ALBERT

Description: Nontypeable Haemophilus influenzae (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. A current effort in NTHi vaccine development has focused on generating humoral responses and has been greatly impeded by antigenic variation among the numerous circulating NTHi strains. In this study, we showed that pulmonary immunization of mice with killed NTHi generated broad protection against lung infection by different strains. While passive transfer of immune antibodies protected only against the homologous strain, transfer of immune T cells conferred protection against both homologous and heterologous strains. Further characterization revealed a strong Th17 response that was cross-reactive with different NTHi strains. Responding Th17 cells recognized both cytosolic and membrane-associated antigens, while immune antibodies preferentially responded to surface antigens and were highly strain specific. We further identified several conserved proteins recognized by lung Th17 cells during NTHi infection. Two proteins yielding the strongest responses were tested as vaccine candidates by immunization of mice with purified proteins plus an adjuvant. Immunization induced antigen-specific Th17 cells that recognized different strains and, upon adoptive transfer, conferred protection. Furthermore, immunized mice were protected against challenge with not only NTHi strains but also a fully virulent, encapsulated strain. Together, these results show that the immune mechanism of cross-protection against pneumonia involves Th17 cells, which respond to a broad spectrum of antigens, including those that are highly conserved among NTHi strains. These mechanistic insights suggest that inclusion of Th17 antigens in subunit vaccines offers the advantage of inducing broad protection and complements the current antibody-based approaches.

Description: Streptococcus pneumoniae is among the top causes of bacterial endophthalmitis, an infectious disease of the intraocular fluids. The mechanisms by which S. pneumoniae grows and thrives in the intraocular cavity are not well understood. We used a bacterial genome-wide assessment tool (transposon insertion site sequencing) to determine genes essential for S. pneumoniae growth in vitreous humor. The results indicated that an ascorbic acid (AA) transport system subunit was important for growth. We created an isogenic gene deletion mutant of the AA transcriptional activator, ulaR2, in 2 strains of S. pneumoniae. Growth curve analysis indicated that ulaR2 deletion caused attenuated growth in vitro for both strains. However, in vivo vitreous humor infection in rabbits with either strain determined that ulaR2 was necessary for growth in one strain but not the other. These results demonstrate that ulaR2 may be important for fitness during S. pneumoniae endophthalmitis depending on the background of the strain.

Description: Introduction: BCMA is a tumor necrosis factor (TNF) receptor superfamily transmembrane glycoprotein essential for the maturation and survival of plasma cells. CC-93269 is an asymmetric 2-arm humanized IgG TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format (Seckinger A, et al. Cancer Cell. 2017;31:396-410). The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking leading to T cell activation, and release of proinflammatory cytokines and cytolytic enzymes, resulting in myeloma cell death. In preclinical studies with CC-93269 and related molecules, 2+1 BCMA TCEs induced tumor regression in animal models and promoted myeloma cell death in primary pt myeloma cells. Here we report interim results from a phase 1 dose-finding study (CC-93269-MM-001; NCT03486067) evaluating CC-93269 in pts with RRMM. Methods: Eligible pts had RRMM and had received ≥ 3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on Days 1, 8, 15, and 22 for Cycles 1-3; Days 1 and 15 for Cycles 4-6; and on Day 1 for Cycle 7 and beyond, all in 28-day cycles. Dose escalation involved 2 stages: in stage 1, CC-93269 was given in fixed doses; in stage 2, pts received a fixed first dose on Cycle 1 Day 1, followed by intrapatient dose escalation on Cycle 1 Day 8. Primary objectives were