ALBERT

Description: The immunoproteasome (iP) has been proposed to perform specialized roles in MHC class I antigen presentation, cytokine modulation, and T cell differentiation and has emerged as a promising therapeutic target for autoimmune disorders and cancer. However, divergence in function between the iP and the constitutive proteasome (cP) has been unclear. A global peptide library-based screening strategy revealed that the proteasomes have overlapping but distinct substrate specificities. Differing iP specificity alters the quantity of production of certain MHC I epitopes but does not appear to be preferentially suited for antigen presentation. Furthermore, iP specificity was found to have likely arisen through genetic drift from the ancestral cP. Specificity differences were exploited to develop isoform-selective substrates. Cellular profiling using these substrates revealed that divergence in regulation of the iP balances its relative contribution to proteasome capacity in immune cells, resulting in selective recovery from inhibition. These findings have implications for iP-targeted therapeutic development.

Description: Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance.

Description: Recent clinical studies have identified the proteasome as an important therapeutic target for hematologic malignances. The proteasome inhibitor, bortezomib, has been approved for the treatment of relapsed or refractory multiple myeloma and ongoing clinical trials suggests a potential benefit for the treatment of Non-Hodgkin’s lymphoma. PR-171 is a novel epoxomicin derivative that is a potent and irreversible inhibitor of the human proteasome. It inhibits the chymotrypsin-like activity of purified human 20S proteasome with a kinact/Ki of 34,000 M−1s−1 and is 〉300-fold selective over the other proteasome catalytic activities. In addition, PR-171 has been found to exhibit minimal activity in a broad diversity panel of biochemical assays that includes 67 receptor/ligand and 37 enzyme assays. PR-171 retains its potency for inhibition of the proteasome chymotrypsin-like activity in mammalian cells displaying IC50 values

Description: Clinical studies using the boronic acid-based proteasome inhibitor bortezomib (VelcadeTM) have validated the proteasome as a therapeutic intervention point for the treatment of multiple myeloma and non-Hodgkin’s Lymphoma. Despite encouraging clinical response rates with this drug, significant toxicities, including neutropenia, thrombocytopenia and peripheral neuropathy have restricted the intensity of bortezomib dosing. PR-171 is a novel peptide epoxyketone inhibitor that selectively and irreversibly inhibits the chymotryptic subunit of the 20S proteasome. We have characterized the pharmacokinetics, pharmacodynamics and anti-tumor efficacy of PR-171 in rodents and non-human primates. PR-171 is rapidly cleared from the plasma compartment following intravenous bolus administration, with a terminal half-life in rats and monkeys of 15 and 7.2 min, respectively. Despite this rapid clearance, PR-171 administration results in a prolonged dose-dependent inhibition of the 20S proteasome in all tissues examined with the exception of brain. Single doses of PR-171 that are tolerated in mice, rats and monkeys result in greater than 90% inhibition of proteasome activity in blood and many tissues. Recovery of proteasome activity following exposure to PR-171 is dependent upon synthesis of new proteasome subunits and occurs with a t1/2 of ~ 24 hr in nucleated cells. Recovery of proteasome activity in erythrocytes is dependent upon red blood cell turnover and occurs more slowly in animals. The safety of PR-171 has been assessed in rodents using multiple dosing schedules including weekly, biweekly, daily and BID administration. In rats, daily administration of PR-171 at doses that resulted in 〉80% inhibition of proteasome activity in whole blood and selected tissues were well tolerated. Recovery of proteasome activity following repeated daily administrations was unchanged from that seen after a single dose. PR-171 was also well tolerated when administered daily to monkeys at equivalent doses on a body surface area comparison. A transient thrombocytopenia was noted in both rats and monkeys but neutrophil and lymphocyte counts were not decreased in response to PR-171 administration. PR-171 induced a significant anti-tumor response in beige-nu-xid (BNX) triple immunodeficient mice bearing established HS-Sultan Burkitt’s lymphoma tumors and in Balb/c mice challenged with A20 lymphoma cells. We have also demonstrated anti-tumor activity of PR-171 in several mouse models of solid tumors including syngeneic and human tumor xenograft models of colorectal cancer. These studies demonstrate the tolerability, anti-tumor activity and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies utilizing dose intensive schedules.

