Search

Summary Background Treatment of multiple myeloma is not curative, but targeting CD38 improves patient survival. To further explore this therapeutic approach, we investigated the safety and activity of MOR202, a novel monoclonal antibody targeting CD38, in patients with multiple myeloma. Methods This is a multicentre, open-label, phase 1–2a trial done at ten hospitals in Germany and Austria. Enrolled patients were aged 18 years or older with relapsed or refractory multiple myeloma and Karnofsky performance status of 60% or higher. Patients were assigned to the different treatment regimens with MOR202 ranging between 0·01 mg/kg and 16 mg/kg in a 3 + 3 design. Dose-escalation and expansion was done either with MOR202 intravenous infusions alone (MOR202 q2w [twice a week] and q1w [weekly] groups) or in combination with dexamethasone (MOR202 with dexamethasone group), with dexamethasone plus pomalidomide (MOR202 with dexamethasone plus pomalidomide group) or plus lenalidomide (MOR202 with dexamethasone plus lenalidomide group). Primary endpoints were safety, MOR202 maximum tolerated dose (or recommended dose) and regimen, and immunogenicity. The primary analysis was assessed in the safety population, which included patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov , NCT01421186 . Findings Between Aug 24, 2011, and Aug 1, 2017, 91 patients were treated, 35 with MOR202 monotherapy, and 56 with MOR202 combination regimens (18 in the MOR202 with dexamethasone group, 21 in the MOR202 with dexamethasone plus pomalidomide group, and 17 in the MOR202 with dexamethasone plus lenalidomide group). MOR202 intravenous infusions were safely administered within 30 min. Infusion-related reactions occurred in 14 (40%) of 35 patients receiving MOR202 monotherapy without steroids, and in four (7%) of 56 patients receiving MOR202 combination treatment. MOR202 maximum tolerated dose was not reached and the recommended regimens were MOR202 administered as an intravenous infusion for 30 min at doses up to 16 mg/kg with dexamethasone (40 mg), or in combination with dexamethasone plus lenalidomide (25 mg) or pomalidomide (4 mg). 35 (38%) of 91 patients developed lymphopenia, 30 (33%) developed neutropenia, and 27 (30%) developed leukopenia; these were the most common grade 3 or higher treatment-emergent adverse events. Serious adverse events were reported in 51 (56%) of 91 patients. None of the deaths were associated with MOR202. One pomalidomide-associated death occurred in the MOR202 with dexamethasone plus pomalidomide group. No anti-MOR202 antibodies were detected in patients. Interpretation MOR202 is safe and its clinical activity in patients with relapsed or refractory multiple myeloma is promising. Further clinical investigations of combinations with an immunomodulatory drug and dexamethasone are recommended. Funding MorphoSys AG.

Introduction Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT) have a poor prognosis. Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19, which is broadly expressed across B-cell malignancies, including DLBCL. The immunomodulatory drug lenalidomide (LEN) has antiproliferative and antiangiogenic effects. L-MIND (NCT02399085) is an ongoing, open-label, single-arm, Phase II study of tafasitamab + LEN in patients with R/R DLBCL who are ineligible for ASCT. L-MIND results from prespecified patient subgroup analyses were presented previously (primary analysis: data cut-off Nov 30, 2018). Here, we report long-term clinical efficacy from the L-MIND study after a median follow-up of 31.8 months for overall survival (OS) (data cut-off: Nov 30, 2019). Methods Patients enrolled were aged ≥18 years with R/R DLBCL (1-3 prior systemic therapies, including ≥1 CD20-targeting regimen), ASCT-ineligible and with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12. LEN (25 mg orally) was administered on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint is objective response rate (ORR; partial response [PR] + complete response [CR]), assessed centrally by an independent review committee. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), OS and safety analyses. Results Of 81 patients enrolled, 80 patients received tafasitamab + LEN and were included in the full analysis set (FAS) for efficacy. Median follow-up was 22.7 months. In the FAS, ORR was 57.5% (95% confidence interval [CI]: 45.9-68.5) (Figure 1A). The CR rate was 40.0% (n=32/80), of which 90.6% (n=29/32) were PET-confirmed. Median time to response (PR or CR) was 2.0 months and median time to CR was 6.1 months. Median DOR was 34.6 months (95% CI: 26.1-34.6); median PFS was 12.1 months (95% CI: 6.3-not reached [NR]); and median OS was 31.6 months (95% CI: 18.3-NR). The 24-month DOR and OS rates were 71.3% (95% CI: 52.8-83.7) (Figure 1B) and 57.2% (95% CI: 45.1-67.5) (Figure 1C), respectively. In the subgroup analysis, patients with CR as best objective response had better outcomes than those with PR: median DOR, NR (95% CI: 26.1-NR) vs 5.6 months (95% CI: 2.2-34.6); 24-month DOR rate, 86.4% (95% CI: 61.3-95.7) vs 38.5% (95% CI: 14.1-62.8); and 24-month OS rate, 90.6% vs 42.7%. Patients with 1 prior line of therapy had a trend for better outcomes than those with ≥2 prior lines: ORR, 67.5% vs 47.5%; 24-month OS rate, 67.9% vs 46.3%. The 24-month DOR rate was similar by the number of prior lines (1 prior line: 67.9% [95% CI: 42.5-84.0] vs ≥2 prior lines: 77.8% [95% CI: 51.1-91.0]). ORR was similar by primary refractory vs non-primary refractory status (53.3% vs 58.5%); however, primary refractory status impacted 24-month DOR (50.0% vs 74.8%, respectively). Patients refractory to their last line of therapy achieved similar ORRs to those who were not (60.0% vs 55.6%). The 24-month DOR was similar regardless of refractory status to last therapy (Figure 1B), and 24-month OS rates were higher in non-refractory patients (Figure 1C). As expected, patients with a low/low-intermediate International Prognostic Index score had better outcomes than those with an intermediate-high/high score: ORR, 67.5% vs 47.5%; 24-month DOR rate, 92.1% vs 44.3%; and 24-month OS rate, 76.5% vs 36.5%. Based on the Hans algorithm, outcomes were encouraging independent of germinal center B-cell (GCB) DLBCL (n=38) or non-GCB DLBCL (n=22) disease: ORR, 47.4% vs 68.2%; median DOR, 34.6 vs 26.1 months; 24-month DOR rate, 66.7% vs 62.9%; and 24-month OS rate, 51.3% vs 65.0%. Conclusions Long-term L-MIND subgroup data show that encouraging activity observed at primary analysis remains durable after ≥2 years of follow-up; patients with CR continue to experience long DOR and high OS. Although the influence of poor prognosis risk factors is still evident, the clinical activity of tafasitamab in combination with LEN followed by tafasitamab monotherapy continues to show promise in difficult-to-treat ASCT-ineligible patients with R/R DLBCL. Disclosures Maddocks: Pharmacyclics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Duell:Morphosys: Research Funding. González-Barca:Sandoz: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Roche: Honoraria; MorphoSys: Other; Celtrion: Consultancy; Kiowa: Consultancy; Celgene: Consultancy. Jurczak:Janssen, MeiPharma, Merck, Pharmacyclics, Roche, Tekeda, TG Therapeutics: Research Funding; Jagiellonian University: Ended employment in the past 24 months, Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology: Consultancy, Current Employment. Liberati:Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Janssen: Honoraria, Research Funding; Oncopeptides: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Onconova: Research Funding; Verastem: Research Funding. de Vos:Bayer: Consultancy; Verastem: Consultancy. Nagy:MorphoSys AG: Patents & Royalties. Obr:Roche: Honoraria. Gaidano:Sunesys: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. André:Celgene: Other, Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy, Research Funding; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Takeda: Consultancy; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment. Dreyling:Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astra Zeneca: Consultancy; Beigene: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau. Menne:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Travel costs, Speakers Bureau; Pfizer: Honoraria, Other: Travel costs, Speakers Bureau; Celgene: Honoraria, Other: Travel grants; Roche: Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Takeda: Honoraria, Speakers Bureau. Dirnberger-Hertweck:MorphoSys AG: Current Employment. Weirather:MorphoSys AG: Current Employment. Ambarkhane:MorphoSys AG: Current Employment. Salles:Takeda: Honoraria; BMS/Celgene: Honoraria, Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; Epizyme: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria.

Tafasitamab; B-cell lymphoma Tafasitamab; Linfoma de células B Tafasitamab; Limfoma de cèl·lules B Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months’ follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months’ follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.

Patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) whose treatment failed with a Bruton's tyrosine kinase inhibitor have poor outcomes. We investigated tafasitamab plus idelalisib (cohort A) or venetoclax (cohort B) in this patient population in a phase II study (NCT02639910). In total, 24 patients were enrolled (cohort A: n = 11, median time on study, 7.4 months; cohort B: n = 13, median time on study, 15.6 months). The most common treatment-emergent adverse event (TEAE) in cohort A was anemia (63.6%) and in cohort B was infusion-related reaction (53.8%). The most common severe TEAE was neutropenia (cohort A: 45.5%; cohort B: 46.2%). The best overall response rate was 90.9% (cohort A) and 76.9% (cohort B). Undetectable minimal residual disease in peripheral blood was achieved in 2/8 patients (cohort A) and 6/7 patients (cohort B). Overall, these results suggest that anti-CD19 antibody-based combinations may be important in the treatment of patients with CLL.

Summary Background Patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for autologous stem-cell transplantation have poor outcomes and few treatment options. Tafasitamab (MOR208) is an Fc-enhanced, humanised, anti-CD19 monoclonal antibody that has shown preclinical and single-agent activity in patients with relapsed or refractory B-cell malignancies. Preclinical data suggested that tafasitamab might act synergistically with lenalidomide. We aimed to assess the antitumour activity and safety of tafasitamab plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for autologous stem-cell transplantation. Methods In this multicentre, open-label, single-arm, phase 2 study (L-MIND), patients older than 18 years with histologically confirmed diffuse large B-cell lymphoma, who relapsed or had refractory disease after previous treatment with one to three systemic regimens (with at least one anti-CD20 therapy), were not candidates for high-dose chemotherapy and subsequent autologous stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0–2, and had measurable disease at baseline were recruited from 35 academic and community hospitals in ten countries. Patients received coadministered intravenous tafasitamab (12 mg/kg) and oral lenalidomide (25 mg/day) for up to 12 cycles (28 days each), followed by tafasitamab monotherapy (in patients with stable disease or better) until disease progression. The primary endpoint was the proportion of patients with an objective response (centrally assessed), defined as a complete or partial response according to the 2007 International Working Group response criteria for malignant lymphoma. Antitumour activity analyses are based on all patients who received at least one dose of both tafasitamab and lenalidomide; safety analyses are based on all patients who received at least one dose of either study medication. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov , NCT02399085 . Findings Between Jan 18, 2016, and Nov 15, 2017, 156 patients were screened: 81 were enrolled and received at least one dose of either study medication, and 80 received at least one dose of both tafasitamab and lenalidomide. Median follow-up was 13·2 months (IQR 7·3–20·4) as of data cutoff on Nov 30, 2018. 48 (60%; 95% CI 48–71) of 80 patients who received tafasitamab plus lenalidomide had an objective response: 34 (43%; 32–54) had a complete response and 14 (18%; 10–28) had a partial response. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (39 [48%] of 81 patients), thrombocytopenia (14 [17%]), and febrile neutropenia (ten [12%]). Serious adverse events occurred in 41 (51%) of 81 patients. The most frequently reported serious adverse events (in two or more patients) were pneumonia (five [6%]), febrile neutropenia (five [6%]), pulmonary embolism (three [4%]), bronchitis (two [2%]), atrial fibrillation (two [2%]), and congestive cardiac failure (two [2%]). Interpretation Tafasitamab in combination with lenalidomide was well tolerated and resulted in a high proportion of patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem-cell transplantation having a complete response, and might represent a new therapeutic option in this setting. Funding MorphoSys.

Introduction Patients with diffuse large B-cell lymphoma (DLBCL) that is refractory to primary immunochemotherapy are well recognized as a high-risk population with poor prognosis, and have a typical median overall survival (OS) of 6-13 months [Farooq U, et al. 2017]. Patients with 'double-hit' (MYCand eitherBCL2orBCL6) and 'triple-hit' (MYC, BCL2andBCL6) genetic aberrations are also considered to be a high-risk/poor prognosis group [Davies A. 2019]. Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal anti-CD19 antibody that is under investigation in combination with lenalidomide (LEN) in autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) DLBCL in the Phase II L-MIND study (NCT02399085) [Salles G, et al. 2020]. We report efficacy data for patients with high-risk DLBCL (primary refractory disease and double/triple-hit lymphoma [DHL/THL]) who received tafasitamab + LEN in L-MIND (data cut-off: Nov 30, 2019; median follow-up for OS, 31.8 months). Methods In the L-MIND study, patients enrolled were aged ≥18 years with R/R DLBCL (1-3 prior systemic therapies, including ≥1 CD20-targeting regimen), with an Eastern Cooperative Oncology Group performance status of 0-2 and ineligible for ASCT. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12. LEN (25 mg orally) was administered on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was objective response rate (ORR) (partial response [PR] + complete response [CR]), assessed centrally by an independent review committee. Primary refractory disease was defined as no response (CR or PR) to or progression during or within 6 months of frontline DLBCL therapy.MYC,BCL2andBCL6aberrations were determined via fluorescencein situhybridization using tumor biopsy. Results The L-MIND cohort included 15 patients with primary refractory DLBCL and two patients with DHL/THL. Patients with primary refractory DLBCL at baseline had a median age of 73 years (range 48-82; n=9 ≥70 years) and were previously exposed to a median of 2 lines of treatment (range 1-4). Of these patients, ten had stage III/IV disease, ten showed lactate dehydrogenase greater than the upper normal limit, 12 patients had germinal center B-cell DLBCL and eight exhibited intermediate-high or high-risk International Prognostic Index (IPI) status at study baseline. All 15 patients received R-CHOP or equivalent as first-line therapy; two patients previously achieved no response, whereas 13 patients had relapsed within 6 months (ten had achieved a CR and 3 a PR) after frontline therapy. Six patients had received only 1 prior therapy, whereas nine patients had ≥2 lines before L-MIND enrollment. Median time to progression after first-line therapy was 162 days (range 28-182 days); two of 15 patients had progressed within 90 days. Of the 15 patients, 13 were refractory to their last line of therapy before L-MIND. In the 15 patients with primary refractory disease, ORR was 53.3% (95% confidence interval [CI]: 26.6-78.7) and the CR rate was 33.3%, with a 30-month duration of response (DOR) rate of 50% (95% CI: 15.2-77.5) - median DOR not reached (NR). Individual response duration is shown in Figure 1 (swimmer plot): four patients who achieved CR remain in remission after >30 months. Median progression-free survival (PFS) was 5.3 months (95% CI: 0.9-NR) and PFS rate at 30 months was 33.9% (95% CI: 11.0-58.8). Median OS was 13.8 months (95% CI: 1.3-NR) and OS at 36 months was 38.1% (95% CI: 14.6-61.6). Regarding patients with DHL/THL: one with DHL achieved PR only; another patient with THL (also part of the primary refractory subgroup) achieved CR and remains in remission after >30 months. Conclusions The combination of tafasitamab + LEN showed encouraging activity, with a clinically meaningful ORR and CR rate in patients with primary refractory DLBCL, and positive responses in DHL and THL. Patients with primary refractory disease were frequently ≥70 years with stage III/IV disease and poor-risk IPI scores. Although these data should be interpreted with caution due to the small patient subgroup sizes, these clinically relevant results warrant further research with this immunotherapy in patients with difficult-to-treat DLBCL. Disclosures González-Barca: MorphoSys:Other;Janssen:Consultancy, Honoraria;Sandoz:Consultancy;Gilead:Consultancy;Roche:Honoraria;Takeda:Honoraria;Abbvie:Honoraria;Celgene:Consultancy;Kiowa:Consultancy;Celtrion:Consultancy.Duell:Morphosys:Research Funding.Sancho:Bristol-Myers Squibb:Honoraria;Celgene:Consultancy, Honoraria;Gilead:Consultancy, Honoraria;Janssen:Consultancy, Honoraria;Kern-Pharma:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;Roche:Consultancy, Honoraria;Takeda:Honoraria;Celltrion:Consultancy;Sandoz:Consultancy.Nagy:MorphoSys AG:Patents & Royalties.Abrisqueta:Celgene:Consultancy, Honoraria;AbbVie:Consultancy, Honoraria, Speakers Bureau;Roche:Consultancy, Honoraria, Speakers Bureau;Janssen:Consultancy, Honoraria, Speakers Bureau.Panizo:Clínica Universidad de Navarra:Current Employment;Bristol-Myers Squibb, Kyowa Kirin:Speakers Bureau;Janssen, Roche:Membership on an entity's Board of Directors or advisory committees.Augustin:Morphosys:Research Funding;AstraZeneca:Consultancy, Research Funding;Roche:Consultancy;Novartis:Consultancy, Research Funding;Merck:Consultancy;IPSEN:Consultancy, Research Funding;Pfizer:Consultancy, Research Funding;BMS:Consultancy, Research Funding.Weirather:MorphoSys AG:Current Employment.Ambarkhane:MorphoSys AG:Current Employment.Maddocks:Seattle Genetics:Consultancy, Honoraria;Celgene:Consultancy, Honoraria;Pharmacyclics:Consultancy, Honoraria;Morphosys:Consultancy, Honoraria;ADC Therapeutics, AstraZeneca:Consultancy;BMS:Consultancy, Research Funding;Karyopharm:Consultancy.Kalakonda:Celgene:Research Funding.Salles:BMS/Celgene:Honoraria, Other: consultancy or advisory role;Takeda:Honoraria;Karyopharm:Honoraria;Genmab:Honoraria, Other;Debiopharm:Consultancy, Honoraria, Other: consultancy or advisory role;Autolos:Other: consultancy or advisory role;Abbvie:Other: consultancy or advisory role;Roche:Honoraria, Other: consultancy or advisory role;Novartis:Honoraria, Other: consultancy or advisory role;MorphoSys:Honoraria, Other: consultancy or advisory role;Janssen:Honoraria, Other: consultancy or advisory role;Epizyme:Honoraria, Other: consultancy or advisory role;Kite, a Gilead Company:Honoraria, Other: consultancy or advisory role .