to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D). Minimal residual disease (MRD) was assessed after clinical response in pt bone marrow aspirate samples by Next Generation Flow using the EuroFlow panel. MRD negativity was reported only if a minimum sensitivity of 〈 1 tumor cell in 105 nucleated cells was achieved. Results: As of May 24, 2019, 19 pts had received CC-93269. Median age was 64 years (range 51-78), with a median of 6.2 years (range 1.4-13.9) since initial diagnosis. The median number of prior regimens was 6 (range 3-12) and included treatment with autologous stem cell transplantation (73.7%), allogenic stem cell transplantation (10.5%), lenalidomide (100%), pomalidomide (84.2%), bortezomib (100%), carfilzomib (84.2%), and daratumumab (DARA; 94.7%). All pts had MM refractory to their last line of therapy, with 16 (88.9%) refractory to DARA, 17 (89.5%) to their last proteasome inhibitor, and 16 (84.2%) to their last immunomodulatory agent. CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.6 weeks (range 1.6-32.0) with pts receiving a median of 4 cycles (range 1-8). Grade 3-4 treatment-emergent adverse events were reported in 15 (78.9%) pts and included 10 (52.6%) pts with neutropenia, 8 (42.1%) with anemia, 5 (26.3%) with infections, and 4 (21.1%) with thrombocytopenia. No pt required dose modifications. Cytokine release syndrome (CRS) was reported in 17 (89.5%) pts, the majority of whom reported a maximum grade 1 (n = 11 [57.9%]) or grade 2 (n = 5 [26.3%]), and occurred most frequently with the first or second dose (n = 22 of 27 events [81.5%]). CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in pts receiving ≥ 6 mg. Of 27 CRS events, 8 (29.6%) were managed with dexamethasone and 10 (37.0%) with tocilizumab. One pt receiving 6 mg CC-93269 as first dose and 10 mg on Cycle 1 Day 8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines, was observed in pts. Of the 12 pts treated with ≥ 6 mg CC-93269 in Cycle 1, 10 pts achieved a partial response (PR) or better (overall response rate; 83.3%), including 7 (58.3%) with a very good partial response (VGPR) or better and 4 (33.3%) with a stringent complete response (sCR) (Table); 9 (75.0%) pts achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0-13.1), and 10 of 10 responses were ongoing with follow-up ranging from 2.1 to 4.7 months. The NTD, MTD, and RP2D have not yet been reached. Conclusions: CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose escalation phase. Updated safety and efficacy data will be presented at the meeting. Disclosures Costa: Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Karyopharm: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Wong:Genentech: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding; Fortis: Research Funding; Juno: Research Funding. Bermúdez:MSD: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Fresenius: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Mateos:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:BMS: Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Novartis: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Rodríguez-Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Li:Celgene Corporation: Employment, Equity Ownership. Sarmiento:Celgene Corporation: Employment. Lardelli:Celgene Corporation: Employment, Equity Ownership. Gaudy:Celgene Corporation: Employment, Equity Ownership. Boss:Celgene Corporation: Employment, Equity Ownership. Kelly:Celgene Corporation: Employment. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant.

Description: Although survival in AL patients is related in part to the number of marrow clonal plasma cells (PC) (1, 2), staging for AL patients is based on end-organ damage without a clear role for cytogenetic aberrations in clonal PC. Recently several groups have described potential roles for gain 1q and t(11;14) as prognostic markers in AL, and possibly as predictive of response to therapy (3-5). In multiple myeloma, del 17p is a cytogenetic aberration present in about 10% at diagnosis and its prognostic impact depends on the percentage of clonal PC with del 17p (6). The relevance of del 17p in AL is undefined. We report our initial analysis of the outcomes and survival of the