (SD). PTR to 1RCT (median): 45% (range: 40-80). All second IO (2nd-IO) treatments consisted of PD1 inhibitors (nivolumab) and 6 received rescue CT (2RCT) at PD (ERBITAX: 1; wkCDDP-Cetuximab: 2; EXTREME: 3). Only 1of 6 evaluable patients responded to 2nd-IO with 5 PD as best response. Median duration of 2nd-IO: 3 months (range: 1-6). ORR to 2RCT (5 evaluable): 4 PR, 1 PD. PTR to 2RCT (median): 30% (range: 30-80). No G3/4 toxicities were detected during 2nd-IO. Conclusions: No new safety signals were encountered during PD-1 blockade in patients with SCCHN previously treated with PD-(L)1 inhibitors. First and second IO treatments associated with increased response rates to subsequent CT compared with historical data. Clinical trials should try to address the optimal treatment sequence in the IO era.
Regulatory T cells mediate resistance to radiotherapy in head and neck squamous cell carcinoma.
Authors: Oweida Ayman , Darragh Laurel , Bhatia Shilpa , Raben David , Heasley Lynn , Nemenoff Raphael , Clambey Eric , Karam Sana 
Published: July 2019

70 Background: Head and neck tumors are highly enriched in regulatory T cells which dampen the response to radiotherapy by creating an immune-inhibitory microenvironment. We explored mechanisms of Treg infiltration and assessed their modulation by RT in murine models of HNSCC. Methods: Mechanisms of Treg infiltration were investigated in murine HNSCC tumors using whole genome sequencing and flow cytometry. Mice were treated with anti-CTLA-4, anti-CD-25 and/or anti-PD-L1 alone and in combination with RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T cell populations. Multiplex ELISA was performed for assessment of cytokines. RNA Sequencing was performed to interrogate mechanisms of response and resistance to treatment. Results: Treatment with anti-CD-25 concurrently with RT led to significant tumor growth delay, enhanced T cell cytotoxicity, decreased Tregs and improved survival. In contrast CTLA-4 blockade did not affect tumor growth or survival. Treg depletion induced an influx of CD8 and CD4 T cells when combined with RT. In addition, Treg depletion in combination with RT transformed myeloid populations decreasing M2 macrophages and MDSCs and increasing M1 macrophages. Mechanistically, tumors secrete CCL20, a potent Treg chemoattractant responsible for creating a highly immunuosuppressive tumor microenvironment and potentially responsible for treatment resistance. Conclusions: These data reveal a critical role for regulatory T cells in mediating resistance to RT. Targeted depletion of Tregs represents an important mechanism of sensitizing tumors to RT. Our data support the design of clinical trials integrating targeted Treg inhibitors in the standard of care for cancer patients receiving RT.
Clinical practice guidelines: Machine learning and natural language processing for automating the rapid identification and annotation of new evidence.
Authors: Whittington Craig , Feinman Todd , Zelman Lewis Sandra , Lieberman Greg , del Aguila Michael 
Published: July 2019

77 Background: In February 2018, ASCO published a guideline on how clinicians should manage immune-related adverse events (irAEs) in cancer patients treated with immune checkpoint inhibitors (ICPis). Recommendations were based on informal consensus due to a lack of "high-quality" evidence. Our objective was to determine whether DOC Search, a cloud-based AI search engine, could be used to rapidly determine if any new evidence matches the inclusion criteria of the guideline. Methods: PubMed, ASCO abstracts, and 85 RSS feeds were queried within DOC Search to identify publications since the guideline search was last conducted. DOC Search automatically includes comprehensive synonym lists for the search terms entered, and annotates co-occurring characteristics, interventions and outcomes. Results: Between 11/1/2017 and 10/31/2018, 1178 published references were identified (85.7% from PubMed, 13.8% from ASCO, and 0.5% from official RSS feeds). Title/abstract screening of a sample of the most recent articles indicated that 44% were relevant, and of these, 8% specifically reported research on the management of irAEs. Through automated term indexing of search results, some of the most frequently reported terms were melanoma, corticosteroids, and colitis (Table). Conclusions: DOC Search employs robust ontology mapping—including UMLS, ASCO’s proprietary toxonomy, and more—which obviated the need for complex search strings. The machine learning and natural language processing technology provided real-time analysis and automated term indexing of search results, improving our understanding of the rapidly changing evidence landscape. This analysis met the objective to use DOC Search for rapid identification and review of new published evidence for an existing guideline.[Table: see text]
Assessing community physician ability to identify and manage immune-mediated adverse events (imAEs) through online continuing medical education (CME).
Authors: Pender Lori Keys , Caracio Richard 
Published: July 2019

78 Background: Immune checkpoint inhibitors (ICIs) produce a wide variety of imAEs that differ dramatically from chemotherapy adverse events. This study assessed whether online CME activities improve the knowledge, competence, and confidence of community physicians across disciplines in guideline management of imAEs in patients receiving ICI therapy. Methods: Data from a series of online, CME-certified, educational activities consisting of case-based video discussion between expert faculty were analyzed to determine the efficacy of education among oncologists and other specialists regarding imAE recognition, management, and referral. Three multiple-choice knowledge/competence questions and 1 confidence question were presented to learners before and immediately after each activity. A pre-/post-assessment study design was used. Chi-square tests assessed educational effect for each activity. The activities launched online in March 2018. Data were collected through July 15, 2018. Results: Over 18,000 community physicians completed the assessment questions and were included in the study. Results are summarized by discipline in the table. Conclusions: This study demonstrates the success of online, case-based video discussions on improving knowledge, competence, and confidence of community-based specialists related to diagnosis and management of imAEs among patients who are receiving ICI-based therapy. [Table: see text]