Description: The ubiquitin-proteasome pathway constitutes a major intracellular system for protein degradation. Substrates for this pathway include misfolded or unassembled proteins as well as short-lived regulatory proteins that play key roles in signaling and proliferative pathways. The majority of cell types express the standard, or “constitutive”, form of the proteasome, while cells of the immune system also express the immunoproteasome, a form of the proteasome that contributes to class I major histocompatibility complex restricted antigen processing. Non-immune cells can also express immunoproteasome in response to interferon gamma exposure. The immunoproteasome retains the same structural subunits as the constitutive proteasome but has three different catalytic subunits. The catalytic activities of both forms of the proteasome have been traditionally characterized with purified enzyme preparations and fluorogenic peptide substrates. Such fluorogenic peptide substrates suffer from two characteristics that limit their utility in measuring proteasome activities in complex cell or tissue lysates: 1) they cannot distinguish proteasome activities from other proteolytic activities within the lysate; and 2) they can not distinguish between constitutive and immunoproteasome activities. We have developed an ELISA-based proteasome-specific binding (PSB) assay that can detect and quantify the chymotryptic-like proteasome active sites of the beta-5 constitutive proteasome subunit and the LMP7 immunoproteasome subunit. The assay utilizes a biotin-modified peptide epoxyketone probe that covalently and irreversibly interacts with the active site threonine present in catalytic proteasome subunits. Once bound to the probe, the labeled subunits are recovered on streptavidin-conjugated beads and detected with subunit-specific antibodies. The PSB assay is both quantitative and sensitive. We have demonstrated that the assay is capable of measuring constitutive proteasome and immunoproteasome binding activity in human whole blood and peripheral blood mononuclear cell preparations, respectively. In experiments with the epoxyketone-based proteasome inhibitor PR-171, the dose response for inhibition of the PSB assay is equivalent to that measured with a conventional fluorogenic peptide proteasome substrate. In addition, the PSB assay can effectively measure the level of PR-171 mediated inhibition of both the constitutive and immunoproteasome in the RPMI-8226 multiple myeloma cell line that co-expresses both proteasome types. Thus, the PSB assay overcomes the limitations of conventional fluorogenic substrate-based proteasome activity assays when applied to cell or tissue lysates that contain multiple proteolytic activities or mixtures of constitutive and immunoproteasomes. Potential applications of the PSB assay include the measurement of the pharmacodynamic response to proteasome inhibitors and the evaluation of constitutive vs. immunoproteasome selectivity of inhibitors both in vitro and in vivo.