first multinational retrospective study of AL patients with del 17p as a feature of their clonal plasma cell disease and include preliminary findings from an age-based case-control analysis. AL patients with del 17p were identified and their clinical characteristics and outcomes summarized. Methods for determining the presence of del 17p were reviewed. We compared the overall survival (OS) of patients in whom del 17p was identified in 〈 or ≥ 50% of clonal cells, and evaluated the impact of bortezomib-based therapy and cardiac stage on OS in newly diagnosed and relapsed patients. These cases were then matched for age (± 5 years) with a control cohort from the Amyloidosis Treatment and Research Center in Pavia, IT, representing a subset of patients reported previously (7). Differences between cases and controls for OS were evaluated by Kaplan-Meier with statistical significance by the log-rank test. P 〈 0.05 was the threshold for significance. Thirty-four AL patients with del 17p in clonal cells were identified, 30 at diagnosis and 4 at relapse. Thirty-one cases had del 17p assessed on CD138-selected marrow cells and 3 on marrow mononuclear cells; for the latter, the percentage of marrow PC was used to estimate the del 17p fraction. Commercially available methods were used at all centers. Median age was 66 years and males constituted 53% of cases. Cardiac involvement was present in 72% of cases, 41% of whom had stage III involvement. Ninety-four percent had free light-chain (FLC) clones of lambda isotype with a median difference between involved and uninvolved FLC (dFLC) of 249mg/L and a median percentage of marrow PC of 18%. In all 34 cases the median percentage of clonal PC with del 17p by FISH was 42% (range 2-93%) while in newly diagnosed AL patients it was 37%. Eighty-three percent of cases had del 17p in combination with other cytogenetic abnormalities including t(11;14) in 36% and gain 1q in 18%. Among the newly diagnosed cases, 32% had ≥ 50% of clonal cells with del 17p and had a median OS of 23.5 months while those with 〈 50% survived a median of 33 months (P = 0.12). Seventy-three percent of patients responded to initial therapy and 32% had ≥ VGPR. Twenty-three percent had a cardiac response to initial therapy. There was no difference in OS between patients who had bortezomib-based therapy and those who did not, and no difference between the OS of cardiac stage 1/2 and stage 3 patients. One patient with 37% del 17p and a complex karyotype at baseline progressed at relapse to both advanced AL cardiac involvement and plasma cell leukemia with over 90% del 17p containing PC, suggesting that del 17p may confer risk in AL as in MM under certain circumstances. In the preliminary case-control analysis, OS was no different between cases and controls (Fig 1, P = 0.32). Recent data indicate that the more common cytogenetic abnormalities in AL, namely t(11;14) and gain 1q, are associated with differences in response to melphalan or bortezomib. In this series of AL cases with del 17p, we find suggestive evidence that high levels of clonal cells with del 17p may confer a poorer prognosis than already exists as a consequence of the tropism of AL light chains for the heart. We are seeking more cases for inclusion in this series and conducting both a multivariate analysis and a detailed case-control comparison which may shed light on this issue. References (1) Comenzo et al. Blood 2001;98(3):714-20. (2) Warsame et al. Blood Cancer Journal 2015;5, e-310, e-pub 1 May 2015 (3) Bochtler et al. Amyloid. 2014 Mar;21(1):9-17. (4) Bochtler et al. J Clin Oncol. 2015 Apr 20;33(12):1371-8. (5) Zhou et al. Clin Lymphoma Myeloma Leuk 2012;12(1):49-58. (6) An et al. Clin Cancer Res; 21(9); 2148-56. (7) Palladini et al. Blood 2015, e-pub 18 May 2015 Figure 1. Figure 1. Disclosures Hegenbart: Janssen: Honoraria. Landau:Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Avet-Loiseau:onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hansen:Celgene GmbH: Honoraria. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Comenzo:Janssen: Research Funding; Prothena: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Research Funding; Karyopharm: Research Funding.

