19 results on '"Jessica Sachs"'
Search Results
2. Summit: A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)
- Author
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Cem Akin, Frank Siebenhaar, Michael W. Deininger, Daniel J. DeAngelo, Tracy I. George, Mariana Castells, Matthew Giannetti, Jason Gotlib, Jessica Sachs, Amanda Pilla, Hina A. Jolin, and Prithviraj Bose
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Qualitative Research to Understand the Patient Experience in Non-Advanced Systemic Mastocytosis
- Author
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Frank Siebenhaar, Cem Akin, Jennifer Nicoloro SantaBarbara, Jean Paty, Chad Gwaltney, Michelle Watson, Jessica Sachs, Hina Jolin, Casey Judge, and Mariana Castells
- Subjects
Immunology ,Immunology and Allergy - Published
- 2023
4. A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)
- Author
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Frank Siebenhaar, Jason Gotlib, Michael W. Deininger, Daniel J. DeAngelo, Francis Payumo, George Mensing, Hina Jolin, Jessica Sachs, and Tracy I. George
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Systemic mastocytosis (SM) is characterized by mast cell infiltration of ≥ 1 extracutaneous organs and encompasses a spectrum of diagnoses that can range from a non-advanced to advanced disease (Shomali et al, 2018). There are two nonadvanced variants of SM: indolent systemic mastocytosis (ISM), which accounts for approximately 85% and smoldering systemic mastocytosis (SSM), which includes about 5% of the general SM population (Cohen et al, 2014, Jennings et al, 2014). ISM is characterized by 0 or 1 B-findings and SSM by 2 or more B findings and absence of organ damage or an associated hematologic neoplasm (Gotlib et al, 2018). There are currently no approved therapies to treat the underlying disease of ISM or SSM. Although anti-mediator therapies (e.g. anti-H1 and H2 antihistamines, leukotriene receptor antagonists, cromolyn sodium, corticosteroids) are used to control symptoms such as anaphylaxis, GI intolerance, and flushing to improve quality of life, their effectiveness and tolerability are variable. Many patients experience a persistently high symptom burden despite maximized anti-mediator therapies. Because the molecular pathogenesis of SM is driven by KIT D816V mutations in 95% of patients (Garcia-Montero et al, 2006, Jara-Acevedo et al, 2015, Vaes et al, 2017), other agents targeting this mutated kinase have been used to treat the spectrum of SM variants; however, toxicities such as cognitive impairment, GI effects, intracranial hemorrhage, and edema may limit dosing and thus efficacy. In addition to targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Furthermore, bezuclastinib has demonstrated minimal brain penetration and no CNS toxicities have been identified in preclinical studies. Preliminary clinical activity with bezuclastinib has been observed in patients with advanced solid tumors or locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST). A reduction in KIT exon 17 mutational burden was observed in patients treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018). This is a multi-center, Phase 2, double blind, placebo-controlled, 3-part clinical study to evaluate the safety, efficacy, and biomarker correlates (e.g. bone marrow mast cell percentage, serum tryptase level, and KIT D816V mutation burden) of the KIT inhibitor bezuclastinib in patients with ISM and SSM. This study will enroll patients with SSM and moderate-to-severe ISM who have inadequate control of their symptoms despite at least 2 anti-mediator treatments. Part 1 of the study is intended to determine the recommended dose of bezuclastinib in Part 2. Subjects will be randomized to placebo or 1 of 3 doses of bezuclastinib which will be administered in combination with a baseline regimen of best supportive care (BSC). Part 2 will evaluate the efficacy of bezuclastinib at the selected dose as compared with placebo. Efficacy will be measured by the reduction of symptom burden as assessed by the mastocytosis activity score (MAS), a disease specific patient reported outcome tool (Siebenhaar et al, 2018). In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study, including those initially randomized to placebo, may participate in a long-term extension and receive open-label bezuclastinib in combination with BSC. The study will enroll approximately 138 subjects. Data from this study will support further development of bezuclastinib in SM. Disclosures Gotlib: Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deininger: Novartis: Consultancy, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees. DeAngelo: Incyte: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. Payumo: Cogent Biosciences, Inc: Current Employment. Mensing: Cogent Biosciences, Inc.: Current Employment. Jolin: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. George: Bristol Meyers Squibb: Consultancy; Blueprint Medicines: Consultancy; Celgene: Consultancy; Incyte Corporation: Consultancy. OffLabel Disclosure: study of investigational agent
- Published
- 2021
5. Preclinical Data with KIT D816V Inhibitor Bezuclastinib (CGT9486) Demonstrates High Selectivity and Minimal Brain Penetrance
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John A. Robinson, Francis J. Sullivan, Jessica Sachs, Howard Ball, Karyn Bouhana, Shannon L. Winski, LouAnn Cable, Mark Joseph Chicarelli, and Anna Guarnieri
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business.industry ,Immunology ,High selectivity ,Cancer research ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,Penetrance ,Preclinical data ,Kit d816v - Abstract
The molecular pathogenesis of Systemic Mastocytosis (SM) is driven by mutations in the KIT gene, with 95% of patients having a mutation in exon 17, D816V, leading to constant proliferation of mast cells (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Targeted therapeutics have revealed clinical activity in these patients, but toxicities such as cognitive effects, intracranial hemorrhage, hypertension, and edema may limit dosing and availability of these therapies. While the exact cause of these effects is difficult to determine, numerous closely related kinases, such as wild type PDGFRα, PDGFRβ, KIT, VEGFR2 (KDR), and CSF1R (FMS), are considered to be anti-targets, with previous evidence of their inhibition linked to observed clinical toxicities (Liu & Kurzrock, 2015; Giles et al., 2009; Jayson et al., 2005). Bezuclastinib (CGT9486) was designed to selectively inhibit KIT D816V versus these other closely related kinase anti-targets. Additionally, we demonstrate that bezuclastinib has minimal brain penetration, together with no observed CNS-related toxicities in nonclinical studies. Herein, we present results from cell-based kinase profiling assays, which demonstrate that bezuclastinib has a significant and unique selectivity to KIT D816V relative to the aforementioned kinases when tested head-to-head against other clinically relevant compounds in SM. Additionally, a similar selectivity profile was observed for a broader panel of kinases, ion channels, transporters, and enzymes, which will be presented here, including drug concentrations and target engagement achieved with recent in vivo studies. Importantly, we also show that bezuclastinib has minimal brain penetration, a preferred feature of an anti-Kit molecule due to CNS-related adverse events observed in these indications. In a tissue distribution study performed in rats, bezuclastinib shows a brain:plasma ratio Disclosures Guarnieri: Cogent Biosciences: Current Employment. Cable: Cogent Biosciences: Current Employment. Bouhana: Cogent Biosciences: Current Employment. Sullivan: Cogent Biosciences: Current Employment. Ball: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. Winski: Cogent Biosciences: Current Employment. Robinson: Cogent Biosciences: Current Employment.