Context: Tafasitamab, a humanized anti-CD19 antibody, has demonstrated encouraging activity with durable responses with lenalidomide (LEN) in autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the Phase II L-MIND study ( NCT02399085 ). In the primary analysis (cut-off November 30, 2018), the objective response rate (ORR) was 60.0%, median duration of response (DOR) was 21.7 months and median follow-up was 17.3 months. Objective: To report the long-term clinical efficacy and safety of tafasitamab + LEN in the L-MIND study after one additional year of follow-up (cut-off November 30, 2019). Design & Setting: An open-label, single-arm, Phase II study. Patients: Aged ≥18 years with R/R DLBCL (1–3 prior systemic therapies, including ≥1 CD20-targeting regimen), an ECOG performance status 0–2, and ASCT ineligible. Interventions: Tafasitamab (12 mg/kg intravenously, 28-day cycles) was administered once weekly during Cycles 1–3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4–12. LEN (25 mg orally) was self-administered on Days 1–21 of Cycles 1–12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. Main Outcome Measure(s): The primary endpoint was ORR (independent review committee). Secondary endpoints included DOR, progression-free survival (PFS), overall survival (OS), and safety. Results: In this long-term analysis, 80 of 81 enrolled patients received tafasitamab + LEN and were included in the efficacy analysis. ORR was 58.8% (n=47/80); 41.3% (n=33/80) with complete response; and 17.5% (n=14/80) with partial response. Median DOR was 34.6 months (95% confidence interval [CI]: 26.1–not reached [NR]). Median OS was 31.6 months (95% CI: 18.3–NR) with a median follow-up of 31.8 months. Median PFS was 16.2 months (95% CI: 6.3–NR) with a median follow-up of 22.6 months. No unexpected toxicities were reported. Conclusions: After a minimum of two years' follow-up, outcomes are consistent with the primary analysis and confirm the durability of response and meaningful OS of tafasitamab + LEN followed by tafasitamab in ASCT-ineligible patients with R/R DLBCL. Along with an acceptable safety profile, these data support a clinically relevant benefit with this immunological combination.

7513 Background: L-MIND (NCT02399085) is an ongoing, open-label, Phase II study of tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, plus LEN in ASCT-ineligible patients (pts) with R/R DLBCL. Primary analyses and 2-year efficacy results were previously presented; we report an updated efficacy analysis with ≥35 months follow up (cut-off: October 30, 2020). Methods: Pts were aged ≥18 years with ASCT-ineligible R/R DLBCL, had 1–3 prior systemic therapies (Tx), including ≥1 CD20-targeting regimen, with an ECOG status of 0–2. Pts received 28-day cycles (C) of tafasitamab (12 mg/kg IV), once weekly during C1–3, with a loading dose on Day 4 of C1, then every 2 weeks (Q2W) during C4–12. LEN (25 mg PO) was administered on Days 1–21 of C1–12. After C12, progression-free pts received tafasitamab Q2W until disease progression. The primary endpoint was objective response rate (ORR), assessed by IRC. Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Results: Eighty of 81 enrolled pts received tafasitamab + LEN and were included in the full analysis set (1 prior Tx, n=40; 2+ prior Tx, n=40). At data cut-off, the overall ORR was 57.5% (n=46/80), including complete response (CR) in 40% of pts (n=32/80) and partial response (PR) in 17.5% of pts (n=14/80) (Table). Kaplan-Meier estimates: median DoR=43.9 months (95% CI: 26.1–not reached [NR]), and NR in pts who achieved a CR (95% CI: 43.9–NR); median PFS=11.6 months (95% CI: 6.3–45.7), with median follow-up 33.9 months; median OS=33.5 months (95% CI: 18.3–NR), with median follow-up 42.7 months. There were no unexpected toxicities or new safety signals. Conclusions: Combination Tx with tafasitamab + LEN followed by tafasitamab monotherapy provided durable responses in pts with R/R DLBCL not eligible for ASCT, with a manageable safety profile. These long-term data indicate the potential of tafasitamab + LEN followed by extended tafasitamab monotherapy in achieving prolonged remission and survival benefit in this patient population, especially at first relapse. Clinical trial information: NCT02399085. [Table: see text]

Objective The present study analyzed the effect of CD4 + Forkhead box protein 3 negative (Foxp3 − ) T-cells and Foxp3 + CD4 + T-cells on infarct size in a mouse myocardial ischemia-reperfusion model. Approach and results We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30 minutes of coronary ligation followed by 24 hours of reperfusion. CD4 + T-cell deficient MHC-II KO mice showed smaller histologically determined infarct size (34.5 ± 4.7% in MHCII KO versus 59.4 ± 4.9% in wildtype (WT)) and better preserved ejection fraction determined by magnetic resonance tomography (56.9 ± 2.8% in MHC II KO versus 39.0 ± 4.2% in WT). MHC-II KO mice also displayed better microvascular perfusion than WT mice after 24 hours of reperfusion. Also CD4 + T-cell sufficient OT-II mice, which express an in this context irrelevant T-cell receptor, revealed smaller infarct sizes compared to WT mice. However, MHC-II blocking anti-I-A/I-E antibody treatment was not able to reduce infarct size indicating that autoantigen recognition is not required for the activation of CD4 + T-cells during reperfusion. Flow-cytometric analysis also did not detect CD4 + T-cell activation in heart draining lymph nodes in response to 24 hours of ischemia-reperfusion. Adoptive transfer of CD4 + T-cells in CD4 KO mice increased the infarct size only when including the Foxp3 + CD25 + subset. Depletion of CD4 + Foxp3 + T-cells in DEREG mice enabling specific conditional ablation of this subset by treatment with diphtheria toxin attenuated infarct size as compared to diphtheria toxin treated WT mice. Conclusions CD4 + Foxp3 + T-cells enhance myocardial ischemia-reperfusion injury. CD4 + T-cells exert injurious effects without the need for prior activation by MHC-II restricted autoantigen recognition.

This deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373357/ This publication hasn't any creative commons license associated. In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissue-resident leukocytes and with an accumulation of activated CD4+Foxp3-(forkhead box P3) IFN-γ+T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population. Bundesministerium für Bildung und Forschung grants: (BMBF01, EO1004); German Research Foundation grant: (DFG SFB688, TP A10, and B07); Brazilian National Council for Scientific and Technological Development. info:eu-repo/semantics/publishedVersion

Background— Activation of innate immunity, especially infiltration of monocytes, is critical for proper wound healing and scar formation after myocardial infarction (MI). Therefore, we tested the hypothesis that interleukin-13 (IL-13), which influences the differentiation of monocytes/macrophages and has profibrotic properties, modulates wound healing and remodeling after MI. Methods and Results— MI was induced by permanent ligation of the left coronary artery in both male and female wild-type (WT)/IL-13 −/− mice. Real-time polymerase chain reaction demonstrated that expression of IL-13 was induced in left and right ventricular myocardium of WT mice within days in response to MI. Fifty-six–day survival was significantly impaired (65% in WT versus 34% in IL-13 −/− ) in male but not female IL-13 −/− (55% in WT versus 54% in IL-13 −/− ) mice. Serial echocardiography showed significantly increased left ventricular dilation in male IL-13 −/− compared with WT mice starting from day 1 after MI, despite comparable infarct size. Fluorescence-activated cell sorter analysis revealed less leukocyte infiltration in male IL-13 −/− mice on day 3. Real-time polymerase chain reaction analysis demonstrated reduced expression of marker genes of alternative activation in monocytes sorted from the infarct zone of male IL-13 −/− in comparison with WT mice on day 3 after MI. Conclusions— Genetic deficiency of IL-13 worsens outcome after MI in male mice. Our data indicate that IL-13 regulates leukocyte recruitment and induces M2-like monocyte/macrophage differentiation, which modifies wound healing within the infarct zone.

