ALBERT

Description: Background: Natural killer (NK) cells exhibit innate anti-tumor activity owing to the expression of a multitude of activating receptors. Celularity has developed a GMP process for generating off-the-shelf and allogeneic human Placental Hematopoietic Stem Cell derived Natural Killer (PNK-007) cells. To develop a tumor targeted approach, we have engineered PNK cells to express Chimeric Antigen Receptor (CAR) against tumor antigen CD38. PNK cells expressing CD38 CAR (PNK-CAR38) have enhanced anti-tumor function against CD38+ lymphoma and multiple myeloma (MM) cell lines in pre-clinical studies and do not exhibit on-target off-tumor cytotoxicity against healthy CD38+ cells. Here we report the development of a CD38 CAR specific NK cell therapy. Methods: PNK-CAR38 cells were generated through transduction of human placental CD34+ cells with a retroviral vector carrying second generation anti-CD38 chimeric antigen receptor (CAR2-anti-CD38 A2; CD38scFv-CD28CD3ζ) followed by expansion and differentiation of transduced CD34+ cells into NK cells in presence of cytokines including thrombopoietin, SCF, Flt3 ligand, IL-7, IL-15 and IL-2. The anti-tumor activity of untransduced PNK and PNK-CAR38 cells was assessed against Lymphoma (Daudi and Raji) and Multiple Myeloma (Molp8, LP1 and OPM2) cell lines at various effector to target (E:T) ratios. PNK-CAR38 in vivo anti-tumor activity was assessed in a disseminated lymphoma xenograft model in NSG mice. Briefly, luciferase-expressing Daudi cells (3×106) were intravenously (IV) injected at Day0, followed by IV injection of PNK-CAR38 cells (20×106) at Day1 and Day3. Tumor burden was assessed weekly by Bioluminescence Imaging (BLI). Differences between the groups were calculated using two-tailed Student t-test. Results: Placental CD34+ cells were efficiently gene-modified using a retroviral vector and achieved a median of 64% (range 38% to 87%; n=11 donors) CD38 CAR expression in PNK cells at the end of 35-day culture. The median PNK-CAR38 cell yield achieved was 29,000-fold (range 7,800-48,000 fold; n=8) with NK purity 〉90% measured by CD3-CD56+ population. In vitro an overall improvement in anti-tumor response by PNK-CAR38 over PNK cells was observed. In a NK resistant lymphoma cell line model Daudi, PNK-CAR38 cells from various donors (n=8) elicited 72%±10% lysis versus 6%±3.5% lysis by PNK alone (p

Description: Background: Multiple myeloma remains an incurable malignancy of plasma cells. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a protein that is selectively expressed by B-lineage cells, including Multiple Myeloma (MM) cells, and represents a suitable target for T cell therapy. We have developed an allogeneic T cell therapy approach utilizing genetic engineering of donor-derived T cells to express an anti-BCMA Dimeric Antigen Receptor (DAR) using a proprietary non-viral vector Knock out/knock in (KOKI) technology. Preclinical data demonstrate potent anti-tumor activity both vitro and in vivo against BCMA-expressing MM cell lines. Methods: Anti-BCMA DAR-T cells were generated through genetic engineering of T cells derived from healthy donors by inserting the anti-BCMA DAR construct into the TRAC gene locus, resulting in loss of endogenous TCR expression while expressing the DAR. Distinct DAR constructs were utilized differing only in their intracellular signaling components, namely combinations of 4-1BB, CD28, and CD3zeta. The anti-BCMA DAR-T cells were expanded and purified for subsequent preclinical studies. Using in vitro assays, the different anti-BCMA DAR-T cells were evaluated against multiple myeloma cell lines for specific cytotoxicity as well as stimulus-induced cytokine secretion and cell expansion. The in vivo anti-tumor activity was assessed using luciferase-expressing RPMI8226 cells in NSG mice in a model of disseminated disease. A single dose of anti-BCMA DAR-T cells or relevant control cells was administered, and tumor burden was assessed weekly using bioluminescence imaging. Results: After purification, the anti-BCMA DAR T cells population contained less than 1% TCR-expressing ab T cells. The DAR-positive T cell population was between 20-50%. All anti-BCMA DAR-T cells exhibited BCMA-specific activation, including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. The DAR-T cells using a third generation signaling configuration containing components from 4-1BB, CD28 and CD3zeta signaling domains performed best overall. Conclusions: All tested anti-BCMA DAR-T cells exhibited effective anti-tumor activity. Direct comparison of different cytoplasmic signaling compositions of the DAR allowed for selection of the most potent construct, namely the anti-BCMA DAR utilizing a 3rd generation signaling domain configuration. Based on these data, further development of anti-BCMA DAR-T therapy for hematological malignancies is warranted. These allogeneic abTCR-negative anti-BCMA DAR-T cells have been selected for clinical development. Disclosures Ding: Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Gray:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zhang:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Cao:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Krapf:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Deng:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Wei:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zeldis:Sorrento Therapeutics Inc: Employment, Equity Ownership. Knight:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Guo:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

