A Binding Domain on Mesothelin for CA125/MUC16 Kaneko, Osamu; Gong, Lucy; Zhang, Jingli ...
Journal of biological chemistry/The Journal of biological chemistry,
02/2009, Volume:
284, Issue:
6
Journal Article
Peer reviewed
Open access
Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may ...facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296–359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296–359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.
BackgroundTIL therapy, a personalized cell therapy comprising T cells that have been expanded ex vivo, is a promising treatment approach for advanced solid tumors. Retention of tumor-specific T-cell ...clonotypes and maintenance of stemness, characteristics associated with improved clinical efficacy, are compromised during conventional manufacturing.1 New approaches are needed to optimize ex vivo TIL expansion processes to preserve relevant T-cell clones and stemness.LYL845 is an investigational autologous TIL therapy produced with Lyell’s epigenetic reprogramming (Epi-R™) protocol, which generates populations of tumor-reactive T cells with stem-like qualities and a more favorable phenotype (including CD8 skewing) associated with improved clinical outcomes relative to control TIL expanded with conventional processes.1–3 Preclinical data demonstrate these findings in both immunologically hot (melanoma, non-small cell lung cancer NSCLC) and cold (colorectal cancer CRC) tumors, supporting clinical development in these tumor types.2 LYL845-101 is a Phase 1, first-in-human, multicenter, single-arm, open-label, dose-escalation and -expansion trial (NCT05573035) designed to evaluate the safety and anti-tumor activity of LYL845 in patients (pts) with advanced solid tumors.MethodsThe trial is enrolling adult pts with locally advanced or metastatic melanoma, NSCLC, or CRC that has progressed after ≥1 line of therapy, including an immune checkpoint inhibitor (melanoma, NSCLC) or chemotherapy (CRC). Pts must have ECOG status 0-1; life expectancy ≥3 months; and measurable disease, including a target lesion evaluable per RECIST and an additional resectable lesion for TIL manufacturing. Bridging therapy is allowed during LYL845 manufacturing.Part A (dose escalation) will evaluate 2 planned dose level ranges of LYL845 using the modified toxicity probability interval-2 (mTPI-2), with a 28-day dose-limiting toxicity (DLT) period. Part B (dose-expansion) will treat 15-30 pts in each disease cohort at the recommended phase 2 dose range (RP2DR), determined in Part A.After TIL tumor tissue collection surgery and successful LYL845 manufacturing, pts receive fludarabine and cyclophosphamide followed 2-5 days later by a single infusion of LYL845. After LYL845 infusion, high-dose intravenous interleukin-2 is administered every 8 hours for up to 6 doses as tolerated. Primary objectives include evaluation of safety, tolerability, and determination of the RP2DR. The secondary objective is evaluation of anti-tumor activity. Exploratory objectives include measurement of tumor mutational burden, clonal diversity of the TIL drug product, T cell clonal expansion and persistence in the periphery and the presence of TIL drug product derived T cell clones in the tumor post-infusion. The trial is open and currently enrolling.Trial RegistrationNCT05573035ReferencesPatel Y, Harris B, Bedard M, et al. The Epi-R technology produces a polyclonal TIL product (LYL845) with a greater expansion success rate across hot and cold tumors, improved product phenotype, and maintenance of TCR diversity. J ImmunoTher. 2022;10(Suppl 2):A389.Harris BD, Patel Y, Ha N-H, et al. Epi-R technology produces a polyclonal TIL product (LYL845) with diverse tumor-reactive clones that have stem-like qualities and anti-tumor function. J ImmunoTher. 2022;10(Suppl 2):A358.Krishna S, Lowery FJ, Copeland AR, et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science. 2020;370:1328-1334.Ethics ApprovalThe trial was approved by the WCG IRB (IRB Tracking Number 20224274) as well as individual clinical trial sites’ IRBs. All patients give written informed consent before participating in the trial.