Background: CD19 is broadly and homogeneously expressed across different B-cell malignancies and represents an attractive target antigen in patients with B-cell non-Hodgkin's lymphoma (NHL). Tafasitamab (MOR208) is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody. This ongoing study is investigating the single agent antitumor activity in adult patients with relapsed or refractory (r/r) NHL who had received at least one prior rituximab-containing therapy. Patients and Methods: The study enrolled 92 r/r NHL patients: diffuse large B-cell lymphoma (DLBCL; n=35), mantle cell lymphoma (MCL; n=12), follicular lymphoma (FL; n=34), or other indolent NHL (iNHL; n=11). The median number of prior systemic therapies was three (range 1-15) for the entire patient population. The primary efficacy endpoint was investigator-assessed overall response rate (ORR) based on the revised International Working Group Response Criteria (Cheson et al., et al. J Clin Oncol 2007). Secondary objectives were to evaluate the time-to-response, duration of response (DoR), time to progression and progression-free survival (PFS), and to establish the safety and tolerability of tafasitamab. Patients received up to three 28-day cycles with weekly infusions of 12 mg/kg body weight of tafasitamab. Premedication, including antipyretics, histamine H1 receptor blockers and glucocorticosteroids, was administered for the first three infusions. Patients with ongoing at least partial remission (PR) at the end of Cycle 3 received further tafasitamab treatment until disease progression, either monthly or every second week. Results: The investigator-assessed best response (intent-to-treat analysis) in the different subgroups at cut-off date (28 Sep 2018) is shown in Table 1. Five patients in complete remission (CR) (one DLBCL, two FL, two other iNHL) were ongoing and still on tafasitamab treatment at the cut-off date. These patients were on treatment for more than 4 years. The median DoR was 20.1 months in DLBCL and 24 months in FL (Table 2). The median PFS was 2.7 (95% confidence interval [CI] 2.1-13.2 months) and 6.6 months (95% CI 5.3-20.5 months) in DLBCL and FL, respectively. The PFS rate at 12 months was 34.3% and 39.2% for DLBCL and FL, respectively (Table 2). Similar PFS was observed in rituximab-refractory as well as non-refractory patients. Patients with a peripheral blood natural killer (NK) cell count >100 cells/µL at baseline had a median PFS of 4.2 months (DLBCL) or 8.8 months (FL/iNHL), as compared with patients who had Conclusion: Tafasitamab monotherapy until progression resulted in durable responses and was well tolerated in patients with both aggressive and indolent NHL subtypes. Disclosures Jurczak: Celgene: Research Funding; Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Servier: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; MorphoSys: Research Funding; Celtrion: Research Funding; Gilead: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Incyte: Research Funding. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hess:Janssen: Consultancy, Honoraria, Other: personal fees; Celgene: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; Roche: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; Pfizer: Other: personal fees, Research Funding; CTI: Consultancy, Employment, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria. Provencio:Takeda: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Novartis: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; AstraZeneca: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Pierre Fabre: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Boehringer Ingelheim: Consultancy, Other: Travel, accommodation and expenses, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel, accommodation and expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; MSD: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau. Nagy:Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Robak:Morphosys AG: Research Funding; BeiGene: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding. Maddocks:Teva: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Buske:Amgen: Research Funding; Bayer: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau; Hexal: Honoraria, Speakers Bureau. Ambarkhane:MorphoSys: Employment. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Dirnberger-Hertweck:MorphoSys: Employment. Tillmanns:MorphoSys AG: Employment. Weirather:MorphoSys: Employment.

Introduction Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT) have a poor prognosis. Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19, which is broadly expressed across B-cell malignancies, including DLBCL. Lenalidomide (LEN) is an immunomodulatory drug with antiproliferative and antiangiogenic effects. Combined tafasitamab + LEN has shown enhanced activity in in vitro and in vivo lymphoma models. L-MIND (NCT02399085) is an ongoing, open-label, single-arm, Phase II study of tafasitamab + LEN in patients with R/R DLBCL who are ineligible for ASCT. Here, we present results from prespecified patient subgroup analyses from L-MIND. Methods Patients aged ≥18 years with R/R DLBCL (1-3 prior systemic therapies, including ≥1 CD20-targeting regimen) with an Eastern Cooperative Oncology Group performance status 0-2, and who were ineligible for ASCT were enrolled. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12. LEN (25 mg orally) was administered on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint is objective response rate (ORR; partial response [PR] + complete response [CR]), assessed centrally by an independent review committee (IRC) per International Working Group criteria 2007, incorporating PET-based imaging. Secondary endpoints include ORR (investigator-assessed), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and biomarker analyses. Results Of 81 patients enrolled, 80 patients received tafasitamab + LEN and were included in the full analysis set (FAS) for efficacy (data cut-off 30 Nov 2018). Median follow-up was 17.3 months. In the FAS, ORR was 60.0% (95% confidence interval [CI]: 48.4-70.8) (Figure 1A). The CR rate was 42.5% (n=34/80), of which 88.2% (n=30/34) were PET-confirmed. Median time to response (PR or CR) was 2.0 months and median time to CR was 7.1 months. Median DOR was 21.7 months (95% CI: 21.7-not reached [NR]); median PFS was 12.1 months (95% CI: 5.7-NR); and median OS was NR (95% CI: 18.3-NR) with a median follow-up of 19.6 months. The 12-month DOR and OS rates were 71.6% (95% CI: 55.1-82.9) (Figure 1B) and 73.7% (95% CI: 62.2-82.2) (Figure 1C), respectively. In the subgroup analysis, patients with CR as best objective response (BOR) had better outcomes than those with PR: median DOR, NR (95% CI: 21.7-NR) vs 4.4 months (95% CI: 2.0-9.1); 12-month DOR rate, 93.2% (95% CI: 75.4-98.3) vs 14.4% (95% CI: 1.1-43.7); and 12-month OS rate, 97.1% vs 76.9%. Patients with one prior line of therapy had a trend for better outcomes than those with ≥2 prior lines: ORR, 70.0% vs 50.0%; and 12-month OS rate, 86.9% vs 60.1%. However, the 12-month DOR rate was similar regardless of the number of prior lines (one prior line: 70.5% [95% CI: 47.2-85.0] vs ≥2 prior lines: 72.7% [95% CI: 46.3-87.6]). For patients who were refractory to primary therapy or their last line of therapy, similar ORRs were observed to non-refractory patients (60.0% vs 60.0%); 12-month DOR was similar regardless of refractory status to last therapy; and 12-month OS rates were higher in non-refractory patients (Figure 1C). As expected, patients with a low/low-intermediate International Prognostic Index (IPI) score had better outcomes than those with an intermediate-high/high score: ORR, 70.0% vs 50.0%; 12-month DOR rate, 86.5% vs 50.4%; and 12-month OS rate, 87.0% vs 59.9%. Based on Hans algorithm, encouraging outcomes were reported in patients with germinal center B-cell (GCB) DLBCL (n=37), and outcomes were even better in those with non-GCB DLBCL (n=21): ORR, 48.6% vs 71.4%; median DOR, NR vs 21.7 months; 12-month DOR rate, 53.5% vs 83.1%; and 12-month OS rate, 65.4% vs 84.2%. Conclusions Tafasitamab + LEN combination followed by tafasitamab monotherapy shows encouraging activity with durable responses in ASCT-ineligible patients with R/R DLBCL. L-MIND includes a substantial number of poor prognosis patient subgroups. While the influence of these risk factors is evident, the clinical activity of tafasitamab + LEN in these difficult-to-treat patients is promising, particularly in those who were refractory to prior therapies. Disclosures Duell: Regeneron Pharmaceuticals, Inc.: Research Funding. Maddocks:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Merck: Research Funding; BMS: Research Funding. González-Barca:Janssen: Consultancy, Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Honoraria. Jurczak:TG Therapeutics: Research Funding; Roche: Research Funding; Takeda: Research Funding; Servier: Research Funding; Celtrion: Research Funding; Novo Nordisk: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Liberati:Incyte: Consultancy; Janssen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol & Mayer: Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Nagy:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Dreyling:Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Novartis: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board; Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau. Menne:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau. Dirnberger-Hertweck:MorphoSys: Employment. Weirather:MorphoSys: Employment. Ambarkhane:MorphoSys: Employment. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria.

