tbuckley/cabot-search huggingface dataset:
Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children with relapsed ALL.
Authors: Shannon L. Maude, David Maxwell Barrett, Susan R. Rheingold, Richard Aplenc, David T. Teachey, Colleen Callahan, Pamela A Shaw, Jennifer Brogdon, Regina Young, John Scholler, Katherine Marcucci, Irina Kulikovskaya, Farzana Nazimuddin, Zhaohui Zheng, Bruce Levine, David L. Porter, Simon F. Lacey, Jan Joseph Melenhorst, Carl H. June, Stephan A. Grupp
Journal: Journal of Clinical Oncology (2016)

3007 Background: Targeted immunotherapy with CTL019, CD19-specific CAR-modified T cells, can produce potent, sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). However, a subset of patients has limited persistence. We now report on retreatment with murine (CTL019) or humanized (CTL119) CD19-directed CAR T cells. Methods: Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding a CAR with CD3z, 4-1BB, and murine or humanized anti-CD19 scFv domains and activated/expanded with anti-CD3/CD28 beads. Results: Of 55 patients in CR at 1 month after CTL019 infusion (55/59 CR), 3 patients received a repeat infusion of murine CTL019 for CD19+ relapse and 17 for poor persistence at 3 and/or 6 months after initial infusion. Remission was achieved in 1/3 children treated for CD19+ relapse. Of 3 patients reinfused for CD19+ MRD, 1 progressed to CD19+ relapse, 1 became MRD- but had B cell recovery, and 1 had reduced MRD. Reinfusion induced B cell aplasia for a second time in 1/7 children treated for B cell recovery, while 6/7 children reinfused for CD19+ hematogones demonstrated continued B cell aplasia 6-21 months after repeat infusion. Of this group, 6 remained in remission 9-24 months after initial infusion, and 1 experienced a CD19- relapse. Eight children previously treated with CAR T cells (CTL019, n = 5; other, n = 3) were treated on a phase 1 study of humanized CTL119 for B cell recovery (n = 3), CD19+ relapse (n = 4), or no response to prior CAR T cells (n = 1). Cytokine release syndrome (CRS), seen in 4 patients, did not require vasopressor or respiratory support. Responses were seen in 4/8 patients with an ongoing CR of 7 months in 1 patient. 2/4 responding patients were previously resistant to reinfusion of murine CTL019. Conclusions: Reinfusion of murine CTL019 may prolong B cell aplasia in patients with early evidence of poor persistence but is less effective for B cell recovery, suggesting that examination of anti-CAR immune responses will be important to improve durable remission rates. Human CARs may overcome anti-murine immunity, and in the first study of a humanized anti-CD19 CAR, CTL119 induced remission in 50% of patients refractory to murine CAR T cells. Clinical trial information: NCT02374333.
TCT-872 Quantitative Flow RatIo in Myocardial Infarction for the Evaluation of Non-Infart Related Arteries: The QIMERA Pilot Study
Authors: Carlos Cortes, Silvio Vera, Pablo Catala, Hipolito Gutierrez, Roman Arnold, Williams Hinojosa, Itziar Gomez, Manuel Carrasco, Juan Luis Gutiérrez-Chico, Ignacio Amat-Santos
Journal: Journal of the American College of Cardiology (2018)
TCT-182 Outlook of patients undergoing transcatheter aortic valve implantation after prior balloon aortic valvuloplasty: insights from the multicenter RISPEVA trial
Authors: Arturo Giordano, Nicola Corcione, Paolo Ferraro, Francesco Bedogni, Gennaro Sardella, Fabrizio Tomai, Alessandro Iadanza, Giuseppe Biondi-Zoccai
Journal: Journal of the American College of Cardiology (2018)
Plasma androgen receptor <i>(</i>p<i>AR</i>) status and activity of taxanes in metastatic castration resistant prostate cancer (mCRPC).