OBJECTIVE:--The purpose of this study was to examine the association between parental history of type 2 diabetes and glycemic control among diabetic urban African Americans. RESEARCH DESIGN AND ...METHODS--Study participants included 359 African Americans with type 2 diabetes from Baltimore, Maryland, enrolled in Project Sugar 2. Participants underwent an interview-administrated questionnaire that asked about family history, sociodemographics, clinical characteristics, and knowledge and perception of adequate glycemic control. Regression analysis was used to determine the association between parental history of diabetes and glycemic control, as measured by A1C. RESULTS:--In the comparisons between participants with and without a parental history of diabetes, those with a positive parental history tended to be younger, have higher glucose levels, and have higher blood glucose levels before calling a doctor (all P < 0.05). After adjustments for age, sex, and BMI, there was a significant association (P = 0.02) between A1C and parental history with the mean A1C difference between those with a positive and a negative parental history being 0.58%. However, after adjustment for duration of diabetes, the association was no longer significant (P = 0.11). However, there was a tendency for individuals with two diabetic parents to have higher A1C (P = 0.011). CONCLUSIONS:--From these results, we conclude that among the urban African American participants who were aware of their parental history of diabetes, a positive parental history was associated with worse glycemic control, partly due to longer duration of diabetes. Parental history did not appear to be associated with better knowledge or perception of adequate glycemic control.
Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). ...However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.
•Liso-cel was associated with manageable toxicities and rapid and deep responses in patients with relapsed/refractory CLL/SLL.•With successful manufacturing of liso-cel for patients with CLL/SLL and the encouraging phase 1 results, a phase 2 study is underway.
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Introduction
Treatment of CLL is rapidly evolving, now including oral targeted agents and novel combinations. However, complete response (CR) rates remain low and continuous therapy is required. ...Eradication of minimal residual disease (MRD) is an increasingly important endpoint and an independent predictor of improved survival.
Lisocabtagene maraleucel (liso-cel; JCAR017) is an investigational CD19-directed 4-1BB CAR T cell product administered in a defined composition of CD8:CD4 CAR T cells. TRANSCEND CLL 004 is an open-label Phase 1/2 trial of liso-cel in patients (pts) with relapsed/refractory (R/R) CLL (NCT03331198). Preliminary safety, pharmacokinetic (PK), and efficacy results from the Phase 1 monotherapy dose-finding portion of this study are reported.
Methods
Pts with CLL/SLL were eligible if they had received 3 (standard risk) or 2 high risk: del(17p), TP53 mutation, unmutated IGVH, or complex karyotype prior lines of therapy, including a Bruton's tyrosine kinase inhibitor (BTKi) unless medically contraindicated. Pts with active untreated CNS disease, ECOG >1, or Richter's transformation were excluded.
After 3 days of lymphodepletion with fludarabine and cyclophosphamide, pts received liso-cel infusion. Two dose levels (DL) have been tested (DL1=5 × 107 CAR T cells; DL2=1 × 108 CAR T cells). Dose escalation followed a modified toxicity probability-interval-2 (mTIPI-2) algorithm. Dose-limiting toxicities (DLTs) were evaluated for 28 days post liso-cel infusion.
Responses were assessed by iwCLL 2008 criteria. MRD was assessed at 10-4 sensitivity by 6-color flow cytometry using peripheral blood and at 10-6 sensitivity by clonoSEQâ (Adaptive) deep sequencing of bone marrow (BM) aspirates. Blood PK of liso-cel was determined using flow cytometry. Serum soluble chemokine and cytokine profiles for 39 analytes were assessed using V-PLEX immunoassays (MSD).
Results
At the time of data cut, 10 pts received liso-cel: 6 pts treated with DL1 and 4 pts with DL2. The median age was 64.5 years (range 51-76); 7/10 pts had high-risk disease. Pts had received a median of 4 prior therapies (range 3-8), including 9/10 pts who had received prior ibrutinib and 6/10 who previously received venetoclax and ibrutinib.
No DLTs were identified. The most common adverse events (AEs) were cytokine release syndrome (CRS) (8/10 pts; all grade G 1/2), anemia (7/10 pts), thrombocytopenia (6/10 pts), and leukopenia (5/10 pts). Neurologic events (NE) were reported in 3/10 pts: G1 impaired concentration and aphasia, G3 encephalopathy, and G3 aphasia. The median time to onset of CRS and NE was 4.5 (range 1-9) and 11 (range 11-21) days respectively, and the median duration of CRS and NE was 5.5 (range 3-30) and 6 (range 2-20) days respectively. Six pts received tocilizumab and/or steroids for the management of CRS and/or NE. Serious AEs, all of which were G3/4, were reported in 5/10 pts.
