tbuckley/cabot-search huggingface dataset:
Characterization of anti-CD19 chimeric antigen receptor (CAR) T cell-mediated tumor microenvironment immune gene profile in a multicenter trial (ZUMA-1) with axicabtagene ciloleucel (axi-cel, KTE-C19).
Authors: Jerome Galon, John Rossi, Sarah Turcan, Corinne Danan, Frederick Lundry Locke, Sattva Swarup Neelapu, David Bernard Miklos, Nancy L. Bartlett, Caron Alyce Jacobson, Ira Braunschweig, Olalekan O. Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Patrick Michael Reagan, Lazaros J. Lekakis, Sherryonne Unabia, William Y. Go, Jeffrey S. Wiezorek, Adrian Bot
Journal: Journal of Clinical Oncology (2017)

3025 Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log 2 fold change &gt; 2, P&lt; 0.05, FDR &lt; 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log 2 fold change &gt; 1.6, P&lt; 0.05, FDR &lt; 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log 2 fold change &gt; 1.6; P&lt; 0.05, FDR &lt; 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.
Interrogating resistance mechanisms to PD-1 blockade therapy with CRISPR.
Authors: Davis Yuri Torrejon, Jesse Meir Zaretsky, Daniel Sanghoon Shin, Mykola Onyshchenko, Gabriel Abril-Rodriguez, Agustin Vega-Crespo, Cristina Puig-Saus, Gardenia Cheung-Lau, Chris Long, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
Journal: Journal of Clinical Oncology (2017)

3077 Background: We tested the biological significance of the loss of function (LOF) mutations in JAK1 or JAK2 within the IFN-receptor-pathway and in beta-2-microglobulin (B2M), which had been found in patient biopsies with resistance to anti-PD-1 therapy. Methods: We used CRISPR/Cas9 genome editing to generate JAK1, JAK2 and B2M knockout (KO) sublines of HLA-A*02:01 MART-1 or NY-ESO-1 positive human melanoma cell lines, tested using in-vitro T cell co-culture systems and in a syngeneic mouse model (MC38) to analyze the in-vivo antitumor activity with anti-PD1 therapy. Results: The JAK2-KO cell line was insensitive to IFN-gamma induced signaling and growth arrest (p &lt; 0.001 compared with IFN-alpha or beta), while the JAK1-KO cell line was insensitive to all three IFNs. Baseline MHC class I expression after JAK1-KO was unaffected (baseline-MFI 1230 JAK1-KO vs 1570 parental, p = 0.66), but the magnitude of change was lower upon IFN-gamma exposure compared to the parental (MFI change with IFN-gamma, 26% decrease for JAK1-KO vs 50% increase for parental). There was no difference in in-vitro cytotoxicity by NY-ESO-1-TCR transgenic T-cells against JAK1-KO-NY-ESO-1+ melanoma cells compared to the parental (78% vs 82% cytotoxicity at 10:1 E:T ratio, p NS). However, B2M-KO was resistant to killing by MART-1 specific T-cells (2% vs 96% cytotoxicity at 10:1 E:T ratio, p &lt; 0.0001). On the other hand, in the MC38 model the significant antitumor activity of anti-PD-1 against the wild type cells was lost in both JAK2-KO and B2M-KO. The percentage of CD8+ T cells has a trend of increase with anti-PD1 compared to untreated in the MC38 wild type (p = 0.1 d12), and a trend of decrease in MC38 B2M-KO (p = 0.2 d12), but no change in JAK2-KO tumors (p = 0.7 d12). Conclusions: JAK1/2 LOF mutations result in insensitivity to IFN induced antitumor effects, but does not impair T cell recognition and cytotoxicity, while B2M LOF results in lack of antigen presentation to T cells and loss of antitumor activity. However both lead to in-vivo resistance to anti-PD-1 therapy, suggesting they do so by independent mechanisms.
Genetic aberrations related to increased risks of brain metastasis in non-small cell lung cancer (GASTO-1036).
Authors: Delan Li, Tao Qin, Qiuxiang Ou, Xue Hou, Kaicheng Wang, Xinru Chen, Shuxiang Ma, Hua Bao, Xue Wu, Xiaonan Wang, Yang Shao, Yonggao Mou, Likun Chen
Journal: Journal of Clinical Oncology (2018)