- Published
- 2021
6. A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM)
- Author
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Hina Jolin, Prithviraj Bose, Michael W. Deininger, Vinod Pullarkat, Jessica Sachs, Jason Gotlib, Daniel J. DeAngelo, Tsewang Tashi, Tracy I. George, Amanda Pilla, and Francis Payumo
- Subjects
medicine.medical_specialty ,Adult patients ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Kit d816v ,Internal medicine ,medicine ,Systemic mastocytosis ,business ,health care economics and organizations - Abstract
Systemic mastocytosis (SM) is characterized by excessive accumulation of mast cells in bone marrow and other extracutaneous tissues encompassing a spectrum of variants ranging from non-advanced to advanced disease (Shomali et al, 2018). Advanced systemic mastocytosis (AdvSM) is an aggressive and life-threatening form of SM with an overall survival from The molecular pathogenesis of SM is driven by mutations in the KIT gene leading to ligand-independent proliferation of mast cells, with 95% of patients carrying the D816V mutation in exon 17 (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Bezuclastinib, an oral, highly selective tyrosine kinase inhibitor with potent activity against KIT D816V has shown preliminary clinical activity and a tolerable safety profile in a Ph 1/2 study of patients with advanced solid tumors including gastrointestinal stromal tumor (GIST). In that study, a reduction in KIT exon 17 mutational burden was observed in subjects treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018). Other agents targeting the KIT D816V mutations have shown activity in the treatment of AdvSM; however, toxicities such as cognitive impairment, intracranial hemorrhage, and edema may limit dosing and appropriateness of these therapies. Besides targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Additionally, minimal brain penetration has been observed with bezuclastinib, and no CNS toxicities have been identified in preclinical studies. This is a multi-center, Phase 2, open-label, 2-part clinical study to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of bezuclastinib in subjects with AdvSM. This study will enroll subjects who meet WHO diagnostic criteria for AdvSM, have measurable SM-related organ damage according to modified IWG-MRT-ECNM consensus eligibility and response criteria, and have a baseline serum tryptase of ≥20 ng/mL. The diagnosis of AdvSM and evidence of measurable disease will be confirmed by an Eligibility Committee prior to enrollment. This study will enroll approximately 140 patients. Part 1 will consist of a dose optimization period to determine the optimal dose of bezuclastinib for subjects with AdvSM. Subjects will be randomized into one of four dose cohorts (50, 100, or 200 mg twice daily, or 400 mg once daily) in a 1:1:1:1 manner. A planned interim analysis to assess safety, efficacy, and biomarker endpoints will occur when approximately half the planned number of Part 1 patients have been evaluated through at least 2 cycles of treatment. After all subjects in Part 1 complete at least two cycles, the optimal dose will be selected. Part 2 will enroll subjects at the selected dose level to determine efficacy of bezuclastinib and to further characterize safety, PK, and PD. The primary assessment of efficacy is overall response rate, defined as the percentage of subjects classified as confirmed responders (CR, CR with incomplete hematologic recovery [CRh], partial response [PR], and clinical improvement [CI]) according to modified IWG-MRT-ECNM response criteria as assessed by a Central Response Review Committee (CRRC). Data from this study will support continued development of bezuclastinib in SM including Non-Advanced SM. This study opened in June 2021. Disclosures Gotlib: BMS: Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. George: Celgene: Consultancy; Blueprint Medicines: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy. Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding. Tashi: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Bose: Celgene Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Novartis: Honoraria; Promedior: Research Funding; BMS: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Incyte Corporation: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding. Payumo: Cogent Biosciences, Inc: Current Employment. Pilla: Cogent Biosciences: Current Employment. Jolin: Cogent Biosciences: Current Employment. DeAngelo: Abbvie: Research Funding; Takeda: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. OffLabel Disclosure: Study is for investigational agent
- Published
- 2021
7. Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ non-Hodgkin Lymphoma
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Ann Ranger, Jonathon B. Cohen, Francis Payumo, Veronika Bachanova, Patricia L. Harris, Luke P. Akard, Jason R. Westin, Ian W. Flinn, Samantha Jaglowski, and Jessica Sachs
- Subjects
Oncology ,CD20 ,medicine.medical_specialty ,biology ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Lymphoma ,Fludarabine ,Cytokine release syndrome ,Refractory ,Internal medicine ,medicine ,biology.protein ,Rituximab ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse In DL1 through DL3, as of 27 May 2019, there were no dose-limiting toxicities, AEs of cytokine release syndrome (CRS), serious or severe neurologic AEs, or AEs leading to deaths on treatment. TEAEs reported in >2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.