At 30 days post-dose, 6 of 8 pts who were evaluable for response had an objective response (75%), including 4 CRs (50%). Six of 7 pts (85.7 %) evaluable for MRD had undetectable disease by flow at the day 30 assessment. Of the 5 pts evaluable for response at 3 months post-dose, 4 had ongoing response and 1 progressed with Richter's transformation. All 4 pts with ongoing response continued to have undetectable MRD by flow at 3 months post-dose. Responses, including CRs and undetectable MRD responses, occurred in pts with high-risk and with standard-risk disease. Available BM analyses from clonoSEQâ data corroborate these findings and will be reported.
Median Cmax was 219 CAR T cells/µl (range 0.35-583.46). Median time to peak expansion was 15.5 days (range 13-19) and median AUC was 1528 cells*day/μL (range 590-2847). In the one pt with a best response of progressive disease, minimal CAR T cell expansion was observed. CAR T cells persisted in pts maintaining their response at 3 months post-dose.
Serum analysis showed elevated levels of multiple biomarkers, including CRP, IL6, PLGF, IL16, and IL15, in conjunction with CRS and NE.
Conclusion
Liso-cel toxicities were manageable, including events of CRS and NE, in these heavily pretreated pts with CLL. CRs and undetectable MRD were rapidly achieved in pts with both high-risk and standard-risk CLL who previously received ibrutinib, with the majority also having had received venetoclax. These preliminary data support continued development of single-dose liso-cel treatment in CLL.
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Siddiqi:Juno Therapeutics: Other: Steering committee. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Dubovsky:Juno Therapeutics: Employment, Equity Ownership. Gillenwater:Juno Therapeutics: Employment, Equity Ownership. Gong:Juno Therapeutics: Employment, Equity Ownership. Mitchell:Juno Therapeutics: Employment, Equity Ownership. Thorpe:Juno Therapeutics: Employment, Equity Ownership. Yang:Juno Therapeutics: Employment, Equity Ownership.
Background: The advent of oral-targeted drugs has improved treatment outcomes for patients (pts) with CLL. Nonetheless, some pts prove intolerant or resistant to therapy and/or fail to achieve ...complete response (CR) with uMRD. Liso-cel is an investigational, anti-CD19, defined composition, 4-1BB CAR T cell product administered at a target dose of CD4+ and CD8+ CAR T cells. TRANSCEND CLL 004 is an open-label phase 1/2 study of liso-cel in pts with R/R CLL/SLL (NCT03331198).
Methods: Eligible pts with CLL/SLL had received at least 3 (standard-risk disease) or at least 2 (high-risk disease: del17p, TP53 mutation, unmutated IGHV, or complex karyotype) prior lines of therapy, including a Bruton's tyrosine kinase inhibitor unless contraindicated. Pts with active untreated central nervous system disease, Eastern Cooperative Oncology Group performance status >1, or Richter's transformation were excluded. After 3 days of lymphodepletion with fludarabine/cyclophosphamide, pts received liso-cel infusion; 2 dose levels (DLs) were tested: DL1=50×106 and DL2=100×106 CAR+ T cells. Dose-limiting toxicities (DLTs) were evaluated for 28 days postinfusion. Responses were assessed by 2018 International Workshop on CLL criteria. MRD was assessed at a sensitivity of ≤10-4 in blood and/or bone marrow (BM) lymphocytes. Liso-cel CAR T cells were monitored by flow cytometry of blood cells from treated pts over time. Serum cytokines and chemokines were assessed via an electrochemiluminescence platform.