9092 Background: Metastatic cancer to the brain has a poor prognosis and subject patients to limited therapeutic options. Lung cancer represents the most common primary tumor giving rise to brain metastasis (BM). Understanding molecular alterations that are associated with increased risks of BM is of great importance to develop more effective intervention and therapeutic strategies for patients. Methods: Sixty-one non-small cell lung cancer (NSCLC) patients who underwent surgery for BM removal between 2000 and 2016 were retrospectively studied. Twenty-five patients had synchronous brain metastatic tumors at diagnosis, while the rest had metachronous presentation of BM during the course of their disease progression. We performed mutation profiling using targeted next-generation sequencing for 416 cancer-relevant genes on resected FFPE tumor samples of both lung and brain lesions of these patients. BM-free survival and disease-free survival were assessed in the metachronous cohort by using Kaplan-Meier test and Cox regression model. Results: Mutations of oncogenes and tumor suppressors, such as EGFR, TP53, KRAS, PIK3CA, and gene fusions (ALK and RET), were identified in a total of 85% (52/61) of the patients, which were highly concordant between BM and primary lung tumors, albeit discordance was also observed suggesting a unique genetic evolution. Mutations targeting CDKs/CDK inhibitors, PI3K pathway, MET and ERBB2 are more enriched in the metastatic brain foci than the primary lung tumor, suggesting the association of those genes with increased risks of developing BM. Indeed, patients with activated PI3K pathway were found to have significantly shorter BM-free survival (hazard ratio = 8.77, p < 0.001) as well as shorter disease-free survival (hazard ratio = 7.43, p < 0.001). In addition, activation of WNT pathway, in particular, missense mutations of CTNNB1, also tends to be associated with higher risks for disease spread and developing BM from NSCLC. Conclusions: Our findings shed lights on genetic concordance and divergence of primary lung and brain metastatic tumors, and also show that activated PI3K and WNT pathways are significantly associated with increased risks of brain metastasis in NSCLC.
P05.52 The phenomenon of pseudoprogression in diffuse astrocytic and oligodendroglial tumors (grade II-III),treated with photon beam radiotherapy and temozolamide. Report of a single institution
Authors: E Fotopoulou, G Soulimioti, A Theodoridou, S Tzorakakis, E Athanasiou
Journal: Neuro-Oncology (2018)

Pseudoprogressive disease (PsPD) after brain tumor treatment is a phenomenon that affects overall approach of patients in an uncertain way. Radiologically pseudoprogression is defined as emerging or enlarging area(s) of contrast agent enhancement, without measurable tumor growth, which diminishes or stabilizes without alterations to treatment schedule. of the study is to report the incidence of radiological proven pseudoprogression in grade II-III diffuse astrocytic and oligodendroglial tumors after treatment of radiation therapy and temozolamide in our department and the impact on treatment strategy Between 2009 and 2017 seventeen patients age >18 years with grade II-III diffuse astrocytic and oligodendroglial tumors (histologically proven) were treated with photon beam (3D-conformal) radiation therapy and temozolamide. Clinical and imaging (MRI) data were reviewed. Among them 9 patients had anaplastic astrocytoma grade III, 3 patients anaplastic oligodendroglioma grade III, 3 patients with oligodendroglioma grade II, 2 patients with grade II diffuse gliomas. Pseudoprogression was defined as a new enhancing lesion occurring after RT and subsequently disappearing or remaining stable for at least one year without therapy, or dexamethasone. All patients received RT and temozolamide. The prescribed dose was 60Gy with 2Gy per/fraction for high grade gliomas (grade III) and 45-54Gy with 2Gy per/fraction for low grade gliomas (grade II). The median follow-up was 4 years (range 1‒9 y). Among patients, three patients (17.6%) presented pseudoprogression (two with anaplastic astrocytoma and one with anaplastic oligodendroglioma) and received no other oncological treatment or medication(dexamethasone) until proof of progressive disease. PsPD always occurred within the PTV that received 60G. In our cohort pseudo progression was observed among a small percentage of patients with grade III diffuse astrocytic and oligodendroglial tumors but not among patients with grade II tumors. The decision of new line treatment was postponed until conclusive evidence of progressive disease.
The outcome of high-grade B-cell lymphoma with <i>MYC</i> and <i>BCL2</i> and/or <i>BCL6</i> rearrangements or NOS compared to DLBCL patients from a single institution.
Authors: Joanna Romejko-Jarosinska, Grzegorz Rymkiewicz, Katarzyna Domanska-Czyz, Katarzyna Blachnio, Ewa Paszkiewicz-Kozik, Michal Osowiecki, Beata Ostrowska, Beata Grygalewicz, Renata Woroniecka, Agnieszka Druzd-Sitek, Anna P. Dabrowska-Iwanicka, Martyna Kotarska, Lukasz Targonski, Marcin Szymanski, Lidia Poplawska, Monika Prochorec-Sobieszek, Barbara Pienkowska-Grela, Jan Andrzej Walewski
Journal: Journal of Clinical Oncology (2017)