Description: Background: CC-90009 is a novel cereblon E3 ligase modulator (CELMoD), which is currently under investigation in a first-in-human, phase I study (CC-90009-AML-001; NCT02848001) in patients with R/R AML. In preclinical models, CC-90009 drives the binding of the target protein, translation termination factor G1 to S phase transition 1 (GSPT1), to cereblon and induces its ubiquitination and proteasome-dependent degradation. Loss of GSPT1 results in activation of the integrated stress response (ISR), inhibition of nonsense-mediated decay (NMD), and induction of apoptosis. Deep degradation of GSPT1, mediated by CC-90009, led to AML cell death in vitro and potent antitumor activity in patient-derived AML xenograft models. In the ongoing phase I study, CC-90009 has demonstrated antileukemic activity. Here, we characterize the pharmacodynamic responses using a suite of novel assays to support CC-90009 dose and schedule optimization. Methods: Adult patients with R/R AML received intravenous CC-90009 daily on Days 1-5 (D1-5 schedule) or on Days 1-3 and 8-10 (D1-3/8-10 schedule) of a 28-day cycle. Peripheral blood samples taken before, during, and after dosing in the first treatment cycle were analyzed. Levels of intracellular GSPT1 in blasts and normal blood cell types were quantitated by flow cytometry analysis. Transcript levels of ISR and NMD variants in peripheral blood mononuclear cells (PBMC) were measured by qPCR. Bone marrow (BM) core biopsies at screening, Cycle 1 Day 5 and 28, and Cycle 2 and 4 Day 28, were analyzed for GSPT1, cleaved caspase 3, and CD34 protein expression by immunohistochemistry. ATF3 and DDIT3 mRNA levels were assessed in BM samples by RNA in situ hybridization. Results: The rate and depth of GSPT1 loss in T cells and in circulating AML blasts increased with dose. A marked reduction in GSPT1 was observed in T cells and blast cells of most patients after the first dose of CC-90009 at all dose levels, and GSPT1 levels approached the assay floor between Days 2 and 5 at doses of 1.2 mg and higher on the D1-5 schedule. At 2.4 mg and higher on the D1-5 schedule, a reduction in GSPT1 levels of 〉 90% was observed in T cells (19 of 29 patients) and in blast cells (11 of 29 patients), with stronger GSPT1 reductions detected in AML blasts and normal T cells compared with B cells or granulocytes. In the 3 mg D1-5 cohort, patients with sustained GSPT1 reduction in peripheral blasts in the days following treatment had more persistent blast suppression compared with patients showing an earlier rebound of GSPT1. At 3 mg and 3.6 mg dose levels, continuous treatment (D1-5) resulted in slower kinetics of GSPT1 rebound and conferred superior antileukemic activity compared with the intermittent dosing schedule (D1-3/D8-10). In addition to measuring the direct target of CC-90009, GSPT1, we also investigated markers downstream of GSPT1 degradation. Several patients with deep and sustained GSPT1 loss in the high-dose cohorts (2.4 mg and above) showed increased levels of ISR-related transcripts (ATF3 and DDIT3) and NMD-associated splice variants (SRSF3 and SRSF6) in on-treatment PBMC samples. Similarly, in BM, deep GSPT1 loss coincided with induction of ATF3 and DDIT3 mRNA, increased cleaved caspase 3 expression, and reduced CD34+ blasts. These clinical findings are consistent with our preclinical studies in which GSPT1 loss culminated in apoptosis, which may be mediated through activation of ISR and inhibition of NMD pathways. Conclusions: CC-90009 is a novel CELMoD and a first-in-class GSPT1 degrader. A suite of novel pharmacodynamic assays performed on patient-derived peripheral blood cells and BM demonstrated a dose-dependent modulation of GSPT1, and showed that the preclinical mechanisms of ISR induction, NMD inhibition, and apoptosis can be confirmed in AML cells in patients. Deeper and more rapid GSPT1 degradation as well as delayed rebound were associated with more rapid, deeper, and more persistent blast reductions. Characterization of these pharmacodynamic responses in ongoing dose-schedule explorations will help identify the optimal scheme for the expansion phase and provide further insight into the mechanism of clinical response. Disclosures Fan: Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Yao:Celgene Corporation: Employment. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Zeidan:Pfizer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Montesinos:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Jazz Pharmaceuticals, Inc.: Consultancy; Takeda Pharmaceuticals: Consultancy; Shire: Consultancy; GlycoMimetics: Research Funding; Pfizer, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy; Celgene Corporation: Consultancy; AbbVie, Inc.: Research Funding; Blue print Medicines: Consultancy, Research Funding; Amgen: Consultancy. Altman:Novartis: Consultancy; Cancer Expert Now: Consultancy; Biosight: Other: US Lead; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee. Koprivnikar:Amgen: Speakers Bureau; Abbvie: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau. Vyas:Astellas: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding. Fløisand:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Honoraria. Gjertsen:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; EU Horizon 2020: Research Funding; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; ERA PerMed: Research Funding; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Research Council of Norway: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ACTII AS: Equity Ownership. Buchholz:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership.