- Published
- 2019
8. A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma
- Author
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Matthew McKinney, Francis Payumo, Ann Ranger, Samantha Jaglowski, Jessica Sachs, Patrick J. Stiff, Iris Isufi, Luke P. Akard, Patricia Harris, and Javier Munoz
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Fludarabine ,Cytokine release syndrome ,Kite Pharma ,Internal medicine ,Cohort ,medicine ,Rituximab ,business ,Adverse effect ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in >3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred >7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.
- Published
- 2019
9. Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study
- Author
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Sam Song, Franco Locatelli, Thomas Klingebiel, Kathleen A. Neville, Gregory Song, Aurora Medina-Sanson, Judith Kinley, Nathalie Aladjidi, Jessica Sachs, Christine Mauz-Koerholz, Anna Llort, Stephen Daw, Ashish Suri, Kristen Hoffman, Stephen Zhang, Judith Landman-Parker, Keith J. August, Lia Gore, Auke Beishuizen, Marta Pillon, and Pediatrics
- Subjects
Male ,medicine.medical_specialty ,Immunoconjugates ,Adolescent ,Population ,brentuximab vedotin ,hodgkin's disease ,reed sternberg cell ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,Brentuximab vedotin ,education ,Child ,Anaplastic large-cell lymphoma ,Brentuximab Vedotin ,education.field_of_study ,business.industry ,Standard treatment ,Hematology ,BRENTUXIMAB ,medicine.disease ,Hodgkin Disease ,Lymphoma ,Transplantation ,Tolerability ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,Child, Preschool ,Lymphoma, Large-Cell, Anaplastic ,Female ,business ,Progressive disease ,030215 immunology ,medicine.drug - Abstract
Summary Background Despite remarkable progress in the treatment of newly-diagnosed classical Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, treatment of relapsed or refractory disease remains challenging. The aims of this study were to assess the safety, tolerability, recommended phase 2 dose, and efficacy of brentuximab vedotin in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. Methods This open-label, dose-escalation phase 1/2 study was done at 12 centres across eight countries (France, Germany, Italy, Mexico, The Netherlands, Spain, UK, and USA). We recruited paediatric patients aged 7–18 years with relapsed or refractory classical Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, for whom standard treatment was unavailable or no longer effective. Participants were allocated to receive brentuximab vedotin at 1·4 mg/kg (phase 1) or 1·8 mg/kg (phases 1 and 2) via intravenous infusion once every 3 weeks for up to 16 cycles. Dose escalation was done via a 3+3 design. Key exclusion criteria were stem-cell transplantation less than 3 months before administration of the first dose of study drug, presence of cytomegalovirus infection after allogeneic stem-cell transplantation, previous treatment with an anti-CD30 antibody, and concurrent immunosuppressive or systemic therapy for chronic graft-versus-host disease. Primary outcomes were safety profile in the safety-evaluable population and maximum tolerated dose, recommended phase 2 dose, pharmacokinetics (phase 1), and proportion of patients who achieved best overall response (phase 2; evaluated by an independent review facility) in the response-evaluable population. This trial is registered with ClinicalTrials.gov , number NCT01492088 . Findings Between April 16, 2012, and April 4, 2016, we screened 41 paediatric patients and enrolled 36 (aged 7–18 years), of whom 19 had relapsed or refractory classical Hodgkin's lymphoma and 17 had relapsed or refractory systemic anaplastic large-cell lymphoma. At the data cutoff (Oct 12, 2016), all 36 patients had discontinued study drug treatment; the most common reason was progressive disease (15 patients). The maximum tolerated dose was not reached. The recommended phase 2 dose was 1·8 mg/kg. The proportion of patients who achieved overall response was 47% (95% CI 21–73) for classical Hodgkin's lymphoma and 53% (28–77) for systemic anaplastic large-cell lymphoma. All 36 patients had a treatment-emergent adverse event and 16 patients (44%) had at least one grade 3 or worse treatment-emergent adverse event. The most common treatment-emergent adverse events were pyrexia (16 [44%] of 36) and nausea (13 [36%]). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (four [11%]), increased γ-glutamyl transpeptidase (two [6%]), and pyrexia (two [6%]). 12 (33%) patients had transient, limited-severity peripheral neuropathy. Eight patients (22%) had a serious adverse event; three (8%) had a drug-related serious adverse event. One patient died of cardiac arrest (disease progression of a large huge mediastinal mass, unrelated to the study drug). Paediatric pharmacokinetic profiles were consistent with those from studies of adult patients. Interpretation Brentuximab vedotin has manageable toxicity and is associated with clinically meaningful responses in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, and could allow subsequent stem-cell transplantation in some patients who were initially ineligible for stem-cell transplantation. Funding Millennium Pharmaceuticals Inc.