7560 Background: 2016 update of the WHO 2008 classification of lymphoid neoplasms introduced new categories of highly aggressive B lymphomas (BCL): high grade B lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (HGBLR) and HGBL not otherwise specified (NOS). The prognosis for HGBL is generally considered poor, the optimal therapy is unknown. Here we evaluated outcome after first line treatment in patients with a diagnosis of HGBLR, HGBL, NOS, and DLBCL at our institution. Methods: Medical records of 591 consecutive patients with aggressive BCL were evaluated, archived pathology reports and samples were reviewed, diagnosis revised if necessary according to 2016 update of WHO classification. We identified 16 cases of HGBLR (3%), 26 cases of HGBL, NOS (4%), and 565 cases of DLBCL (93%). Response to first line therapy, progression free survival (PFS), and overall survival (OS) were calculated and compared between these three entities. Results: DLBCL patients were treated with RCHOP between 2005-2012, HGBL patients were treated between 2005-2016 with RDAEPOCH (n = 31, 5%), RCHOP or other regimens. For the first line treatment in patients with DLBCL, HGBLR and HGBL NOS, the overall response/complete response rate was 92%/75%, 81%/56%, 93%/65%, respectively (p = NS). After a median (range) follow up of 42(1-155) months, median PFS and OS for DLBCL was not reached. For both HGBLR and HGLB, NOS patients median PFS was 10 months, median OS was 16 months. The HR for risk of progression in patients with HGBLR vs DLBCL and HGBL NOS vs DLBCL was 2.4 (1.1-4.7), p = 0.01 and 2.0 (1.1-3.5), p = 0.01. The HR for risk of death, for HGBLR vs DLBCL and HGLB NOS vs DLBCL was 2.59(1.32-5.07), p &lt; 0.01 and 1.8(0.9-3.3), p = 0.08. The risk of progression and the risk of death in HGBLR vs HGBL, NOS was similar, for PFS: 1.08 (0.46- 2.5), p = NS for OS: 1.2 (0.5 -3,1) p = NS. Conclusions: Our data confirms reports by others on poor prognosis for patients with a diagnosis of HGBL with MYC and BCL2 and/or BCL6 rearrangements as well as HGBL, NOS with an increased risk of death and risk of progression compared to DLBCL patients. There was no difference in outcome between HGBL-R and HGBL, NOS patients in our series.
A phase 1b dose escalation study to evaluate safety, tolerability and pharmacokinetics of oral monotherapy with KX2-391 in elderly subjects with acute myeloid leukemia who are refractory to or have declined standard induction therapy.
Authors: Margaret T. Kasner, Ellen K. Ritchie, David Cutler, Gerald J. Fetterly, Douglas Kramer, David Hangauer, James E. Thompson
Journal: Journal of Clinical Oncology (2017)