Results: At data cutoff, 23 pts were evaluable for safety and 22 for efficacy. Median age was 66 (range, 49‒79) years; 83% (19/23) of pts had high-risk disease. Pts had a median of 5 (range, 2‒11) prior therapies. All pts had received prior ibrutinib; 56.5% (13/23) had progressed on ibrutinib and received therapy with venetoclax; 91% (21/23) were refractory to, or had relapsed on, ibrutinib; and 9% (n=2) were intolerant to ibrutinib. Liso-cel was successfully manufactured in 96% of pts, with the established process. Nine pts were treated at DL1 and 14 pts at DL2. Two pts had DLTs (all at DL2: grade 4 hypertension in 1 pt; grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor lysis syndrome in 1 pt). The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia, 70%; anemia, 96%; neutropenia, 56.5%; leukopenia, 43.5%. Two pts had grade 3 cytokine release syndrome (CRS); 5 pts had grade ≥3 neurological events (NEs), including encephalopathy (n=3). Median time to onset of CRS and NE was 4 (range, 1-10) days and 4 (range, 2-21) days, respectively. The median duration of CRS and NE was 5 (range, 2-30) days and 21 (range, 6-169) days, respectively. To manage CRS and/or NE, 61% (n=14) of pts received tocilizumab and 48% (n=11) received corticosteroids. Lymph node tumor burden correlated with NE (P=0.025). Additional disease distribution correlates are being evaluated and will be presented. Cytokine analyses revealed that NE onset was preceded by elevated TNFα and IL16 early after liso-cel infusion (P<0.01). The table shows best responses at median follow-up of 9 months. Among evaluable pts, the best overall response rate was 82%; the best CR/CRi rate was 45.5%. Sixty-eight percent (15/22) of pts achieved objective response by Day 30; 78% (7/9) of responders with ≥9 months of postdose follow-up have remained progression-free. In 6 pts, responses deepened over time (3 from partial response PR to CR, 2 from stable disease SD to PR, and 1 from SD to CR). Among 20 pts evaluable for MRD, most achieved blood and/or BM uMRD (Table); 60% (12/20) achieved BM uMRD by Day 30. All pts who achieved blood and/or BM uMRD have remained uMRD to date.
Conclusions: In this population of heavily pretreated pts with R/R CLL/SLL (all received prior ibrutinib and half failed both prior venetoclax and ibrutinib), liso-cel toxicities, including CRS and NE, were manageable at both DLs tested. Objective responses, CRs, and uMRD were rapidly achieved, with durable responses past 6 months. Updated safety, pharmacokinetic, and efficacy results from the phase 1 monotherapy part of the study will be reported. The phase 2 portion of the study is currently enrolling at DL2.
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Siddiqi:Kite, A Gilead Company: Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; PCYC: Consultancy, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; BeiGene: Research Funding. Soumerai:BeiGene: Research Funding; BostonGene: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Genentech/Roche: Research Funding; TG therapeutics: Research Funding. Dorritie:Juno: Research Funding. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Kipps:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Gillenwater:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Gong:Celgene: Employment, Equity Ownership. Dubovsky:Celgene: Employment. Rytlewski:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership; Adaptive Biotechnologies: Equity Ownership. Yang:Juno Therapeutics, a Celgene Company: Employment. Wierda:AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Juno Therapeutics: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Cyclcel: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding.
Until the late 1980s, the former South Korean tobacco monopoly KT&G was focused on the protected domestic market. The opening of the market to foreign competition, under pressure from the U.S. Trade ...Representative, led to a steady erosion of market share over the next 10 years. Drawing on company documents and industry sources, this paper examines the adaptation of KT&G to the globalization of the South Korean tobacco industry since the 1990s. It is argued that KT&G has shifted from a domestic monopoly to an outward-looking, globally oriented business in response to the influx of transnational tobacco companies. Like other high-income countries, South Korea has also seen a decline in smoking prevalence as stronger tobacco control measures have been adopted. Faced with a shrinking domestic market, KT&G initially focused on exporting Korean-manufactured cigarettes. Since the mid-2000s, a broader global business strategy has been adopted including the building of overseas manufacturing facilities, establishing strategic partnerships and acquiring foreign companies. Trends in KT&G sales suggest an aspiring transnational tobacco company poised to become a major player in the global tobacco market. This article is part of the special issue 'The emergence of Asian tobacco companies: Implications for global health governance'.
Until the late 1980s, the former South Korean tobacco monopoly KT & G was focused on the protected domestic market. The opening of the market to foreign competition, under pressure from the U.S. ...Trade Representative, led to a steady erosion of market share over the next 10 years. Drawing on company documents and industry sources, this paper examines the adaptation of KT & G to the globalization of the South Korean tobacco industry since the 1990s. It is argued that KT & G has shifted from a domestic monopoly to an outward-looking, globally oriented business in response to the influx of transnational tobacco companies. Like other high-income countries, South Korea has also seen a decline in smoking prevalence as stronger tobacco control measures have been adopted. Faced with a shrinking domestic market, KT & G initially focused on exporting Korean-manufactured cigarettes. Since the mid-2000s, a broader global business strategy has been adopted including the building of overseas manufacturing facilities, establishing strategic partnerships and acquiring foreign companies. Trends in KT & G sales suggest an aspiring transnational tobacco company poised to become a major player in the global tobacco market. This article is part of the special issue 'The emergence of Asian tobacco companies: Implications for global health governance'.
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