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- 2018
10. Abstract A003: Safety and preliminary efficacy of ACTR707, autologous T lymphocytes expressing an antibody-coupled T-cell receptor, in combination with rituximab in subjects with relapsed or refractory CD20-positive B-cell lymphoma
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Greg Motz, Veronika Bachanova, Patricia L. Harris, Luke P. Akard, Kathleen E. McGinness, Jonathon B. Cohen, Jessica Sachs, Ann Ranger, Ian W. Flinn, and Samantha Jaglowski
- Subjects
Oncology ,CD20 ,Cancer Research ,medicine.medical_specialty ,Cyclophosphamide ,biology ,business.industry ,medicine.medical_treatment ,Immunology ,Neutropenia ,medicine.disease ,Fludarabine ,Cytokine release syndrome ,Cancer immunotherapy ,hemic and lymphatic diseases ,Internal medicine ,medicine ,biology.protein ,Rituximab ,business ,Febrile neutropenia ,medicine.drug - Abstract
Background: Autologous T cells engineered to express a universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res 2014]. ACTR707 was identified through rigorous preclinical screening of more than 100 different ACTR variants. It is composed of the extracellular domain of CD16, the cytoplasmic signaling domain of CD3ζ, and the costimulatory domain of CD28. Study ATTCK-20-03 (NCT03189836) is the first clinical trial of ACTR707. ACTR707 in combination with rituximab is being studied in subjects with relapsed or refractory CD20+ B-cell lymphoma previously treated with anti-CD20 monoclonal antibody (mAb) therapy. Herein we report data from the first dose level of ACTR707, where 6 subjects have been enrolled and treated.Methods: ATTCK-20-03 is a first-in-human, multicenter phase 1 dose escalation study of ACTR707 in combination with rituximab. The primary objective is to evaluate the safety of ACTR707 in combination with rituximab, and secondary objectives include evaluation of antitumor activity, assessment of T-cell expansion and persistence, cytokine levels, and rituximab pharmacokinetics. Eligible subjects must have histologically confirmed relapsed or refractory aggressive CD20+ B-cell lymphoma of DLBCL, MCL, PMBCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb therapy in combination with chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and a single infusion of ACTR707. Additional doses of rituximab are administered, one dose every 3 weeks in the absence of disease progression. The study is separated into two sequential phases, a dose escalation and a safety expansion phase. During dose escalation, ACTR707 will be tested at increasing doses in combination with rituximab. Results: Six subjects received ACTR707 in combination with rituximab at the first dose level: 5 diagnosed with DLBCL (83%) and 1 with Gr3b FL (17%). Median age was 61 years (range: 57-76), 83% were male, 50% were treated with ≥ 3 lines of prior therapy, and 67% had no response to or progression within 6 months of immediate prior therapy. ACTR707 was successfully manufactured for all subjects. ACTR+ T cells demonstrated expansion and were detectable at D28 post-ACTR707 infusion for all subjects tested. There were no dose-limiting toxicities observed in the 4 subjects evaluable for DLTs (2 subjects were not DLT-evaluable due to early disease progression). There were no serious adverse events of cytokine release syndrome, neurotoxicity, or autoimmune events and no deaths on study. Grade 3 or higher AEs included neutropenia (n=2), febrile neutropenia (n=2), and thrombocytopenia (n=1). Antitumor activity was assessed in all 6 subjects. Three subjects experienced disease progression and 3 subjects demonstrated investigator-reported complete responses at the first disease response assessment (D42). Responses are ongoing at the time of the data cut-off. Conclusions: In the first dose level studied in subjects with relapsed or refractory aggressive CD20+ B-cell lymphoma, ACTR707 in combination with rituximab induced complete responses in 3 out of 6 treated subjects, with no serious events of cytokine release syndrome or neurotoxicity. ACTR+ T-cells were detectable in all subjects and ACTR+ T-cells persisted in the presence of continued rituximab administration. These results support the continued dose escalation of ACTR707 in combination with rituximab. Citation Format: Veronika Bachanova, Jonathon Cohen, Luke Akard, Samantha Jaglowski, Jessica Sachs, Ann Ranger, Patricia Harris, Kathleen McGinness, Greg Motz, Ian Flinn. Safety and preliminary efficacy of ACTR707, autologous T lymphocytes expressing an antibody-coupled T-cell receptor, in combination with rituximab in subjects with relapsed or refractory CD20-positive B-cell lymphoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A003.
- Published
- 2019
11. A Phase 1 Study of Two Investigational Agents, ACTR087, an Autologous T Cell Product Expressing an Antibody-Coupled T Cell Receptor, in Combination with SEA-BCMA, a Novel Non-Fucosylated Monoclonal Antibody, in Subjects with Relapsed or Refractory Multiple Myeloma
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Don M. Benson, Megan M. O'Meara, Luke P. Akard, Ben Exter, Jessica Sachs, Tooba A. Cheema, Ann Ranger, Parameswaran Hari, Django Sussman, Iga Sienczylo, and Houston Holmes
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,T cell ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Internal medicine ,medicine ,Multiple myeloma ,CD20 ,biology ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Chemotherapy regimen ,Fludarabine ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Rituximab ,business ,medicine.drug - Abstract