7043 Background: Treatment of elderly AML patients is complicated by poor tolerance to standard therapies and multi-drug resistance. It is imperative to explore novel agents which are tolerable and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerase. We conducted a phase I open-label safety and activity study in elderly subjects with AML who were refractory to or declined standard induction chemotherapy. Five dose levels were tested from 40 to 160 mg daily. Methods: 24 subjects were recruited from 3 institutions with an average age of 74 years (range 63-86). The majority had previously received HMAs. 1 subject was treated at 40 mg, 2 at 80 mg, 8 at 120 mg, 12 at 140 mg, and 1 at 160 mg. Of the 24 subjects enrolled, 7 (29%) were on treatment for 12 days or less; 9 (38%) from 15 to 29 days, 5 (21%) from 33 to 58 days and 3 (13%) from 77 to 165 days. One subject treated at 120 mg for 165 days had a reduction in splenomegaly from 16 cm to 4 cm BLCM, and survived 373 days. A second subject was treated at 120 mg for 154 days until disease progression. One subject was dosed at 160 mg for 12 days and remained treatment-free for about 18 months. Results: DLTs occurred in 8 subjects at: 120mg (AST/ALT, elevated bilirubin); 140 mg (Mucositis, Allergic Reaction, 2 elevated LFTs, acute kidney injury) and 160 mg (Mucositis). The most common (≥ 25%) treatment-related adverse events were nausea/vomiting; diarrhea; anorexia; fatigue/weakness; increase ALT/AST; hypokalemia; hypotension; febrile neutropenia; dyspnoea; abdominal pain; constipation; dizziness. The RPTD for KX2-391 is 120 mg given once daily. KX2-391 bone marrow concentrations are similar to the target IC50 of 142 ng/mL. Conclusions: This is the first study conducted to determine whether KX01 can be safely given to this high risk, frail AML patient population. The data from this study support proceeding with further studies including alternative dosing phase 1 studies (higher dose, shorter course followed by drug-free intervals) and phase 2 studies to assess efficacy. Clinical trial information: NCT01397799.
Phase 2 trial of the IDO pathway inhibitor indoximod plus checkpoint inhibition for the treatment of patients with advanced melanoma.
Authors: Yousef Zakharia, Olivier Rixe, John Harris Ward, Joseph J. Drabick, Montaser F. Shaheen, Mohammed M. Milhem, David Munn, Eugene Paul Kennedy, Nicholas N. Vahanian, Charles J. Link, Robert R. McWilliams
Journal: Journal of Clinical Oncology (2018)

9512 Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to prevent and evade anti-tumor immunity. Inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. Pre-clinical data and an increasing body of clinical data support evaluating the combination of a checkpoint inhibitor (CI) with an IDO pathway inhibitor as potential treatment for advanced melanoma. Methods: Advanced melanoma patients were enrolled in a single arm Phase 2 trial evaluating the addition of indoximod to standard of care CI as approved for melanoma. Prior therapy excluding CI was allowed. Investigators administered their choice of approved CI (pembrolizumab (P), nivolumab (N), ipilimumab (I). Indoximod was administered continuously (1200mg po BID), concurrent CI dosed per approved US label. Study endpoint was best overall response (overall response rate (ORR) = complete response (CR) + partial response (PR)) per site reported RECIST 1.1. Results: 102 patients were enrolled in Phase 2. 70 patients with unresectable stage III or IV cutaneous or mucosal melanoma were treated with P and had an on treatment imaging meeting the per protocol, pre-specified definition of evaluable for efficacy (EE). Additionally, 15 patients had uveal melanoma, 4 received I, 4 received N, and 1 was never treated. 8 patients came off study prior to the first on-treatment imaging study. The ORR for the EE population was 55.7% (39/70, 36 confirmed) with CR of 18.6% (13/70, all confirmed). Median PFS was 12.4 months (95% CI 9.0-NA). Archival tissue was available from 41 of 70 EE patients. The PD-L1 staining ≥ 1% was 54% (22/41). The combination was well tolerated and most common AEs regardless of attribution were fatigue, nausea, pruritus. An additional 21 patients have been enrolled to a biopsy cohort. Conclusions: The combination of indoximod and pembrolizumab demonstrates an ORR of 55.7%, CR 18.6% which compares favorably with reported ORR for P alone (33%). Updated data including biopsy cohort will be presented. Clinical trial information: NCT02073123.
Feasibility and benefit of molecularly-informed enrollment into early phase trials for patients with recurrent gliomas.
Authors: Capucine Baldini, Nadia Younan, Eduardo Castanon Alvarez, Sarah Naomie Dumont, Franck Bielle, Jean-Sebastien Frenel, Anna Luisa Di Stefano, Augusti Alentorn, Rastislav Bahleda, Andreea Varga, Guillaume Louvel, Antoine Hollebecque, Khe Hoang-Xuan, Jean-Yves Delattre, Frederic Dhermain, Marc Sanson, Jean-Charles Soria, Ahmed Idbaih, Christophe Massard, Mehdi Touat
Journal: Journal of Clinical Oncology (2018)