Description: Chronic extensive, severe graft-versus-host-disease (GVHD) is a major cause of morbidity and mortality following an allogeneic hematopoietic stem cell transplant (HSCT). Patients with progressive chronic GVHD (cGVHD) following standard treatments have limited options. Patients with extensive refractory cGVHD have a decreased performance status (PS) and an increased non-relapsed mortality. Extensive sclerodermatous cGVHD responds poorly to standard treatments. Colchicine is a well-known anti-inflammatory drug that has been used in the treatment of many inflammatory disorders (1). We report a series of 8 patients with extensive cGVHD who were refractory to multiple lines of therapy and then were treated with colchicine. All patients had improvements in ECOG PS, skin GVHD and/or oral GVHD after starting colchicine. All patients were able to decrease their immunosuppressive therapies (IST) after starting colchicine. We retrospectively examined 8 patients with refractory extensive cGVHD, treated with colchicine (0.6 mg QD or BID). IST for cGVHD was defined by the following: steroids, extracorporeal photopheresis (ECP), imatinib, mycophenolate mofetil (MMF), tacrolimus, bortezomib, montelukast, cyclophosphamide (Cy), pentostatin, and rituximab. National Institutes of Health 2014 cGVHD consensus criteria (2) were used to grade the cGVHD prior to colchicine and at the time of best response after colchicine was started. Baseline patient characteristics are listed in Table 1. Conditioning regimen for allogeneic HSCT consisted of PPT (ECP, pentostatin, TBI) (4/8), busulfan/Cy (2/8), Cy-TLI (1/8), or Cy/TBI (1/8). GVHD prophylaxis involved CSA/MTX (7/8), tacrolimus/MTX (1/8) and ATG in addition to CSA/MTX (1/8). Median number of organs involved in cGVHD was 4.5 (range 2-5). All patients had extensive cGVHD with skin (8/8), oral (8/8), eye (8/8), GI (7/8), lung (6/8), liver (2/8), and/or genital (2/8) involvement. Median number of failed IST was 3.5 (range 1-6). Patients failed steroids (7/8), ECP (6/8), MMF (5/8), imatinib (3/8), cyclophosphamide (2/8) and bortezomib (1/8). Median number of IST immediately before colchicine was 2.5 (range 1-6). Most patients required twice daily dosing of colchicine (5/8). Median follow-up since beginning colchicine was 11 weeks (range 3-67 weeks). At best response with colchicine, all patients had clinical improvement of chronic GVHD (Figure 1). Patients with extensive cGVHD of the skin, including all patients with extensive sclerodermatous changes, responded to the addition of colchicine, and had steroid and MMF doses lowered, and/or were stopped on IST. Median number of IST fell to 2 (range 0-5). Four patients had a reduction in the number of IST. One patient was taken off 4 IST (ECP, imatinib, Cy and MMF). Another patient was able to stop ECP. Five patients had a reduction in prednisone with median reduction of 5mg (range 5-40 mg), while 2 had reductions in the total daily dose of MMF. Adverse events were uncommon and included 2 patients with grade 1-2 diarrhea. The most severe adverse event was grade 2 diarrhea in one patient that led to eventual discontinuation of colchicine. No hematologic toxicity was observed. The rest (7/8) continued on colchicine therapy. In conclusion, patients with extensive cGVHD involving the skin and mouth, refractory to multiple lines of IST, experienced clinical improvement on colchicine. Toxicity was limited to mild GI side effects. These observations need to be validated in a prospective clinical trial. References (1) Slobodnick et al. Am J Med. 2015 May;128(5):461-70. (2) Jagasia et al. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401.e1. Epub 2014 Dec 18. Table 1. Baseline Characteristics Variable Frequency (%) Age, median (range), yr 57 (30-65) Donor/recipient gender Sex-mismatched female/male 1 (13%) Sex-matched 7 (88%) Race White/Caucasian 7 (88%) Disease category Acute myeloid leukemia 4 (50%) Myelofibrosis 2 (25%) Aplastic anemia 1 (13%) Lymphoblastic lymphoma 1 (13%) Remission status at transplantation CR 8 (100%) Graft source BM 1 (13%) PBSC 7 (88%) Donor type Matched sibling 4 (50%) Matched unrelated 3 (38%) Mismatched 1 (13%) GVHD type Progressive 3 (38%) Overlap syndrome 2 (25%) De novo 3 (38%) Figure 1. Figure 1. Disclosures Off Label Use: Colchicine will be discussed as treatment for GVHD. Comenzo:Karyopharm: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Janssen: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Roberts:Millenium: Speakers Bureau. Miller:Biogen Idec: Consultancy; AbbVie: Speakers Bureau; Millennium: Speakers Bureau; Onynx: Speakers Bureau.