Description: Background: Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin’s Lymphoma characterized by being incurable with a low response rate and short progression free survival when treated with conventional chemotherapy agents. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved for the treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a del(q5) cytogenetic abnormality. Lenalidomide has also shown activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide in relapsed/refractory MCL. Methods: Patients with relapsed/refractory MCL and measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fifteen patients with MCL were enrolled. Median age was 67 (45–84) and 7 were female. Median time from diagnosis to lenalidomide was 5.1 (0.7–12.7) years and median number of prior treatment regimens was 4 (2–6). Eight patients (53%) exhibited an objective response (1 complete response (CR), 1 complete response unconfirmed (CRu) and 6 partial responses (PR)), 2 had stable disease (SD) and 5 had progressive disease (PD). All eight responses were in eleven patients having a tumor burden 〈 50 cm2 and a time since last rituximab therapy of ≥ 230 days. No responses were achieved in four patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of 〈 230 days. Four of 5 patients (80%) with a prior stem cell transplant responded. Progression free survival [PFS] is 5.7 months and ongoing. Seven patients (47%) required at least one dose reduction with a median time to first dose reduction of 2.3 months (1.2–4.9). Grade 4 adverse events were neutropenia (13%), thrombocytopenia (13%), and thromboembolism (13%). Most common Grade 3 adverse events were neutropenia (33%) and leukopenia (20%). Conclusion: Lenalidomide oral monotherapy produced a 53% response rate in relapsed/refractory MCL with manageable side effects.

Description: DVd in combination with Thalidomide (T) and the appropriate supportive care measures resulted in a high response rate (88%) as well as an improved quality response (50% CR & NCR) similar to what is achieved with high dose therapy. Immunomodulatory drugs (IMiDs) are potent T derivatives. R is 50 to 2000 times more potent than T in stimulating T-cell proliferation triggered via the T-cell receptor, and 50 to 100 times more potent than T in augmenting IL-2 and IFN-a production. A recent phase I trial showed responses of at least 25% reduction in paraprotein in 17 (71%) of 24. We therefore initiated a phase I/II trial to define MTD of R in combination with DVd, then we proceeded to expand the MTD dose level to evaluate the efficacy and safety of the combination in patients with Rmm. SWOG criteria were used to assess response, and NCR was defined as a decrease of the M-Protein by 〉90%. Refractory patients were defined as those patients progressing on active therapy. R was started a week prior to DVd in cycle 1 to evaluate different coagulation parameters, from there on R was started on day 1 of therapy. The regimen was given as follows: on day 1 D was given at 40 mg/m2 IVPB; V at 2 mg IVP; d at 40 mg PO daily X 4 days; R was started at 5 mg a day for 21 days with one week off. A standard phase 1 dose escalation of R was performed to identify the MTD. 3 pts were enrolled at each dose level, with up to 6 pts assigned to each dose level, depending on DLT. DVd was repeated q 4W, for a minimum of 4 cycles & 2 cycles after best response. Pts were maintained on R +/− prednisone 50 mg QOD. All patients received amoxicillin, acyclovir and aspirin 81mg prophylactically. 25 pts Rmm pts are enrolled with 21 evaluable for toxicity and mature data available for response on 21 pts (refractory: 15 (71%); relapsed: 6 (29%). 17/21 patients were stage 3, median age of 62 ± 9 years, baseline b2 microglobulin level (mean 5.04 ± 2) and serum albumin (mean 3.4 ± 0.7). 14/21 patients failed T containing regimens. The DLT was sepsis/septic shock that occurred at dose level 3 (R 15mg) with two of the patients developing non neutropenic sepsis. The MTD for R was defined at 10mg. Three patients started therapy with a neutrophil count 〈 500/mL and or platelet counts 〈 50k/mL; all 3 patients were responders. There was one grade 4 hyper-coagulation event in the form of a PE that has recovered. This event occurred in a refractory patient with renal failure performance status of 3 who achieved CR after 2 cycles. In the expanded cohort there was 2 grade 3 neutropenia & one grade 3 neuropathy requiring dose reductions of R and D in each pt with resolution of the neutropenia and neuropathy. 3/21 (14%) patients achieved CR, 4/21 (19%) NCR. All CR+NCR patients (33%) are refractory patients. An additional 7 pts achieved PR, and 6 SD 5 of whom showing greater than 25% decrease in the m-protein. All patients except for 4 achieved 〉 25% reduction of the m-protein after one cycle of therapy and 3/4 after 2 cycles. R at 10mg is the MTD in combination with the DVd in RMM. DVd-R is an extremely effective regimen with a SWOG response rate 〉66%, CR+NCR of 33% in refractory stage 3 patients with minimal toxicity.