2004 Background: Recent reports showed that patients (pts) with recurrent glioma may be good candidates for early phase clinical trials (eaCTs), however clinical benefit is often limited to a small subset of pts in all-comers design trials. We aimed to evaluate whether selecting pts through tumor genotyping is associated with better outcome in this population. Methods: From 2008 to 2017, individual records of pts enrolled in eaCTs of cytotoxic therapies, small molecule inhibitors or immune checkpoint blockers were analyzed for clinical and histomolecular characteristics, toxicity, tumor response, and progression-free survival (PFS). The primary objective was to evaluate the feasibility and potential benefit of using tumor genotyping for guiding enrollment in eaCTs. Molecular screening methods included immunohistochemistry and PCR-based assays, array CGH, next-generation sequencing, and RNA sequencing. Results: Seventy pts were enrolled, of whom 41/70 (58.6%) patients were molecularly oriented. Therapeutic targets included FGFR mutations/fusions (n = 11), BRAF (7) and IDH (15) mutations, MDM2 amplification (1) and mismatch repair deficiency (7). In addition, 34 pts participated in the MOSCATO 01 and 02 precision medicine study (NCT01566019), which allowed the identification of potentially actionable targets in 12/34 (35%) pts, of whom 4/12 (33.3%) received a molecularly-informed therapy. Grade 3/4 adverse events were reported in 6/70 (8.6%) pts. In the subgroup of IDH1/2-wild type high-grade tumors, response rate and disease control rate were 16.7% (3/18) and 55.6% (10/18) respectively in pts who were molecularly oriented, versus 0% (0/14) and 31.5% (5/14) in molecularly-unselected pts. There was no statistically significant difference in median PFS between molecularly-oriented and -unselected pts (2.83 months [95% CI 1.3-4.6] vs. 1.54 months [1.05-2.85], P= 0.29). Conclusions: A subset of pts with recurrent glioma may benefit from incorporating tumor genotyping to guide their enrollment in eaCTs. Accelerating the use of prospective genomics could increase the percentage of pts who may benefit from this strategy.
Low molecular weight heparin (LMWH) use in patients with hematologic malignancy-associated venous thromboembolism (VTE) and severe thrombocytopenia.
Authors: Nabin Khanal, Gregory Bociek, Baojiang Chen, Julie Vose, James O. Armitage, Philip Jay Bierman, Lori J. Maness, Matthew Alexander Lunning, Krishna Gundabolu, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2016)

e21588 Background: We have previously demonstrated safety of prophylactic LMWH in patients with platelet count ≤ 50,000/µL (ASH abstract; Blood 2015;126(23):3482), however, the outcome in the subset of patients with platelet count < 10,000/µL is of particular interest. At our institution, patients generally receive prophylactic platelet transfusions for a platelet count < 10,000/µL. Methods: In this retrospective study, the risk of bleeding and clot recurrence was assessed among 24 patients with hematologic malignancy-associated VTE and platelet count < 10,000/µL. The patients were diagnosed between 1999 and 2014, and followed during the entire period of thrombocytopenia (median follow-up > 1 month). Results: Characteristics of the study population were as follow: median age of 52 years, 54% male, 33% non-Hodgkin lymphoma, 33% acute myeloid leukemia, 34% other diagnoses (such as Hodgkin lymphoma and acute lymphocytic leukemia) and 42% status-post hematopoietic cell transplant. Forty-two percent had upper extremity VTE, 38% had pulmonary embolism and 20% had VTE in lower extremity or other sites. Median nadir platelet count during a period of time of perceived need for new or continued anticoagulation was 7,000/µL (range 2,000-10,000/µL). Median duration of thrombocytopenia (platelet < 50,000/uL) was 14 days (range 5-31 days). Twenty patients (83%) received prophylactic or therapeutic dosing of LMWH or heparin. Two patients (8%) had clinically significant bleeding, and one patient (4%) had clot progression (Table). The results were comparable to the risk of clinically significant bleeding (6%) and clot progression (18%) in patients with hematologic malignancy-associated VTE and platelet count > 50,000/µL (n = 81). Conclusions: Within the limits of this retrospective study, prophylactic dosing of LMWH in severely thrombocytopenic patients with hematologic malignancy-associated VTE may be safe. LMWH use in patients with VTE and severe thrombocytopenia. LMWH Number of patients Clinically significant bleeding Clot progression Prophylactic dose 16 1 0 Therapeutic dose 4 1 1 None/ Observation 4 0 0