Introduction: Patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have a poor outcome and are difficult to treat. This ongoing, two-cohort, Phase II trial evaluates the safety and preliminary efficacy of tafasitamab (MOR208), an Fc-enhanced anti-CD19 monoclonal antibody in combination with idelalisib (IDE) (Cohort A) or venetoclax (VEN) (Cohort B) in R/R CLL pts previously treated with a BTKi. Preliminary results were published at EHA 2018 for Cohort A and at ASH 2018 for Cohort B. Here, we report the results of the primary analysis for both cohorts. Methods and Patients: Pts who either progressed or were intolerant to BTKi were enrolled at 12 sites in six countries in Europe and the US from Nov 2016 to Apr 2018. The primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to International Workshop on CLL (IWCLL) 2008 guidelines. Complete response (CR) was confirmed by computed tomography assessment and by bone marrow (BM) biopsy. The exploratory endpoint minimal residual disease (MRD) was assessed centrally by quantitative allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and BM. Each treatment cycle (C) lasts 28 days (D). Dose and administration: tafasitamab intravenous infusion, 12 mg/kg weekly in C1-C3, every other week in C4-C6 and monthly from C7D1; IDE orally, 150 mg twice daily; VEN orally, weekly ramp up starting on C1D8 at 20 mg to full daily dose of 400 mg. Patients: mean time since first CLL diagnosis was 135 months (mos) for pts in Cohort A and 105 mos in Cohort B. Median number of prior therapy lines was five (2-9) and three (1-5), respectively. All pts had received ibrutinib; one pt had subsequent acalabrutinib treatment as last prior therapy line. Mutations of BTK and PLCγ2 were assessed in nine pts in Cohort A and 13 pts in Cohort B. BTK/PLCγ2 mutations were centrally detected in 4/3 pts in Cohort A and in 2/3 pts in Cohort B, respectively. Complex karyotype was observed in six (54.5%) pts in Cohort A and 12 (92.3%) pts in Cohort B. Results with a data cut-off date of 9 Nov 2018 are presented. Results: Cohort A: Median time on study was 9.9 mos (95% confidence interval [CI]: 5.7-not reached). Eleven pts were enrolled and received tafasitamab and IDE. Two pts discontinued treatment due to AEs (aspartate-aminotransferase increased; acute pancreatitis), two due to progressive disease (PD) and one pt by physician's decision. One pt died due to PD and one pt due to cardiac failure. At the cut-off date, treatment was ongoing in four pts. Table 1 summarizes treatment-emergent adverse events (TEAEs) with neutropenia Grade ≥3 being most common (5 [46%]). Fourteen treatment-emergent serious AEs (SAEs) were reported in eight (72.7%) pts. ORR was 90.9% (CR=9.1%, partial response [PR]=81.8%), disease control was achieved in all 11 pts. One of eight pts (12.5%) assessed for MRD status reached MRD-negativity in PB at C14. Cohort B: Median time on study was 12 mos (95% CI: 2.8-not reached). Eleven of 13 enrolled pts received tafasitamab and VEN while two pts received tafasitamab only. Three pts discontinued treatment due to AEs (infusion-related reactions [two pts], diarrhea [one pt], one due to PD and one withdrew consent. At the cut-off date, treatment was ongoing in eight patients. Table 2 summarizes TEAEs, neutropenia Grade ≥3 was most commonly observed (six [46%] pts). Fourteen SAEs were reported in nine (69.2%) pts. The ORR in all 13 pts was 76.9% (CR=23.1%, PR=53.8%, not evaluable=23.1%). Six of seven pts assessed for MRD in PB (46.2% of 13 [100%] pts) reached negative status in PB by C7 at the latest. One of three pts assessed for MRD in BM (7.7% of 13 [100%] pts) reached MRD negative status in BM at C15. Conclusions: This trial demonstrates that in heavily pretreated pts with R/R CLL who failed prior BTKi, tafasitamab in combination with IDE or VEN is a potential therapeutic option. The safety profiles of the combinations are influenced by the combination partner, but both combinations are manageable. The response rates and MRD-negativity rates indicate that combinations of targeted agents with anti-CD19 tafasitamab have valuable antitumor activity and warrant further investigation of tafasitamab-based combinations in CLL. Disclosures Staber: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene Corporation: Research Funding; Incyte: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Brugger:AstraZeneca: Equity Ownership; MorphoSys: Employment. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Xencor: Research Funding; AbbVie: Research Funding. Greil:Mundipharma: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Sandoz: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Janssen-Cilag: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Middeke:Janssen: Consultancy, Speakers Bureau; MSD: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Roche: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Montillo:Roche: Consultancy, Honoraria, Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees. Munir:Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: TBC; AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy. Parikh:Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; MorphoSys: Research Funding; Acerta Pharma: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weirather:MorphoSys: Employment. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background The rupture of atherosclerotic plaques is triggered by inflammation. Specific detection of inflammation is therefore the focus of many investigations. Noninvasive imaging methods, such as positron emission tomography (PET), also are suited for this purpose. 68 Ga-DOTATATE is a 68 Ga-labeled radiotracer with specific affinity to somatostatin receptor subtype-2 (SSTR-2). SSTR-2 was found specifically expressed on human macrophages/monocytes. Objective We aimed to confirm the distribution of SSTR-2 in inflammatory plaques, and to assess its co-localization with macrophages within the plaques. We also assessed 68 Ga-DOTATATE uptakes in plaques by autoradiography. Method Apolipoprotein E (ApoE)−/− mice on a high-cholesterol diet were injected with 68 Ga-DOTATATE. The animals were sacrificed and aorta sections were examined using autoradiography and immunohistochemistry. Furthermore, expression of SSTR-2 was analyzed by flow cytometry. Western blot was conducted to assess SSTR-2 regulation in basal and lipopolysaccharide (LPS)-activated state. To evaluate the specificity of the 68 Ga-DOTATATE, the sections were pre-incubated with monoclonal SSTR-2 antibody before autoradiography. Result Autoradiographic imaging showed uptake of 68 Ga-DOTATATE co-localized with the macrophage-rich plaques by immunohistochemical examination. A high expression of SSTR-2 on macrophages was found by flow cytometry and western blot. Stimulation with lipopolysaccharide did not alter expression of SSTR-2 in macrophages. Conclusion Due to its specific binding to macrophages, 68 Ga-DOTATATE might be a suitable radiotracer for the evaluation of inflammatory activity in unstable plaques.

The present study analyzed the effect of CD4We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30minutes of coronary ligation followed by 24hours of reperfusion. CD4CD4