Authors: Vincenza Conteduca, Anuradha Jayaram, Nuria Romero-Laorden, Daniel Wetterskog, Samanta Salvi, Giorgia Gurioli, Emanuela Scarpi, Elena Castro, Mercedes Marin, Cristian Lolli, Giuseppe Schepisi, Anna Wingate, Ana Medina, Giuseppe Fornarini, Umberto Basso, Begona Mellado, Enrique Gonzalez-Billalabeitia, David Olmos, Gerhardt Attard, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2018)

5074 Background: Plasma AR (pAR) gain identifies CRPC with worse outcome on abiraterone (abi) or enzalutamide (enza). We aimed to evaluate whether taxanes in CRPC are active regardless of AR status Methods: Between May 2011 and June 2017, pretherapy plasma samples were collected from 115 evaluable patients (pts) prior to abi/enza-naïve docetaxel (doce) and 130 prior to cabazitaxel (caba) in biomarker protocols at 19 different Institutions. We used droplet digital PCR to assess pAR copy number (CN). Primary objective was to evaluate associations of pAR gain with treatment outcome. In addition, after incorporating updated data from our prior study of 73 chemotherapy-naïve abi/enza pts, we also investigated if pAR could have a differential impact on taxanes compared with abi/enza pts. Both taxanes were administered at standard or reduced-dose at the discretion of treating physician Results: We observed AR gain in 32 (27.8%) doce pts. No differences were observed in OS/PFS (HR 1.2 95%CI 0.74-1.96 p = 0.45; HR 0.77 95%CI 0.51-1.17 p = 0.21 respectively) or PSA decline ≥50% (OR 1.0 95%CI 0.99-1.0 p = 0.75). A significant interaction was observed between pAR and doce vs abi/enza for OS (p = 0.003) and PFS (p = 0.013). In addition, we showed AR gain in 24 (37.5%) caba pts and confirmed no association of AR status with OS/PFS/PSA response. As an exploratory analysis, we reported in AR gained pts treated with initial reduced dose of taxanes a meaningful shorter OS (HR 2.15 95%CI 1.13-4.06 p = 0.019) in doce pts and a trend toward a worse OS in caba pts (HR 1.67 95%CI 0.94-2.95 p = 0.079). Multivariable analysis, adjusting for AR CN, LDH, alkaline phosphatase, hemoglobin, PSA, sites of metastasis, age, showed only liver metastasis as an independent predictor of OS in doce and caba pts (HR 2.78 95%CI 1.13-6.85 p = 0.026; HR 6.6195%CI 1.65-26.56 p = 0.008 respectively). Conclusions: pAR gained pts do not have a worse outcome when treated with taxanes when compared to pAR normal pts. This contrasts with a significantly worse outcome for pAR gained compared to pAR normal when treated with abi or enza and introduce the opportunity to use pAR status to select for doce vs abi/enza in mCRPC. Prospective evaluation in a randomized trial is warranted
Current and Innovative Pharmacological Options to Treat Typical and Atypical Trigeminal Neuralgia
Authors: G. Di Stefano, A. Truini, G. Cruccu
Journal: Drugs (2018)

Trigeminal neuralgia is a representative neuropathic facial pain condition, characterised by unilateral paroxysmal pain in the distribution territory of one or more divisions of the trigeminal nerve, triggered by innocuous stimuli. A subgroup of patients with trigeminal neuralgia [TN (previously defined as atypical TN)] also suffer from concomitant continuous pain, i.e. a background pain between the paroxysmal attacks. The aim of this review is to provide current, evidence-based, knowledge about the pharmacological treatment of typical and atypical TN, with a specific focus on drugs in development. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), taking into account publications up to February 2018. Two authors independently selected studies for inclusions, data extraction, and bias assessment. Carbamazepine and oxcarbazepine are the first-choice drugs for paroxysmal pain. When sodium channel blockers cannot reach full dosage because of side effects, an add-on treatment with lamotrigine or baclofen should be considered. In patients with atypical TN, both gabapentin and antidepressants are expected to be efficacious and should be tried as an add-on to oxcarbazepine or carbamazepine. Although carbamazepine and oxcarbazepine are effective in virtually the totality of patients, they are responsible for side effects causing withdrawal from treatment in an important percentage of cases. A new, better tolerated, Nav1.7 selective state-dependent, sodium channel blocker (vixotrigine) is under development. Future trials testing the effect of combination therapy in patients with TN are needed, especially in patients with concomitant continuous pain and in TN secondary to multiple sclerosis.