Background: B cell maturation antigen (BCMA) has recently emerged as a promising candidate antigen for therapeutic targeting in multiple myeloma (MM), with several targeted agents in clinical studies including antibody-drug conjugates and bispecific T cell engagers as well as CAR T cells. The Antibody-Coupled T cell Receptor (ACTR) platform is a universal, engineered autologous T cell therapy developed to mediate anti-tumor activity in combination with tumor-targeting antibodies. The ACTR construct is composed of the ectodomain of CD16 fused to intracellular co-stimulatory and CD3ζ signaling domains (Kudo et al., Cancer Res. 2014), which allow ACTR T cells to exert antibody-dependent cell-mediated cytotoxicity, a function otherwise physiologically limited to CD16-expressing natural killer cells and macrophages. ACTR087 expresses a 4-1BB-containing receptor and has been evaluated in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ B cell lymphoma as previously reported (Akard et al., Blood 2017). SEA-BCMA is a novel, humanized non-fucosylated anti-BCMA IgG1 antibody that has been demonstrated pre-clinically to bind to ACTR087 T cells to mediate ACTR T cell activation, cytotoxicity, cytokine release, and proliferation in the presence of BCMA-expressing MM cell lines. These functional activities were demonstrated to be BCMA-specific and SEA-BCMA dose-dependent (Cheema et al., AACR 2017). Here we present preliminary findings from the first 2 single-subject cohorts of the ATTCK-17-01 study (NCT03266692), an ongoing Phase 1 study of ACTR087 in combination with the first-in-human administration of SEA-BCMA. Methods: ATTCK-17-01 is a multicenter, Phase 1, dose-escalation study of ACTR087 in combination with SEA-BCMA. The primary objectives are to characterize the safety and to determine the recommended Phase 2 dose of ACTR087 in combination with SEA-BCMA in subjects with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, ACTR T cell persistence, cytokines, and SEA-BCMA pharmacokinetics (PK); exploratory objectives include the anti-myeloma activity of SEA-BCMA alone. Subjects must have measurable disease and must have received at least 3 prior lines of therapy including treatment with a proteasome inhibitor and an immunomodulatory agent, and hematopoietic stem cell transplant (HSCT) for HSCT-eligible subjects. BCMA expression on MM cells was not a condition of eligibility. Dose escalation of the 2 investigational agents, ACTR087 and SEA-BCMA, is determined according to adaptive design principles. After study enrollment and leukapheresis, subjects receive SEA-BCMA by IV infusion once every 3 weeks until disease progression or treatment discontinuation. After the third dose of SEA-BCMA and lymphodepleting chemotherapy (cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2, each daily for 3 days), subjects receive a single dose of ACTR087. Results: Two subjects enrolled and received ACTR087 at the first dose level in combination with the first 2 dose levels of SEA-BCMA. First-in-human dosing of SEA-BCMA was well tolerated, with no reported SEA-BCMA-related adverse events (AEs) or dose-limiting toxicities (DLTs). Following ACTR087 infusion, ACTR+ T cells were detectable in the peripheral blood and demonstrated expansion post-infusion. No DLTs were observed with the combination of ACTR087 and SEA-BCMA in the first 2 cohorts. Grade 3 or higher treatment-emergent AEs experienced by at least 1 subject, regardless of causality assessment, include cytopenias, increased ALT, and bone pain. Conclusions: ACTR087 in combination with SEA-BCMA was well tolerated in the first 2 subjects treated, with no DLTs or AEs leading to treatment discontinuation. These results support the continued dose escalation of ACTR087 in combination with SEA-BCMA. Enrollment in Cohort 3 is ongoing. Updated data, including SEA-BCMA PK, biomarkers, and preliminary Cohort 3 data, will be presented. Disclosures Holmes: Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Hari:Kite Pharma: Consultancy, Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Exter:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Cheema:Unum Therapeutics Inc.: Employment. Sienczylo:Unum Therapeutics Inc.: Employment. O'Meara:Seattle Genetics: Employment, Equity Ownership. Sussman:Seattle Genetics: Employment. Akard:Gilead: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.
- Published
- 2018
12. Nonalloreactive T Cells Prevent Donor Lymphocyte Infusion–Induced Graft-versus-Host Disease by Controlling Microbial Stimuli
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Megan Sykes, Roderick T. Bronson, Jessica Sachs, Guiling Zhao, Hao Wei Li, and Clarimel Pichardo
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Mice, 129 Strain ,medicine.drug_class ,Lymphocyte ,T cell ,Immunology ,Antibiotics ,Graft vs Host Disease ,Mice, Transgenic ,Article ,Donor lymphocyte infusion ,Mice ,Ciprofloxacin ,T-Lymphocyte Subsets ,immune system diseases ,Lymphopenia ,Metronidazole ,medicine ,Animals ,Immunology and Allergy ,Inflammation ,Mice, Knockout ,Mice, Inbred BALB C ,biology ,Effector ,medicine.disease ,Mice, Inbred C57BL ,Transplantation ,surgical procedures, operative ,Graft-versus-host disease ,medicine.anatomical_structure ,Polyclonal antibodies ,Lymphocyte Transfusion ,biology.protein - Abstract
In mice, graft-versus-host reactions, associated with powerful graft-versus-tumor effects, can be achieved without graft-versus-host disease (GVHD) by delayed administration of donor lymphocyte infusions (DLI) to established mixed chimeras. However, GVHD sometimes occurs after DLI in established mixed chimeric patients. In contrast to mice, in which T cell recovery from the thymus occurs prior to DLI administration, human T cell reconstitution following T cell–depleted hematopoietic cell transplantation is slow, resulting in lymphopenia at the time of DLI. We demonstrate in this study that T cell lymphopenia is an independent risk factor for GVHD following DLI in the absence of known inflammatory stimuli. DLI-induced GVHD was prevented in lymphopenic recipients by prior administration of a small number of nonalloreactive polyclonal T cells, insufficient to prevent lymphopenia-associated expansion of subsequently administered T cells, through a regulatory T cell–independent mechanism. GVHD was not inhibited by T cells with irrelevant specificity. Moreover, administration of antibiotics reduced the severity of GVHD in lymphopenic hosts. Accumulation of DLI-derived effector T cells and host hematopoietic cell elimination were markedly diminished by regulatory T cell–depleted, nonalloreactive T cells. Finally, thymectomized mixed chimeras showed increased GVHD following delayed DLI. Collectively, our data demonstrate that in the absence of known conditioning-induced inflammatory stimuli, T cell lymphopenia is a risk factor for GVHD in mixed chimeras receiving delayed DLI. Our data suggest that the predisposition to GVHD can at least in part be explained by the presence of occult inflammatory stimuli due to the absence of T cells to control microbial infections.