Description: Background: Lenalidomide (Revlimid®), an immunomodulatory drug (IMiD®), was recently approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has demonstrated activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma while thalidomide, a less potent IMiD®, has activity in non-Hodgkin’s lymphoma as both monotherapy and in combination with rituximab. Aim: To assess the safety and activity of lenalidomide monotherapy in subjects with relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). Methods: Subjects with relapsed/refractory aggressive NHL following at least 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated or until disease progression. Response and progression are evaluated using the IWLRC methodology. Results: As of July 25, 2006, 32 subjects of a planned 40 have enrolled and 31 have received drug. Twenty-two subjects are currently evaluable for tumor response. The median age of the 22 response-evaluable subjects is 65 (46–83) and 13 are female. Histology is diffuse large B-cell lymphoma [DLBCL] (n=12), follicular center lymphoma grade 3 [FL] (n=3), mantle cell lymphoma [MCL] (n=5) and transformed [TSF] (n=2). Median time from diagnosis to lenalidomide monotherapy is 2.3 (0.7–7) years and median number of prior treatment regimens per subject is 2 (1–6). Seven subjects (32%) exhibited an objective response (2 complete responses unconfirmed (CRu) and 5 partial responses (PR)), 6 had stable disease (SD) for a tumor control rate (TCR) of 59% and 9 progressive disease (PD). Responses were produced in each of the aggressive histologic subtypes studied: DLBCL (3/12), FL (1/3), MCL (2/5) and TSF (1/2). Five of 11 subjects (45%) with 1–2 prior treatment regimens had an objective response, as did 2 of 3 subjects (67%) who had received a prior stem cell transplant. Median time-to-response was 2 months. Grade 3 or 4 adverse events occurred in 18 of 31 (58%) subjects receiving drug. These were predominantly Grade 3 hematological events (neutropenia, thrombocytopenia) with only 4 subjects (13%) experiencing a Grade 4 adverse reaction. Conclusion: Preliminary results indicate that lenalidomide monotherapy is active with manageable side effects in relapsed/refractory aggressive NHL.

Description: Background: Patients with diffuse large B-cell lymphoma (DLBCL) not cured by first line R-CHOP chemotherapy or second line high-dose chemotherapy with autologous stem cell rescue have a poor prognosis and represent a clear unmet medical need. Lenalidomide (Revlimid®), an immunomodulatory drug, has activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory DLBCL. Methods: Patients with relapsed/refractory DLBCL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test was conducted to investigate and characterize associations of prognostic variables with response. Results: Twenty-six patients with DLBCL lymphoma were enrolled. The median age was 66 (45–86) and 13 were female. Median time from diagnosis to lenalidomide was 2.4 (0.5–12) years and median number of prior treatment regimens was 3 (1–6). Three patients (12%) exhibited an objective complete response (1 complete response (CR) and 2 complete responses unconfirmed (CRu)). Two patients had a partial response (PR) for an overall response rate of 19% and 7 had stable disease (SD). Response to lenalidomide was associated with low disease burden (33% for 〈 50 cm2v 0% for ≥ 50 cm2, P=0.06) and longer time from rituximab to lenalidomide treatment (33% for ≥ 230 days v 0% for 〈 230 days, P=0.05). Patients with favorable values for both these prognostic factors (N = 10) had a 50% response rate [RR] (30% CR/CRu RR) compared with a 0% RR for patients with unfavorable values (N = 16; P 〈 0.004) and a progression free survival (ongoing) of 7.4 months v 1.9 months. Although there were no responses in the poor prognosis group, 4 patients exhibited stable disease with an ongoing median PFS of 〉 4.2 months (〉 3.6 - 〉 6.2). Eight patients (31%) required at least one dose reduction with a median time to first dose reduction of 1.8 months (0.4–2.9). One patient each (4%) had Grade 4 anemia, cauda equinine syndrome, febrile neutropenia, intermittent rash, lymphopenia, neutropenia, pneumonitis and thrombocytopenia. Most common Grade 3 adverse events were neutropenia (19%), thrombocytopenia (15%) and leukopenia (12%). Conclusion: The prognostic factors of tumor burden and time from last dose of rituximab appear to identify relapsed/refractory DLBCL patients with a high likelihood of response to lenalidomide oral monotherapy.