Introduction: The CD19 antigen is broadly and homogeneously expressed across different B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). MOR208 is an Fc-enhanced, humanized, monoclonal antibody that targets CD19, leading to natural killer (NK) cell-mediated antibody-dependent cytotoxicity, macrophage-mediated antibody-dependent phagocytosis and direct cytotoxicity. The immunomodulatory drug, lenalidomide (LEN), has both antiproliferative and antiangiogenic effects, and can stimulate the activity of immune effectors, such as NK cells. MOR208 and LEN have each shown single agent activity in patients with relapsed or refractory (R-R) DLBCL. In addition, MOR208 and LEN have shown synergy in in vitro and in vivo lymphoma models. We present results of an ongoing, multicenter phase II study designed to assess the safety and efficacy of MOR208 combined with LEN in patients with R-R DLBCL (NCT02399085). Methods:Patients >18 years of age diagnosed with DLBCL, an Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function, who had relapsed after or were refractory to at least one but not more than three prior systemic therapies, including at least one CD20-targeting regimen, and who were not candidates for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), were eligible. Patients with primary refractory disease (defined as no response to or progression during or within 6 months after completion of frontline therapy for DLBCL) were excluded. Treatment comprises up to twelve 28-day cycles of MOR208, administered intravenously at a dose of 12 mg/kg weekly during cycles 1-3 (plus a loading dose on day 4 of cycle 1), and every second week during cycles 4-12. LEN was administered orally at a daily dose of 25 mg on days 1-21 of each cycle, for up to 12 cycles. Patients who were progression-free after 12 cycles received MOR208 every second week until progression. The primary endpoint is the objective response rate (ORR), centrally assessed, as per the International Working Group criteria 2007, incorporating PET-based imaging. Secondary endpoints include ORR as per investigator assessment, duration of response (DoR), progression-free survival (PFS) and overall survival (OS), safety, and analysis of outcomes by cell of origin and other biomarkers. Results: As of November 2017, 81 patients had been enrolled and recruitment is complete. We report here updated preliminary results with a data cutoff of 5 June 2018. Median age was 72 years (range 41-87); 40 (49%) patients had received ≥2 prior lines of therapy (median 2, range 1-4); 31 (38%) had rituximab refractory disease; 33 (41%) were refractory to the previous line of therapy, 43 (53%) had Ann Arbor stage ≥III disease; and 42 (52%) had an International Prognostic Index of 3-5 at study entry, indicating poor prognosis. The most common treatment-emergent adverse events (any grade/grade ≥3) were neutropenia in 39/35 (48%/43%) patients, thrombocytopenia in 26/14 (32%/17%), anemia in 25/7 (31%/9%), diarrhea in 24/1 (30%/1%), pyrexia in 18/1 (22%/1%) and asthenia in 16/2 (20%/2%) patients. Thirty-four (42%) patients required dose reduction with LEN, 58 (72%) patients overall could stay on a daily LEN dose of 20 mg or higher. Based on investigator assessments, complete and partial responses were observed in 27 (33%) and 20 (25%) patients, respectively, resulting in an ORR of 58%. A further 12 (15%) patients had stable disease. With a median follow-up of 12 months, the median PFS was 16.2 months (95% CI: 6.3-not reached [NR]). Responses were durable with a median DoR not reached (95% CI: NR-NR) and 70% of responding patients were without progression at 12 months (Kaplan-Meier estimate). A significant proportion of patients (37/81; 46%) are still on study treatment, with 19 having been treated for over 12 months. Median OS has not been reached (95% CI: 18.6-NR); the 12-month OS rate was 73% (95% CI: 63-85). Conclusions: MOR208 in combination with LEN has shown highly encouraging activity in patients with R-R DLBCL who were ineligible for HDC and ASCT and who had a poor prognosis. These results indicate a significant improvement in outcome for these patients who have very limited treatment options. MOR208 plus LEN was well tolerated in this population, without evidence of additive toxicity. Treatment and follow-up are currently ongoing, as are cell of origin and other biomarker analyses. Disclosures Salles: Novartis: Consultancy, Honoraria; Epizyme: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Acerta: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. González-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Jurczak:Pharmacyclics: Research Funding; MorphoSys: Research Funding; Merck: Research Funding; Nordic Nanovector: Research Funding; Janssen: Research Funding; Epizyme: Research Funding; Celgene: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Afimed: Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy; European Medicines Agency: Consultancy; AstraZeneca: Consultancy; Acerta: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Gaidano:Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kalakonda:Celgene: Research Funding. Dreyling:Bayer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sandoz: Consultancy. Zinzani:Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dirnberger-Hertweck:MorphoSys: Employment. Weirather:MorphoSys: Employment. Ambarkhane:MorphoSys: Employment. Maddocks:Pharmacyclics: Research Funding; Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; AstraZeneca: Honoraria; Teva: Honoraria; Merck: Research Funding; BMS: Research Funding.

Rationale: In patients after acute myocardial infarction (AMI), the initial extent of necrosis and inflammation determine clinical outcome. One early event in AMI is the increased cardiac expression of atrial natriuretic peptide (NP) and B-type NP, with their plasma levels correlating with severity of ischemia. It was shown that NPs, via their cGMP-forming guanylyl cyclase-A (GC-A) receptor and cGMP-dependent kinase I (cGKI), strengthen systemic endothelial barrier properties in acute inflammation. Objective: We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI. Methods and Results: Necrosis and inflammation after experimental AMI were compared between control mice and littermates with endothelial-restricted inactivation of GC-A (knockout mice with endothelial GC-A deletion) or cGKI (knockout mice with endothelial cGKI deletion). Unexpectedly, myocardial infarct size and neutrophil infiltration/activity 2 days after AMI were attenuated in knockout mice with endothelial GC-A deletion and unaltered in knockout mice with endothelial cGKI deletion. Molecular studies revealed that hypoxia and tumor necrosis factor-α, conditions accompanying AMI, reduce the endothelial expression of cGKI and enhance cGMP-stimulated phosphodiesterase 2A (PDE2A) levels. Real-time cAMP measurements in endothelial microdomains using a novel fluorescence resonance energy transfer biosensor revealed that PDE2 mediates NP/cGMP-driven decreases of submembrane cAMP levels. Finally, intravital microscopy studies of the mouse cremaster microcirculation showed that tumor necrosis factor-α–induced endothelial NP/GC-A/cGMP/PDE2 signaling impairs endothelial barrier functions. Conclusions: Hypoxia and cytokines, such as tumor necrosis factor-α, modify the endothelial postreceptor signaling pathways of NPs, with downregulation of cGKI, induction of PDE2A, and altered cGMP/cAMP cross talk. Increased expression of PDE2 can mediate hyperpermeability effects of paracrine endothelial NP/GC-A/cGMP signaling and facilitate neutrophil extravasation during the early phase after MI.

Cardiac remodeling after myocardial infarction (MI) is characterized by deleterious changes in cardiac geometry and constitutes the prevailing pathomechanism in the development of heart failure. Infarct size and the quality of infarct healing represent major remodeling determinants and dictate the severity of maladaptations. After ischemic injury, both coagulative necrosis and a high reactive oxygen burden trigger the immune response comprising humoral and cellular effectors that pivotally modulate postinfarction healing. Notably, a fine-balance between the inflammatory response and inflammation resolution is vital to safeguard proper tissue replacement while preventing an adverse exuberant remodeling. The concept that immunity modulates healing and remodeling after MI has been corroborated over the last decades. Numerous experimental studies indicate that successful immunomodulation improves the clinical outcome post-MI. Where therapeutic approaches have been widely disappointing in the clinical arena, manipulating the immune system may yet constitute a promising modality to ameliorate remodeling in patients with MI.

Although it is well acknowledged that immunological phenomena participate in several cardiac diseases, it has been deeply neglected the fact that the heart is already populated by resident leukocytes before the onset of any sign of disease. In the present work we comprehensively characterized the cardiac-resident leukocyte populations and addressed for the first time in the literature how these cells take part in cardiac physiology and aging. We compared cardiac function, structure and gene expression of healthy naïve C57BL6/J (WT) mice 10 (young), 30 (mid-aged) and 60 (aged) wk old. Flow cytometrical analysis of perfused-digested murine hearts revealed a cardiac-resident leukocyte population comprised of approx. 103 cells/mg (M2-macrophages > B-cells > T-cells > granulocytes). The frequency of resident leukocytes found in cardiac muscle was 17.4 fold higher than in skeletal muscle, suggesting that they might be relevant for cardiac physiology. Importantly, cardiac-resident leukocyte composition shifted towards a pro-inflammatory profile during aging. Additionally, qPCR analysis indicated a significant up-regulation of pro-inflammatory genes such as TNF, IL-1β and IFN-γ in aged mice (e.g. TNF mRNA expression level: 2.1 .10-4 ± 2.0 10-5 in young vs 1.5 .10-3 ± 2.6 .10-4 in aged mice; P < 0.05). Similar results were found regarding to pro-fibrotic and pro-hypertrophic genes expression (e.g. Coll-III, TGF-β and βMyHC). Furthermore, aged WT mice presented increased serum levels of autoantibodies against myosin and higher frequencies of activated T helper cells (CD4+CD69+) in mediastinal lymph nodes as compared to young mice. Echocardiographic and hemodynamic studies revealed that in parallel with increased inflammation, 60 wk old naïve mice spontaneously develop severe cardiac dysfunction (e.g. ejection fraction: 34.6% ± 5.19%). Altogether, these data demonstrated that the heart comprises an important and yet underappreciated resident leukocyte population in the steady-state and that shifts in its composition occur in parallel with the cardiac deterioration observed in aged mice.