- Published
- 2012
13. Role of the thymus and kidney graft in the maintenance of tolerance to heart grafts in miniature swine
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Stuart L. Houser, Jessica Sachs, Louis C. Benjamin, Kazuhiko Yamada, Joren C. Madsen, David H. Sachs, Parsia A. Vagefi, and J.D. Mezrich
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Graft Rejection ,medicine.medical_specialty ,Swine ,medicine.medical_treatment ,Miniature swine ,Thymus Gland ,Nephrectomy ,medicine ,Immune Tolerance ,Animals ,Transplantation, Homologous ,Kidney transplantation ,History, Ancient ,Heart transplantation ,Transplantation ,Kidney ,Immunity, Cellular ,business.industry ,Histocompatibility Testing ,medicine.disease ,Kidney Transplantation ,Surgery ,Thymectomy ,surgical procedures, operative ,medicine.anatomical_structure ,Circulatory system ,Cyclosporine ,Heart Transplantation ,Swine, Miniature ,Lymphocyte Culture Test, Mixed ,business ,Immunosuppressive Agents - Abstract
Background. The authors have examined the mechanism whereby co-transplantation of a kidney and heart from the same donor induces and maintains tolerance to both organs in miniature swine. Methods. Transplants were performed across a major histocompatibility complex class I mismatch, and recipients received cyclosporine for 12 days. Group 1 animals received heart transplants alone (n=5), and all other groups received both heart and kidney allografts. Group 2 animals received no further intervention (n=2). Group 3 animals underwent transplant nephrectomy 8 days after heart and kidney co-transplantation (n=2). Group 4 animals underwent transplant nephrectomy 100 days after co-transplantation (n=2). Skin grafts were placed on group 4 animals, on one group 3 animal, and on two animals from group 2. Group 5 animals underwent thymectomy 100 days after co-transplantation (n=4). Results. Group 1 animals developed cardiac allograft vasculopathy (CAV) and rejection. Group 2 animals never developed CAV and demonstrated in vitro donor-specific unresponsiveness. Group 3 animals suffered CAV and rejection. Group 4 animals developed CAV without concomitant donor-specific cell-mediated lympholysis reactivity, interstitial rejection, or cessation of graft function. Skin grafts on group 3 and group 4 animals led to fulminant rejection of heart and skin grafts, in contrast to grafts on group 2 animals that had no in vivo effect. Group 5 animals developed CAV but no significant increase in interstitial infiltrates. Conclusions. Both the kidney and thymus were necessary for maintenance of tolerance to heart allografts.
- Published
- 2005
14. Phase 1/2 Study Of Brentuximab Vedotin In Pediatric Patients With Relapsed Or Refractory (R/R) Hodgkin Lymphoma (HL) Or Systemic Anaplastic Large-Cell Lymphoma (sALCL): Preliminary Phase 2 Data For Brentuximab Vedotin 1.8 Mg/Kg In The HL Study Arm
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Judith Landman-Parker, Adedigbo Fasanmade, Jingyuan Wang, Franco Locatelli, Jessica Sachs, Christine Mauz-Koerholz, Angelo Rosolen, Anna Franklin, Auke Beishuizen, Kathleen A. Neville, Nathalie Aladjidi, Lia Gore, and Stephen Daw
- Subjects
medicine.medical_specialty ,Chemotherapy ,Leukopenia ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Gastroenterology ,Surgery ,B symptoms ,Internal medicine ,medicine ,medicine.symptom ,Brentuximab vedotin ,business ,Febrile neutropenia ,Progressive disease ,medicine.drug - Abstract
Background Brentuximab vedotin is a CD30-targeted antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Pivotal phase 2 studies reported the efficacy and manageable toxicities of the drug, leading to its approval by the US FDA for use in adult patients with R/R HL and R/R sALCL in 2011. Data for brentuximab vedotin in children with these lymphomas are currently limited but promising. This ongoing phase 1/2 prospective, open-label, multicenter study is the first clinical trial of brentuximab vedotin conducted exclusively in pediatric patients with R/R HL or R/R sALCL (NCT01492088). The phase 1 portion established the recommended phase 2 dose (RP2D) of brentuximab vedotin in pediatric patients with R/R HL or R/R sALCL as 1.8 mg/kg every 3 weeks (Q3wk), and complete response (CR) and partial response (PR) were reported in 88% of patients at the RP2D. Here, we report preliminary phase 2 response, safety and PK findings for the HL patients receiving the RP2D. Methods The phase 2 portion aimed to enroll 15 response-evaluable HL patients at the RP2D, including those R/R HL patients treated at the RP2D in phase 1 (phase 2 data for the sALCL patients are not reported here). The phase 2 primary objective was overall response rate (ORR; CR + PR) at the RP2D; secondary objectives were time to progression, time to response, duration of response, event-free survival, progression-free survival, overall survival, to characterize PK, to further evaluate safety, and to determine immunogenicity of brentuximab vedotin. Patients with R/R HL aged 5 to Results 16 patients with R/R HL received at least 1 dose of brentuximab vedotin at the RP2D; median age was 15 years (range, 8–18); 56% were male; Ann Arbor stage at initial diagnosis was 44% stage II, 6% stage III, 44% stage IV, and 6% unknown; median time from initial diagnosis was 16.7 months (range, 0–38) and 50% had B symptoms at baseline. At data cut-off (June 20, 2013), patients had received a median of 3 cycles of treatment (range, 1–16); 10 (63%) patients had discontinued treatment due to: progressive disease (n=7), AEs (n=2), and allogeneic transplant (n=1). Response data were available for 14 patients at data cut-off. The ORR was 64% (95% confidence interval [CI]: 35, 87); 3 (21%; 95% CI: 5, 51) patients achieved CR and 6 (43%; 95% CI: 18, 71) achieved PR. Reponses were typically observed at C2. 12 of 16 (75%) patients had ≥1 AE, and 7 (44%) had grade ≥3 AEs. The most common (>1 patient) AEs were nausea (38%), pyrexia (31%), neutropenia, paresthesia (each 19%), abdominal pain, upper abdominal pain, constipation, decreased appetite, diarrhea, hepatotoxicity, hypokalemia, leukopenia, myalgia, pharyngitis, and vomiting (each 13%). 7 serious AEs (SAEs) occurred in 5 patients; 4 SAEs in 3 patients were considered related to brentuximab vedotin: grade 3 hepatotoxicity and grade 3 febrile neutropenia (n=1); grade 3 anaphylaxis (n=1); and grade 3 pneumonia (n=1). One patient died on C2D4 of unrelated cardiac arrest due to progressive mediastinum enlargement (disease progression). 2 (13%) patients discontinued, 1 due to grade 3 hepatotoxicity on C1D13 and 1 due to grade 3 peripheral neuropathy on C8D4. Preliminary PK data show that brentuximab vedotin remained detectable in the blood just prior to the next infusion over the treatment period; thus, patients remain exposed to brentuximab vedotin from cycle to cycle. Conclusions Brentuximab vedotin 1.8 mg/kg Q3wk (RP2D) was generally well tolerated in pediatric patients with R/R HL and demonstrated preliminary evidence of activity, with an ORR to date of 64%, including 21% CR. The phase 2 portion is ongoing in pediatric patients with R/R HL and R/R sALCL. Disclosures: Off Label Use: Brentuximab vedotin for the treatment of pediatric patients with relapsed or refractory Hodgkin lymphoma. Franklin:Millennium: The Takeda Oncology Company: Research Funding. Fasanmade:Millennium: The Takeda Oncology Company: Employment, Equity Ownership, Research Funding. Wang:Millennium: The Takeda Oncology Company: Employment. Sachs:Millennium: The Takeda Oncology Company: Employment. Mauz-Koerholz:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees.