Description: Introduction: Lenalidomide (Len), an analog of thalidomide (Thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled phase III trials, Len with dexamethasone (Dex) induced a significantly higher overall response (OR) rate and complete remission (CR) rate, as well as longer time-to-progression (TTP) in comparison with Dex alone. Here, we investigate the long-term overall survival (OS) with Len/Dex. Methods: We evaluated the pooled results from both randomized trials (MM-009, MM-010) of 704 patients who had relapsed or refractory MM, without prior resistance to Dex, who received either Len (25 mg daily for 3 weeks every 4 weeks), or placebo. Dex was given at 40 mg on days 1–4, 9–12, 17–20 every 4 weeks for 4 cycles. From cycle 5 onwards, Dex was given at 40 mg on days 1–4 only. Response rate and TTP are based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Follow-up data on OS were obtained up to January 2007. Forty-seven percent of patients who received placebo/Dex crossed over to receive Len +/− Dex. Results: Of 704 patients, 353 were treated with Len/Dex and 351 with Dex alone. Baseline characteristics were well balanced between patients receiving Len/Dex and those receiving Dex alone. Median TTP, OR, and CR were significantly improved in patients treated with Len/Dex compared with Dex alone (Table). Of patients who progressed on Dex alone prior to unblinding, or were found to be receiving Dex alone after unblinding, 47% crossed over to Len +/− Dex. Despite these patients crossing over to Len +/− Dex at progression or at the time of unblinding, the OS was significantly improved in patients treated with Len/Dex compared with Dex alone (hazard ratio 1.295; 95% confidence interval 1.040–1.614; p=0.02). Median OS in the Len/Dex group was 35 months and 31 in the Dex alone group (p

Description: Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Lenalidomide (L) is an immunomodulatory compound, or IMiD®, which has impressive activity against both relapsed/refractory (RRMM) and newly diagnosed MM (NDMM). Although approximately 15% of NDMM patients (pts) treated with thalidomide (another IMiD®) plus dexamethasone (D)(TD) will develop thromboembolic events (TEEs), less is known about the thrombotic risk associated with LD. In 2 large Phase III studies comparing LD to D + placebo (P)(DP) in RRMM, which did not include routine thrombosis prophylaxis, the overall rate of TEEs in the LD groups were 8 and 14% versus 4% for those treated with DP. Here we describe an unexpectedly higher incidence of TEEs among the first 21 pts enrolled in a Southwest Oncology Group (SWOG) double-blinded Phase III study (S0232) comparing LD to DP in NDMM pts. Methods: Pts received L/P 25 mg/day on days 1–28 plus D 40 mg/day on days 1–4, 9–12, 17–20 for three 35-day induction cycles, followed by L/P 25 mg/day on days 1–21 plus D 40 mg/day on days 1–4, 15–18 in repeating 28-day maintenance cycles. The incidence of TEEs for pts on LD and DP were compared using Fisher’s exact test (two-sided). Baseline clinical data were compared for pts who developed thromboses versus those who did not. Baseline labs, including hemoglobin, platelet count, PT, PTT, D-dimers, fibrinogen, vWF activity, Protein C, Protein S, activated protein C resistance, factor VIII level, and thrombin-antithrombin complexes, were also assessed. Results: Nine of 12 NDMM pts (75%) randomized to LD developed TEEs, compared to zero of 9 (0%) treated with DP (p = 0.0011). All events were lower extremity deep vein thromboses except for one ischemic stroke. Events occurred after a median of 50 days of therapy. There was no association between myeloma stage, pt age or gender, or M-protein Ig subtype and the risk of thrombosis. Although baseline fVIII and vWF levels were elevated in the majority of pts (median 169 and 164.5, respectively) neither these nor other coagulation lab findings correlated with the risk of thrombosis. In all cases except the one pt who suffered a stroke, LD was resumed after full anticoagulation was instituted. Discussion: The 75% incidence of thrombosis for the first 12 newly diagnosed pts treated with LD on S0232 was much higher than expected. No other predictive risk factors, including coagulation-related laboratory abnormalities, were identified. The incidence of thrombosis for pts with NDMM treated on a prior Phase II study of LD administered in 28-day cycles with daily ASA prophylaxis (325 mg/day) was extremely low. This experience, plus evidence that ASA (81 mg/day or 325 mg/day) reduces the risk of TEEs in pts treated with TD or T plus chemotherapy, prompted us to amend the protocol to include ASA 325 mg daily for all pts. The impact of ASA prophylaxis on the incidence of TEEs in pts enrolled subsequent to the 21 pts described here will be reported at the meeting.