Objective— Nuclear imaging of active plaques still remains challenging. Advanced atherosclerotic plaques have a strong expression of P-selectin by the endothelium overlying active atherosclerotic plaques, but not on the endothelium overlying inactive fibrous plaques. We proposed a new approach for noninvasive in vivo characterization of P-selectin on active plaques based on 68 Ga-Fucoidan, which is a polysaccharidic ligand of P-selectin with a nanomolar affinity. Approach and Results— 68 Ga-Fucoidan was tested for its potential to discriminate vulnerable plaques on apolipoprotein E–deficient mice receiving a high cholesterol diet by positron emission tomography and in correlation with 17.6T MRI. Furthermore, 68 Ga-Fucoidan was evaluated on endothelial cells in vitro and ex vivo on active plaques using autoradiography. The cellular uptake rate was increased ≈2-fold by lipopolysaccharide induction. Interestingly, on autoradiography, more intensive tracer accumulation at active plaques with thin fibrous caps and high-density foam cells were observed in comparison with a weaker focal uptake in inactive fibrous plaque segments ( R =1.7±0.3; P R =2.4±0.4; P 68 Ga-Fucoidan was detected in all apolipoprotein E–deficient mice. Anatomic structures of plaque were confirmed by 17.6T MRI. The autoradiography showed a good agreement of 68 Ga-Fucoidan uptake with positron emission tomography. Conclusions— Our data suggest that 68 Ga-Fucoidan represents a versatile imaging biomarker for P-selectin with the potential to specifically detect P-selectin expression using positron emission tomography and to discriminate vulnerable plaques in vivo.

Rationale : An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3 + CD4 + regulatory T cells (T reg cells) contribute to inflammation resolution. Therefore, T reg cells might influence cardiac healing post-MI. Objective : Our aim was to study the functional role of T reg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation. Methods and Results : Using a model of genetic T reg -cell ablation (Foxp3 DTR mice), we depleted the T reg -cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, T reg -cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in T reg -cell–ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody–mediated depletion. In contrast, therapeutic T reg -cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA–treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic T reg -cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing. Conclusions : Our data indicate that T reg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of T reg cells constitutes a novel approach to improve healing post-MI.

Background: The proinflammatory activation of innate immunity by myocardial ischemic injury has been recognized for long time. Our recent data have indicated that activation of CD4+ T cells, presumably by auto-antigen recognition, is a prerequisite for formation of a stable scar and prevention from left ventricular dilation after experimental myocardial infarction in mice. We here hypothesized that regulatory CD4+CD25+Foxp3+CD4+ T cells might improve left ventricular wound healing and prevent from adverse remodeling after myocardial infarction. Results: Experimental myocardial infarction in mice induced the proliferation and activation of CD4+CD25+Foxp3+ regulatory T cells, as demonstrated by intracellular expression of the Ikaros family transcription factor Helios, in heart draining lymph nodes. Pretreatment of mice with an anti-CD25 antibody before myocardial infarction efficiently depleted CD4+CD25+Foxp3+ regulatory T cells and increased mortality after myocardial infarction as compared to mice treated with an isotype-matched control antibody of irrelevant specificity, i.e., 25% survival in anti-CD25 treated mice vs. 55,9% survival in control antibody treated animals. Therapeutic activation of regulatory CD4+CD25+Foxp3+ T cells by a superagonistic anti-CD28 antibody (CD28-SA) applied at day 2 after myocardial infarction prevented, compared to mice treated with an isotype-matched control antibody, from left ventricular rupture and resulted in improved survival (47.1% survival in the control group vs. 76.6% survival in the CD28-SA treated group). CD28-SA treatment lead to expansion of CD4+CD25+Foxp3+ T-cells in the peripheral blood and increased their frequency in the infarcted myocardium. This was associated with increased expression of several molecules known to facilitate wound healing by promoting the formation of a stable scar such as osteopontin and coagulation factor XIII. Conclusion: CD4+CD25+Foxp3+ regulatory T-cells are a prerequisite for proper myocardial wound healing and can be therapeutically activated to improve outcome after experimental myocardial infarction.

Background: We have recently shown that CD4 + but not CD8 + T-cells contribute to ischemia-reperfusion injury of the myocardium. We therefore hypothesized that CD4 + T-cells become activated by autoantigen recognition via their T-cell receptor during reperfusion. Methods and Results: Infarct size as percent of the area-at-risk was determined by combined Evans` blue and triphenyltetrazolium (TTC) staining after 30 minutes of in vivo ischemia followed by 24 hours reperfusion in mice. After 24 hours of reperfusion there was a significantly increased population of CD4 + T-cells which expressed the surface protein CD40L in comparison to sham operated mice [n≥7; p+ CD25 + Foxp3 + T-cells (natural T-regulatory cells) have a low activation threshold and constitute a T-cell subset with reactivity against autoantigens. Depletion of these cells by diphtheria-toxin application in a mouse model expressing the diphtheria-toxin receptor under the Foxp3 promotor also resulted in a significant reduction of infarct size when compared to diphtheria-toxin treated wildtype mice [n≥4; p=0.03; infarct/ area at risk: T reg -depleted DEREG mice 51.9± 3% vs. WT littermates 72.3± 2%]. Conclusion: Our results indicate that CD4 + T-cells that have been activated by an MHC class II/ T-cell receptor dependent mechanism, presumably by autoantigen recognition, contribute to myocardial ischemia-reperfusion injury.

Metastatic castration-resistant prostate cancer (mCRPC) presents a daunting therapeutic challenge for patients who eventually progress after androgen ablation therapy. Although newer AR antagonists show a survival benefit, these patients ultimately relapse. Thus, it is critical to identify new therapies that will work in combination with AR antagonists or in AR-antagonist resistant settings. MOR209/ES414 is a bispecific ADAPTIR™ (modular protein technology) molecule currently under investigation in a phase 1 clinical trial in mCRPC, including patients that have progressed on enzalutamide. In pre-clinical studies, MOR209/ES414 has previously been shown to redirect T cell cytotoxicity against cells expressing Prostate Specific Membrane Antigen (PSMA). Here, we aimed to determine whether enzalutamide affects PSMA expression on CRPC cells in vitro, and could alter the effectiveness of MOR209/ES414 at inducing T-cell mediated tumor cell death. To address these questions, we utilized a CRPC cell line, 22Rv1, which has low expression of PSMA and is resistant to enzalutamide. Treatment of 22Rv1 cells with 10 μM enzalutamide for 3 weeks resulted in increased PSMA cell surface expression as measured by flow cytometry. 22Rv1 cells exposed to enzalutamide were also more sensitive to MOR209/ES414-mediated T-cell lysis, with a 25% increase in cytotoxicity over a 4 hour chromium release assay compared to 22Rv1 cells that were not exposed to enzalutamide. A concomitant decrease in EC50 for MOR209/ES414-mediated lysis from 0.8 pM to 0.5 pM was also observed in 22Rv1 cells exposed to enzalutamide. MOR209/ES414 and enzalutamide were next tested in combination using a PSMA-positive, enzalutamide-sensitive cell line, LNCaP cultured with primary T cells over several days. Suboptimal doses of MOR209/ES414 and enzalutamide were added to the cultures, and surviving LnCaP cells were quantitated 4 days later. Enzalutamide did not interfere with the ability of MOR209/ES414 to target T cells to LNCaP cells, and Combination Index analysis showed the activity of MOR209/ES414 and enzalutamide to be synergistic in vitro. These studies provide a rationale for further examination of combining MOR209/ES414 with enzalutamide, even in enzalutamide-resistant settings. Citation Format: Toddy Sewell, Michelle Blake, Jane A. Gross, Jan Endell, Johannes Weirather, John W. Blankenship. Synergistic in vitro activity of MOR209/ES414 in combination with enzalutamide. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 280.

Background: Monocyte infiltration and extracellular matrix breakdown/ de novo formation critically influence wound healing and remodeling after myocardial infarction (MI). Interleukin-13 (IL-13) has potent pro-fibrotic properties and is a differentiation factor for monocytes/ macrophages. Therefore, we studied whether IL-13 affects myocardial wound healing and remodelling after MI. Methods and results: MI was induced by permanent ligation of the left coronary artery in WT and IL-13-/- mice. Expression of IL-13 was upregulated in the myocardium after MI. IL-13 expression was in part dependent on angiotensin II signalling as in vivo treatment with the Angiotensin-receptor blocker losartan attenuated myocardial IL-13 expression in response to MI. Intracellular FACS analysis of myocardial leukocytes further demonstrated IL-13 expression in a subset of myeloid CD11b+ cells within the myocardium. IL-13-/- mice showed higher mortality than WT mice after MI without difference in infarct size. Echocardiography further demonstrated increased left ventricular dilation in IL-13-/- when compared to WT mice. Histological analysis of the scar collagen did not reveal a difference between WT and IL-13-/- mice. FACS analysis of leukocytes from the infarct zone showed less MHC-II+ CD11b+ cells within the myocardium of IL-13-/- mice on day 7 indicating that IL-13 is required for the differentiation of heart infiltrating monocytes. Conclusions: Expression of IL-13 in response to MI beneficially modulates wound healing after MI.