- Published
- 2013
15. Lymphohematopoietic graft-vs.-host reactions can be induced without graft-vs.-host disease in murine mixed chimeras established with a cyclophosphamide-based nonmyeloablative conditioning regimen
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Guiling Zhao, Megan Sykes, Kirsten Swenson, Yong-Guang Yang, Jessica Sachs, Michele Pelot, and Denise A. Pearson
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Transplantation Conditioning ,Cyclophosphamide ,medicine.drug_class ,Cell ,Graft vs Host Disease ,Spleen ,Major histocompatibility complex ,Monoclonal antibody ,Conditioning regimen ,03 medical and health sciences ,Graft vs Host Reaction ,Mice ,0302 clinical medicine ,Antigen ,Leukocytes ,Medicine ,Animals ,Transplantation, Homologous ,Infusions, Intravenous ,Bone Marrow Transplantation ,Transplantation ,Mice, Inbred BALB C ,biology ,business.industry ,Chimera ,Hematology ,3. Good health ,Hematopoiesis ,Mice, Inbred C57BL ,Haematopoiesis ,surgical procedures, operative ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Mixed hematopoietic chimerism can be induced in mice receiving allogeneic bone marrow transplantation (BMT) after nonmyeloablative host conditioning with depletion T cells with of anti-T cell monoclonal antibodies (mAbs), low-dose (3 Gy) total-body irradiation (TBI), and local thymic irradiation (7 Gy). These mice are specifically tolerant to donor and host antigens. When nontolerant donor T cells are given to chimeras several months after BMT, full donor-type chimerism develops, but graft-vs.-host disease (GVHD) does not occur. The induction of such lymphohematopoietic GVH reactions without GVHD could provide an approach to separating graft-vs.-leukemia (GVL) from GVHD in patients with hematologic malignancies. To make the nonmyeloablative conditioning regimen described above more cytoreductive for such malignancies, we have now modified it by replacing TBI with cyclophosphamide (CP). Treatment with anti-CD4 and anti-CD8 mAbs on day -5, 200 mg/kg CP on day -1, and 7 Gy thymic irradiation on day 0 was only slightly myelosuppressive and allowed fully major histocompatibility complex (MHC)-mismatched (with or without multiple minor antigen disparities) allogeneic bone marrow to engraft and establish long-term mixed chimerism in 40 to 82% of recipients in three different strain combinations. The administration of nontolerant donor spleen cells at 5 weeks or at 5, 8, and 11 weeks posttransplant was capable of eliminating host hematopoietic cells, leading to full or nearly full donor chimerism in six of six and two of four chimeric animals in two different strain combinations. No clinical evidence of GVHD was observed in any recipients of these donor leukocyte infusions (DLI). These studies demonstrate that induction of mixed chimerism with nonmyeloablative conditioning followed at appropriate times by DLI might allow lymphohematopoietic GVH reactions, and hence GVL effects, to eliminate chronic hematologic malignancies without causing clinically significant GVHD. Biol Blood Marrow Transplant 1999;5(3):133-43.
- Published
- 1999
16. The role of the thymus in the maintenance phase of tolerance in miniature swine
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Kazuhiko Yamada, James S. Allan, Jessica Sachs, Joren C. Madsen, L.G Ledgerwood, David H. Sachs, Louis C. Benjamin, J.D. Mezrich, H.C. Amoah, Douglas R. Johnston, Stuart L. Houser, J.A. Kesselheim, and Richard S. Lee
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Pulmonary and Respiratory Medicine ,Transplantation ,business.industry ,Immunology ,Miniature swine ,Maintenance phase ,Medicine ,Surgery ,Cardiology and Cardiovascular Medicine ,business - Published
- 2002
17. Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-κB essential modulator deficiency
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Jonathan N. Glickman, Sung-Yun Pai, Samuel Nurko, Haifa H. Jabara, Jordan S. Orange, Raif S. Geha, Liat Stoler-Barak, Jessica Sachs, and Ofer Levy
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Male ,Allogeneic transplantation ,Adolescent ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Biology ,Article ,Natural killer cell ,Immune system ,Ectodermal Dysplasia ,medicine ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Genetic Predisposition to Disease ,Colitis ,Child ,Immunodeficiency ,Cell Proliferation ,B-Lymphocytes ,Siblings ,Toll-Like Receptors ,Hematopoietic Stem Cell Transplantation ,Immunologic Deficiency Syndromes ,Genetic Diseases, X-Linked ,medicine.disease ,Acquired immune system ,I-kappa B Kinase ,Transplantation ,medicine.anatomical_structure ,Child, Preschool ,K562 Cells - Abstract
Background Boys with X-linked ectodermal dysplasia and immunodeficiency caused by mutations of nuclear factor-κB essential modulator have defects in innate and adaptive immunity, and some have colitis. Objective We sought to determine whether curing the immune defect in such patients by means of allogeneic hematopoietic stem cell transplantation abolishes the susceptibility to colitis. Methods A boy with X-linked hypohydrotic ectodermal dysplasia with immunodeficiency underwent allogeneic transplantation from a matched unaffected sibling identified by means of preimplantation genetic diagnosis. Toll-like receptor (TLR) function was assessed by measuring TLR agonist–induced cytokine production in whole blood tested in vitro . B-cell proliferation was measured by means of tritiated thymidine incorporation. Natural killer cell function was examined in PBMCs by means of K562 target cell lysis. Colitis severity was assessed clinically based on corticosteroid requirement and histology of large intestinal biopsy specimens. Results Defects in cytokine production in response to TLR agonists, CD40-mediated proliferation, and natural killer cell cytotoxicity were all corrected after hematopoietic stem cell transplantation. Despite successful hematopoietic and immune reconstitution, the patient continued to have flares of colitis, often associated with bacterial infection. Conclusions Our findings strongly suggest that nuclear factor-κB essential modulator deficiency intrinsic to the intestinal epithelium is sufficient to predispose to colitis, despite robust correction of immune defects.