Re-visiting <i>EGFR</i> amplification as a target for anti-EGFR therapy: Analysis of cell-free circulating tumor DNA in patients with diverse cancers.
Authors: Shumei Kato, Ryosuke Okamura, Manvita Mareboina, Suzanna Lee, Aaron Goodman, Sandip Pravin Patel, Paul T. Fanta, Richard B. Schwab, Jason K. Sicklick, Victoria M. Raymond, Richard B. Lanman, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2018)

12028 Background: To date, evidence for tissue EGFR amplification (amp)/overexpression as a biomarker for anti-EGFR efficacy has been weak. We investigated the relationship between elevated EGFR copy numbers in cell-free circulating tumor DNA (cfDNA) and the role of anti-EGFR drugs in achieving response. Methods: We evaluated EGFR amp status amongst 1,435 patients with diverse cancers using clinical-grade next generation sequencing (NGS) of cfDNA (Guardant Health) (detects single nucleotide variants [54-73 genes], amp, fusions and indels in selected genes) and analyzed treatments used (NCT02478931). Results: Overall, 6.0% of patients (86/1,435) had EGFR amp on initial cfDNA evaluation (copy numbers, 1+: 2.13-2.39 [N = 40], 2+: 2.40-3.99 [N = 40], 3+: > 4.00 [N = 6]). EGFR amp was most frequent among small cell lung (30.0% [3/10]), breast (11.9% [13/109]) and colorectal cancer (11.0% [14/127]). All patients had co-existing alterations, most commonly in other tyrosine kinase family genes (70.9% [61/86]), MAPK signaling pathway (59.3% [51/86]) or cell cycle-associated genes (53.5% [46/86]). Nine evaluable patients with EGFR amp were treated with anti-EGFR-based regimens. Fifty-six percent (5/9) achieved partial responses, including 2 patients treated with dual anti-EGFR agents (small molecule inhibitor plus antibody) (adenocarcinoma of unknown primary [-44%, 4 months] and gastroesophageal cancer [-70%, 17+ months]. Responses were seen across different degrees of EGFR amp (1+ [N = 1], 2+ [N = 2], 3+ [N = 2]) and included patients with colorectal cancer. Two of 5 responders had tissue NGS showing EGFR amp; 1 of 3 non-responders with tissue NGS showed EGFR amp. Two-month landmark analysis showed median PFS of 3.9 versus 0.57 months among responders versus non-responders (P = 0.11); overall survival, 4.8 versus 0.6 months (P = 0.04). Conclusions: EGFR amp was detected in cfDNA among 6.0% of diverse cancers. Most patients had co-existing alterations. Responses were observed in 5 of 9 patients who received EGFR inhibitors, including 3 who were negative for EGFR amp in tissue. Incorporating EGFR inhibitors in regimens given to patients with EGFR amp in cfDNA merits further study. Clinical trial information: NCT02478931.
Activity of CAR19 T cells secreting ​impact fusion proteins against hematopoietic and solid tumors.