Background— The role of adaptive immunity, especially CD4 + T-helper cells, has not yet been systematically investigated in wound healing and remodeling after myocardial infarction (MI). Therefore, we studied whether CD4 + T cells become activated and influence wound healing after experimental MI in mice. Methods and Results— When we compared sham versus MI in wild-type (WT) mice, T-cell receptor–dependent activation of both conventional Foxp3 − and regulatory Foxp3 + CD4 + T cells could be demonstrated in heart-draining lymph nodes within the first week after MI. Concomitantly, we found infiltration of CD4 + T cells in infarcted myocardium. To study the role of CD4 + T cells in wound healing and remodeling, CD4 + T-cell–deficient mice (CD4 knockout [KO], MHCII Δ/Δ ) and T-cell receptor–transgenic OT-II mice recognizing an irrelevant ovalbumin-derived peptide were studied. Serial echocardiography up to day 56 after MI revealed increased left ventricular dilation in CD4 KO compared with WT mice. Within the infarcted myocardium, CD4 KO mice displayed higher total numbers of leukocytes and proinflammatory monocytes (18.3±3.0 10 4 /mg WT versus 75.7±17.0 10 4 /mg CD4 KO, P Δ/Δ and OT-II mice displayed significantly greater mortality (21% WT versus 48% OT-II, P Δ/Δ , P Δ/Δ mice, as well as in OT-II mice. Conclusions— The present study provides the first evidence that CD4 + T cells become activated after MI, presumably driven by recognition of cardiac autoantigens, and facilitate wound healing of the myocardium.

Background: MOR202, a human anti-CD38 monoclonal antibody, is currently being evaluated in a phase I/IIa clinical trial for the treatment of multiple myeloma (MM). Pharmacodynamically, MOR202 exerts its tumoricidal effect by eliciting antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Aside from a promising single-agent activity profile, experiments in vitro indicate additive or synergistic effects of MOR202 in combination with different types of standard of care compounds in MM such as lenalidomide (LEN) or bortezomib (BOR). Aims: To compare in vitro the ADCC profile of MOR202 on MM cells and normal hematopoietic cellswith the respective profiles of two other anti-CD38 antibodies in clinical development: daratumumab and isatuximab. To determine the tumoricidal efficacy of MOR202 in vivo in combination with either LEN, BOR or melphalan (MEL), representing immunomodulatory drugs (IMiDs), proteasome inhibitors, and alkylating agents, respectively. Method: The in vitro ADCC profile of the antibodies was assessed by fluorescence activated cell sorting using a panel of CD38+ MM cell lines in the presence of peripheral blood mononuclear cells. The potential for cytotoxicity towards normal hematopoietic cells was tested on purified natural killer (NK) cells by measuring NK-NK killing. In the in vivo studies, two independent mouse models were employed to assess combinatorial effects. Firstly, as a model for MM, NCI-H929 cells were inoculated intratibially into the bone marrow to establish an orthotopic model characterized by prototypical hallmarks of the disease, such as bone lysis, and the emergence of serum M protein. Bone density, evaluated by microcomputed tomography (μCT), and M protein serum levels were used as endpoint analyses for treatment efficacy. Secondly, as a model for disseminated lymphoma, Ramos non-Hodgkin lymphoma cells were intravenously injected into immunodeficient mice. Survival served as the primary endpoint, reflecting the success of medication. Combinatorial drug interactions were evaluated according to Clarke, 1997 (Breast Cancer Res Treat; 46:255-78) and Chou, 2006 (Pharmacol Rev; 58:621-81). Results: In the in vitro ADCC studies on MM cell lines, the maximum killing of MOR202 was equivalent to the tested comparator antibodies. In contrast, the potential to induce killing of normal NK cells expressing low levels of CD38 was significantly reduced for MOR202 compared with daratumumab and isatuximab (n=6 donors; median of 7% specific killing vs 30% and 37%, respectively). This appeared to be independent of FcγRIIIa receptor polymorphism status. In the mouse MM model, MOR202 administration at 3 mg/kg significantly reduced bone lysis by up to 72.5%, relative to vehicle control. Treatment with LEN, BOR, or MEL alone also decreased bone lysis significantly, as compared with vehicle control. However, coadministration of MOR202 with LEN, BOR, or MEL completely abolished or dramatically reduced bone lysis (Figure). Drug interaction analyses indicated synergistic efficacy. The markedly reduced bone lysis seen with combination therapy was accompanied by a reduction (>90%) of serum M protein levels indicating a significant decrease in tumor load (Figure). In the disseminated lymphoma model, LEN or BOR administration had no impact on survival time as compared with vehicle control. In contrast, MOR202 treatment resulted in significantly improved survival compared with vehicle control (median 20 and 20.5 days vs 42 and 43.5 days, respectively, in two independent experiments). Notably, coadministration of MOR202/LEN, or MOR202/BOR further improved survival, indicating potentiation of MOR202 activity by agents which by themselves had little effect (i.e., a subtype of synergy). Of note, all mice receiving monotherapy finally succumbed to the tumor. In contrast, 37.5% of mice treated with MOR202/LEN and 40% of mice treated with MOR202/BOR were completely free of tumor until study termination at day 98. Conclusions: MOR202 shows equivalent ADCC to CD38 high expressing MM cells as compared with daratumumab and isatuximab, while provoking significantly reduced off-tumor killing of CD38 low expressing normal NK cells. In addition, MOR202 acts synergistically in vivo in combination with different compounds representative of classes of agents commonly used in the treatment of hematologic malignancies. Figure 1. Figure 1. Disclosures Boxhammer: MorphoSys AG: Employment. Weirather:MorphoSys AG: Employment. Steidl:MorphoSys AG: Employment. Endell:MorphoSys AG: Employment.

7514 Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.

7521 Background: MOR208, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody has shown single agent activity in patients (pts) with R-R DLBCL and encouraging activity when combined with LEN in the phase II L-MIND study. Here we report an update with primary endpoint and subgroup analyses (cut off June 5, 2018). Methods: Key inclusion criteria were adequate organ function, ≤3 prior lines of therapy, including ≥1 anti-CD20 therapy, and ineligibility for stem cell transplantation. Treatment comprised up to 12, 28-day (d) cycles (C) of MOR208, 12 mg/kg IV, q1w C1–3 (loading dose on d4 of C1), and q2w C4–12 + LEN 25 mg PO d1–21, C1–12. Pts progression-free after 12 C received MOR208 q2w until progression. The primary endpoint was independent review committee (IRC)-assessed ORR as per Cheson 2007 criteria. Results: Recruitment is complete (N = 81): median age 72 years (range 41–87), median of 2 prior therapies, 19 (23%) of pts had early relapse (≤12 months [mo] from diagnosis), 32 (40%) were rituximab (RTX) refractory (no response to or progression during or within 6 mo of a prior RTX therapy), 34 (42%) were refractory to their last therapy, 21/40 (26%/49%) pts had non-germinal center B cell-like (GCB)- / GCB-DLBCL, and 42 (52%) had an International Prognostic Index (IPI) of 3–5. MOR208 + LEN therapy was well tolerated; 72% of pts stayed on a LEN dose of ≥20 mg/day. Treatment-related serious adverse events, mainly infections (10%) or neutropenic fever (5%), occurred in 17% of pts. Investigator (INV)-assessed complete response (CR) and partial response rates were 33% and 25%, respectively, giving an ORR of 58%, comparable to the IRC assessment (ORR 54%; CR 32%). ORR was 46% in pts with ≥2 prior therapies, 59%/56% in rituximab- / last treatment-refractory pts, 58% in early relapse pts, 57% in pts with a baseline IPI of 3–5, and 71% in pts with non-GCB- vs 53% with GCB-DLBCL. INV-assessed median PFS and OS (ITT analysis) were 16.2 mo (95% CI: 6.3–NR) and not reached (95% CI: 18.6–NR), respectively. Conclusions: MOR208 + LEN shows encouraging activity including a durable PFS in R-R DLBCL, and in pt subgroups with poor prognosis. Clinical trial information: NCT02399085.