- Published
- 2008
18. Lymphopenia Promotes the Development of Graft-Versus-Host Disease upon Donor Leukocyte Infusion
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Megan Sykes and Jessica Sachs
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business.industry ,T cell ,Immunology ,Inflammation ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Haematopoiesis ,surgical procedures, operative ,Graft-versus-host disease ,Allogeneic Lymphocyte ,medicine.anatomical_structure ,immune system diseases ,Splenocyte ,Medicine ,Bone marrow ,medicine.symptom ,business - Abstract
In murine models of hematopoeitic cell transplantation (HCT), a graft-versus-leukemia (GVL) effect can be effectively separated from graft-versus-host disease (GVHD) by giving delayed donor-leukocyte infusions (DLI) to established mixed hematopoietic chimeras (MC) (Mapara, Transplantation 2003). In these models, the absence of conditioning-induced inflammation at the time of DLI prevents trafficking to GVHD target tissues, limiting the GVH response to the lymphohematopoeitic system (Chakraverty, J Exp Med 2006). While clinical trials have shown that the same outcome is possible in humans, some patients develop severe GVHD following delayed DLI (Dey, Blood Biol Marrow Transplant 2003). In contrast to mice, who recover T cell numbers quickly after HCT through de novo thymopoiesis, humans remain lymphopenic for many months. The current study investigates the role of recipient lymphopenia in the development of GVHD following delayed DLI to MC. Allogeneic (B10.A) or syngeneic (B6) lymphocytes (30 × 106 whole splenocytes) and bone marrow cells (10 × 106) were administered to unconditioned RAG–1 knockout (KO) B6 recipients or to established MC, and animals were followed for development of GVHD. By day 7 after injection, the RAG KO recipients of allogeneic lymphocytes (allogeneic group) had lost significantly more weight (p
- Published
- 2007
19. Requirement for CD4 Help for Optimal GVL Effects of Alloreactive T Cells Given to Established Mixed Chimeras but Not Freshly Irradiated Mice
- Author
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Megan Sykes, Hyeon-Seok Eom, Ronjon Chakraverty, Guiling Zhao, and Jessica Sachs
- Subjects
MHC class II ,biology ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Major histocompatibility complex ,Biochemistry ,Donor lymphocyte infusion ,surgical procedures, operative ,Graft-versus-host disease ,Antigen ,immune system diseases ,MHC class I ,biology.protein ,medicine ,Antigen-presenting cell ,CD8 - Abstract
Donor lymphocyte infusion (DLI) may lead to lymphohematopoietic graft-versus-host (GVH) reactions without graft-versus-host-disease (GVHD). The graft-versus-leukemia (GVL) effect of DLI is greater in mixed chimeras than in full chimeras following fully MHC-mismatched bone marrow transplantation (BMT). Some studies showed, following MHC-mismatched BMT, that only CD8+ T cells are involved in GVL effects of DLI against MHC class I+ class II− tumors, but others showed that the GVL effect of DLI is dependent on both CD8+ and CD4+ T cells. Previously, we have observed that GVL against EL4 is mediated by CD8+ T cells but not CD4+ T cells following DLI in freshly irradiated mice treated with cytokines to reduce GVHD mortality in fully MHC-mismatched BMT. The exact contribution of CD4+ and CD8+ T cells to the GVL effects of DLI in established mixed chimeras is not known. We hypothesized that lethal conditioning leads to the production of many proinflammatory cytokines which may help to generate a CD4 cell-independent, CD8 cell-mediated anti-tumor effect. However, in delayed DLI recipients, CD4+ helper T cells might be needed to induce CD8+ anti-tumor effector cells. We evaluated the role of T-cell subsets in GVL effects of DLI following fully major histocompatibility complex (MHC)-mismatched BMT in freshly irradiated mice and mixed chimeric delayed DLI recipients. While GVL effects of delayed DLI given to established mixed chimeras were dependent on both CD4+ and CD8+ T cells, CD4+ T cells did not contribute to GVL effects in freshly irradiated mice. Consistent with this, MHC class II expression on host antigen-presenting cells (APCs) was needed to optimize GVL effects of DLI in established mixed chimeras. To address whether cross-presentation of tumor antigens (Ag) via class I would permit GVL responses in full chimeras, we generated full chimeras in which donor and recipient shared a class I locus. However, there were no GVL effects of delayed DLI in full chimeras, providing no evidence that cross-presentation of tumor Ag through class I molecules shared by donor and the tumor led to anti-tumor effects in this model. We conclude that following delayed DLI to established mixed chimeras, the GVL response requires extensive MHC disparity, MHC class II expression on host APCs and the presence of CD4+ T cells. In contrast, the requirement for CD4+ T cells can be bypassed in freshly irradiated recipients, but this occurs at the expense of a greater risk of GVHD. Administration of delayed DLI to mixed chimeras permits achievement of optimal GVL effects because large numbers of GVH-reactive T cells can be administered without inducing GVHD.
- Published
- 2004
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