Authors: Fay Dufort, Lihe Su, Lan Wu, Alyssa Birt, Roy Lobb, Christine Ambrose, Paul Rennert
Journal: Journal of Clinical Oncology (2018)

e15046 Background: CAR T cells targeting CD19 (CAR19s) can eradicate B cell leukemias and lymphomas. We have engineered CAR19s to secrete a wide variety of retargeting fusion proteins (FP) by encoding expression cassettes downstream of the CAR sequence in lentiviral vectors. The FP consist of the CD19 extracellular domain linked to one or more scFvs. The FP redirect CAR19 T cell cytotoxic activity to any tumor antigen of interest by coating that antigen with CD19 via the scFv. Further, multiple antigens can be coated with CD19 by using bi-specific FP (bi-FP) formats. Therefore, CAR19s serve as a platform to target diverse antigens. Methods: A lentiviral vector with an MSCV promoter was used to express a CAR19 construct and FP. The FP and bi-FP were designed to encode the extracellular domain of the CD19 protein, followed by one or two scFv sequences, separated from the CAR sequence by a P2A cleavage site, a design termed IMPACT (Integrated Modular Proteins for Adoptive Cell Therapy). Results: The CD19/anti-Her2 FP was highly potent in cytotoxicity assays targeting Her2+/CD19- solid tumor cell lines. The concentration of fusion protein required to reduce tumor cell number by 50% was 10 pM (0.7 ng/ml). Primary donor T cells transduced with the IMPACT vector encoding the CAR19 domain and the CD19/anti-Her2 FP secreted > 20 ng/ml of FP in cell culture. Cytotoxic activity of this redirected CAR19 against Her2+ SKOV3 tumor cells was demonstrated in vitro and in vivo. Normal B cells promoted persistence. A CAR19-CD19/anti-CD20 FP specifically killed malignant B cells expressing CD19, CD19 and CD20, or CD20 alone. A bi-specific FP containing CD19 linked to anti-Her2 and anti-EGFR scFv had specific activity against both antigens with a potency of 0.75 pM. In each example, the potent cytotoxicity was specifically mediated by the secreted fusion protein. Conclusions: The IMPACT platform addresses critical issues in cell therapy including CAR persistence, antigen escape and antigen heterogeneity, and provides important solutions for treating both hematologic and solid tumors. The potency of redirected cytotoxicity supports clinical development of CAR19/IMPACT programs.
A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER).
Authors: Toni K. Choueiri, Andrea B. Apolo, Thomas Powles, Bernard Escudier, Osvaldo Rudy Aren, Amishi Shah, Elizabeth Riley Kessler, James J Hsieh, Joshua Zhang, Burcin Simsek, Christian Scheffold, Robert J. Motzer
Journal: Journal of Clinical Oncology (2018)

TPS4598 Background: Over the past decade, treatment options for advanced RCC have evolved to include multiple agents targeting the vascular endothelial growth factor (VEGF) pathway. In addition, the recent innovation of treating cancer with immunotherapy has further expanded the therapeutic armamentarium. Biomarker studies suggest that promotion of an immune suppressive tumor microenvironment can contribute to anti-VEGF therapy resistance and point to a rationale for combining anti-VEGF therapy with immunotherapy. Cabozantinib, a tyrosine kinase inhibitor with targets including VEGF receptor, MET and the TAM receptor family has shown immunomodulatory properties suggestive of synergistic effects with immune checkpoint inhibitors. Indeed, in a recent phase 1 study, combination of the programmed death-1 (PD-1) inhibitor nivolumab with cabozantinib showed encouraging antitumor activity in pretreated patients with metastatic RCC and other advanced genitourinary tumors (Nadal et al. ASCO GU 2018). This phase 3 study will assess nivolumab plus cabozantinib vs sunitinib in previously untreated patients with advanced or metastatic RCC (NCT03141177). Methods: Key inclusion criteria: Measurable disease with a clear-cell component, no prior systemic therapy for RCC, evaluable tumor biopsy, and age ≥18 years. Key exclusion criteria: Active CNS metastases and autoimmune disease. Patients will be randomized 1:1 to either nivolumab plus cabozantinib or sunitinib. Treatment will continue until disease progression or unacceptable toxicity (maximum nivolumab treatment of 2 years). Stratification factors: International Metastatic RCC Database Consortium (IMDC) risk score, PD-1 ligand 1 (PD-L1) tumor expression, and geographic region. Primary endpoint: Progression-free survival by blinded independent central review (BICR) in all randomized patients; secondary endpoints: Overall survival and objective response rate by BICR in all randomized patients, and safety/tolerability in all treated patients. Enrollment began August 2017 with a target of 580 randomized patients. Clinical trial information: NCT03141177.