Description: Background: CC-90009 is a cereblon (CRBN) E3 ligase modulator (CELMoD) and a first-in-class small molecule that drives the binding of a novel target protein, G1 to S phase transition 1 (GSPT1), to CRBN, resulting in the proteasome-dependent degradation of GSPT1. GSPT1 plays a central role in mRNA translation, and loss of GSPT1 activates an integrated stress response that leads to AML cell death (Matyskiela ME, et al. Nature. 2016;535:252-7; Zhouravleva G, et al. EBMO J. 1995;14:4065-72). In preclinical testing, CC-90009 is active across a range of AML cell lines and primary AML patient (pt) samples in vitro and in vivo and exerts its GSPT1- and CRBN-dependent effects through rapid induction of apoptosis. Here we share the first clinical results in pts with R/R AML. Methods: Adult pts with R/R AML enrolled in the dose-finding phase of this first-in-human, multicenter, open-label phase 1 study to evaluate tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of CC-90009; and to establish the recommended phase 2 dose and schedule (RP2D) (CC-90009-AML-001; NCT02848001). Dose escalation proceeded via a modified 3 + 3 design. Treatment was by daily intravenous administration on either Days 1-5 (D1-5) or Days 1-3 and 8-10 (D1-3/8-10) of a 28-day cycle. Treatment response was assessed after Cycles 1, 2, and 4 by modified International Working Group 2003 criteria. Safety and preliminary response data are presented for all treated pts. PK and PD were analyzed for evaluable pts. Results: As of May 15, 2019, 45 pts with R/R AML had been treated, including 35 pts on the D1-5 and 10 pts on the D1-3/D8-10 schedule. Median age was 66 years (range 27-81); 73% were male. Most pts (n = 36; 80%) were refractory to their last therapy and 17 pts (38%) were refractory to all prior therapy; 14 pts (31%) had secondary AML. Pts were treated at dose levels from 0.3 to 3.6 mg. Dose-limiting toxicities (DLTs) reported (only in dose levels from 2.4 to 3.6 mg) included hypotension, systemic inflammatory response syndrome (SIRS), hyperbilirubinemia, pneumonitis, and pericarditis with tamponade. Exploration of the 3.6 mg dose level is ongoing; the RP2D has not yet been determined. CC-90009-related grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 23 pts (51%); those occurring in 〉1 pt were hypocalcemia (22%); hypotension (13%); and hyperbilirubinemia, hyperglycemia, hypophosphatemia, pneumonitis, sepsis, thrombocytopenia, and tumor lysis syndrome (4%). Preclinically identified hypocalcemia was confirmed as a CC-90009 on-target toxicity in the clinic; it was reversible, manageable and did not lead to any treatment discontinuations. The majority of treated pts experienced ≥1 serious TEAE (80%); most were infections (47%). Two (4%) pts experienced TEAEs leading to permanent discontinuation of the study drug. Dose interruptions due to TEAEs occurred in 12 pts (27%) and dose reductions in 2 pts (4%). Of 40 pts who discontinued treatment, 24 (60%) discontinued due to progressive disease or lack of efficacy. Seven pts discontinued treatment due to death; 4 deaths were secondary to progression from AML, 2 due to sepsis and 1 due to hyperglycemic hyperosmolar nonketotic syndrome. Responses to single-agent treatment were observed in pts treated at 3.0 or 3.6 mg on the D1-5 schedule, with a best response of complete remission (CR; n = 1), morphologic CR with incomplete blood count recovery (CRi; n = 1) and morphologic leukemia-free state (MLFS; n = 1). A dose-dependent decrease in GSPT1 levels in peripheral blood blasts and T cells was observed, with a 〉90% decrease observed for higher dose levels. Evidence of antileukemic activity (decreases in bone marrow and/or peripheral blasts) was seen in pts treated with CC-90009 at 1.2 mg and above with a trend to more sustained reductions at the highest dose levels. Plasma PK analysis demonstrated dose-dependent exposure. Conclusions: In this phase 1 study of CC-90009, a first-in-class agent, evidence of deep GSPT1 degradation, on-target activity and promising antileukemic activity was observed. The observed TEAEs, in addition to those expected in this heavily pretreated R/R AML pt population, were generally well manageable. The study is ongoing with further optimization of dose, schedule and toxicity mitigation. Expansion cohorts in R/R AML and higher-risk myelodysplastic syndromes are planned. Disclosures Uy: GlycoMimetics: Consultancy; Curis: Consultancy; Astellas: Consultancy; Pfizer: Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. DeAngelo:Blue print Medicines: Consultancy, Research Funding; Celgene Corporation: Consultancy; Shire: Consultancy; Pfizer, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; GlycoMimetics: Research Funding; AbbVie, Inc.: Research Funding; Takeda Pharmaceuticals: Consultancy; Amgen: Consultancy. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; France Foundation: Speakers Bureau; PeerView: Speakers Bureau; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Cancer Expert Now: Consultancy; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; prIME Oncology: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Fløisand:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Honoraria. Gjertsen:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; EU Horizon 2020: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; The Norwegian Cancer Society: Research Funding; KinN Therapeutics AS: Equity Ownership; ACTII AS: Equity Ownership; ERA PerMed: Research Funding; Helse Vest Health Trust: Research Funding; Research Council of Norway: Research Funding. Esteve:Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Buchholz:Celgene Corporation: Employment, Equity Ownership. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Fan:Celgene Corporation: Employment, Equity Ownership. Hanna:Celgene Corporation: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Zeidan:Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Cardinal Health: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Astellas: Honoraria.