The value of inflammatory markers in predicting overall survival in older adults with cancer.
Authors: Tomohiro F. Nishijima, Allison Mary Deal, Jennifer Leigh Lund, Kirsten A Nyrop, Hyman B. Muss, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2018)

10032 Background: The widely studied inflammatory markers, neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR) and lymphocyte monocyte ratio (LMR), are associated with survival outcomes in patients with various cancers. However, little is known about the value of these markers in older cancer patients, especially in relation to traditional prognostic factors, such as age and Karnofsky Performance Status (KPS), and a geriatric assessment (GA) derived scale that is predictive of overall survival (OS) [Nishijima, J Geriatr Oncol. in press]. Methods: Our sample includes 144 patients age ≥ 65 years with solid tumor (Carolina Senior Registry NCT01137825) who completed a GA within 3 months of their date of diagnosis in 2010 - 2014 and had pretreatment CBC with differential. Patients were followed for death from any cause for a median of 2.5 years, during which 54 patients died. NLR was dichotomized at the upper limit of normal 3.5 [Forget, BMC Res Notes 2017] while PLR and LMR were dichotomized at the median. The 3-item GA-derived prognostic scale (score ranging 0-3) consisted of (1)
A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation.
Authors: Mallika Lala, Mengyao Li, Vikram Sinha, Dinesh de Alwis, Elliot Chartash, Lokesh Jain
Journal: Journal of Clinical Oncology (2018)

3062 Background: Pembrolizumab is currently approved for use in multiple cancer indications at a dose of either 200 mg or 2 mg/kg Q3W. An alternative extended dosing regimen would provide convenience and flexibility to patients and prescribers. Robust characterization of pembrolizumab pharmacokinetics (PK) and E-R relationships for efficacy and safety allow the use of model-based approaches to support alternative dosing regimens. Methods: The dose for a Q6W schedule was selected by matching exposures with the approved Q3W (200 mg and 2 mg/kg) regimens; efficacy and safety are bridged based on E-R assessments. Exposures were simulated using the established population PK model of pembrolizumab that adequately described PK across multiple tumor types. Regimens are compared on - A) Exposure metrics at steady state: AUCss or time-averaged concentration (Cavg,ss) and trough concentrations (Cmin,ss); B) Predicted clinical endpoints (e.g., objective response rate) in patients with multiple approved tumor types. Safety at the Q6W schedule is bridged by ensuring predicted peak concentrations at steady state (Cmax,ss) are below those at the maximum clinically administered and well-tolerated dose of 10 mg/kg Q2W. Results: The 400 mg Q6W dosing regimen had similar predicted exposures (Cavg,ss or AUCss, geometric mean (GM) ~1% higher) compared to those achieved at 200 mg Q3W. Less than 1% subjects had Cmin,ss lower than that for 200 mg Q3W. The GM of predicted Cmax,ss for 400 mg Q6W was ~65% lower than for 10 mg/kg Q2W. Given the similar exposures and established E-R relationships for pembrolizumab over a 5-fold range of clinically tested doses, the clinical outcomes achieved with 400 mg Q6W are predicted to be similar as with 200 mg Q3W across tumor types. Conclusions: A 400 mg Q6W dosing regimen of pembrolizumab leads to exposures that are similar to the approved 200 mg Q3W dosing regimen. Based on the robust understanding of pembrolizumab clinical pharmacology, including well-established E-R profiles, such a less frequent dosing regimen is expected to produce similar efficacy, safety, and benefit-risk profile in all clinical treatment settings where 200 mg Q3W pembrolizumab is currently approved.
A randomized phase II study of vemurafenib plus cobimetinib continuous versus intermittent in previously untreated BRAF V600-mutation positive patients with unresectable locally advanced or metastatic melanoma.
Authors: Jose A. Lopez-Martin, Alfonso Berrocal, María González-Cao
Journal: Journal of Clinical Oncology (2017)

TPS9599 Background: Previous clinical trials have shown that vemurafenib significantly increases PFS and OS in untreated BRAFV600 mutant advanced melanoma patients. Nevertheless, disease progression occurs after a median of 6-7 months since start of vemurafenib. Several mechanisms of acquired resistance to vemurafenib result in reactivation of MAPK pathway. Upfront addition of a MEK inhibitor (MEKi) to vemurafenib delays secondary resistance to BRAFi. The combination of cobimetinib, a MEKi, plus vemurafenib as a continuous administration was approved by FDA in 2,015 in untreated metastatic BRAFV600 advanced melanoma patients based on an increase in PFS and OS achieved in a phase III trial (coBRIM trial). Preclinical models have shown that continuous vemurafenib dosing promotes the clonal expansion of drug-resistant cells, and intermittent dosing could serve to eliminate the fitness advantage of the resistant cells and delay the onset of drug-resistant disease (Das Thakur, Nature 2013). These observations and some clinical case reports support upfront evaluation of alternative dosing regimens of MAPK pathway inhibition. Methods: This is a randomized phase II study to explore the efficacy and safety of two schedules of administration of vemurafenib in combination with cobimetinib (continuous – 28-day cycles with vemurafenib 960 mg PO BID, Days 1-28, and cobimetinib 60 mg PO QD, Days 1-21 – and intermittent – same dose/schedule during first 12 weeks, and then, same doses with the following schedule: vemurafenib 4 weeks on /2 weeks off, and cobimetinib 3 weeks on/ 3 weeks off), in patients with untreated, BRAFV600 mutated, unresectable, measurable (RECIST 1.1), locally advanced or metastatic melanoma. Prior adjuvant immunotherapy is allowed. Primary endpoint is PFS. Secondary endpoints include: OS, ORR, pharmacokinetic and pharmacodynamic profiles and safety. Additional translational research to analyze predictive factors and mechanism of resistance will be explored. The trial is in progress; 56 of up to 116 planned pts have been recruited at the end of December 2016 (enrollment started in June 2015). Clinical trial information: NCT02583516.
Flt3L-based in situ vaccination for the treatment of lymphoma.
Authors: Linda Hammerich, Joshua Brody
Journal: Journal of Clinical Oncology (2016)

e19040 Background: Low-grade B-cell lymphomas are generally incurable, with standard therapies inducing only temporary remissions. Tumor-targeted vaccines represent promising, novel treatment strategies. In a pre-clinical mouse model, we attempt to develop and optimize an in situ vaccine combining recruitment of dendritic cells (DC) and low-dose local radiotherapy (XRT) with intratumoral (i.t) administration of a toll-like receptor (TLR) agonist. Methods: A20 lymphoma-bearing mice were injected i.t. with Flt3L for 9 days, followed by local XRT (9Gy) and i.t. poly-ICLC for 5 days. Tumors, lymph nodes, and spleens were analyzed by flow cytometry and animals were monitored for tumor growth and survival. Results: Injection of Flt3L induced potent accumulation of DC at the tumor site, tumor-draining lymph node (TDLN) and the spleen, with intratumoral injection being superior to systemic injection in increasing intratumoral and TDLN DCs (Figure 1B). Local XRT increased the amount of mCherry+ DC in the tumor, indicating increased uptake of dying tumor cells (Figure 1C). While combination of FLt3L and local XRT was not able to cure established tumors, the combination of Flt3L and XRT with poly-ICLC induced long-lasting tumor regression in 40% of mice (Figure 1D) as well as regression of untreated tumors. Combination of i.t. GM-CSF with Flt3L increased the number of migratory CD103+/TLR3+ and IRF8+/TLR3+ (CD103 precursors) DC in spleen and tumor. Consistently, GM-CSF injection enhanced the efficacy of the Flt3L-primed in situ vaccine leading to complete tumor regression at the treated site and a significant survival benefit compared to the in situ vaccine without GM-CSF. Conclusions: In situ vaccination combining intratumoral Flt3L/GM-CSF injection with local XRT and poly-ICLC induces a potent anti-tumor immune response able to induce long-term regression of established lymphoma tumors.