Response to Uzi Rubin’s “Comments on the UCS Report on Countermeasures”

We recently received—via a third party—a critique of our report, Countermeasures. The critique, written by Uzi Rubin and titled “Comments on the UCS Report on Countermeasures,” is dated 18 July 2000. Rubin states that his study was “considerably less exhaustive” than the countermeasures report and was done by “a small team of experienced missile engineers.” Rubin’s critique has not been published, but instead has been distributed informally in the United States. Here we respond to Rubin’s points in the order that he makes them. As we will make clear, Rubin’s criticisms are either technically invalid or based on incorrect characterizations of the assumptions that underlay our work

Countermeasures: A Technical Evaluation of the Operational Effectiveness of the Planned US National Missile Defense System

The National Missile Defense system under development by the United States would be ineffective against even limited ballistic missile attacks from emerging missile states. Moreover, its deployment would increase nuclear dangers from Russia and China, and impede cooperation by these countries in international efforts to control the proliferation of long-range ballistic missiles and weapons of mass destruction. The United States should reconsider its options for countering the threats posed by long-range ballistic missiles and shelve the current NMD plans as unworkable and counterproductive

Epac-Rap Signaling Reduces Cellular Stress and Ischemia-induced Kidney Failure

Renal ischemia-reperfusion injury is associated with the loss of tubular epithelial cell-cell and cell-matrix interactions which contribute to renal failure. The Epac-Rap signaling pathway is a potent regulator of cell-cell and cell-matrix adhesion. The cyclic AMP analogue 8-pCPT-2′-O-Me-cAMP has been shown to selectively activate Epac, whereas the addition of an acetoxymethyl (AM) ester to 8-pCPT-2′-O-Me-cAMP enhanced in vitro cellular uptake. Here we demonstrate that pharmacological activation of Epac-Rap signaling using acetoxymethyl-8-pCPT-2′-O-Me-cAMP preserves cell adhesions during hypoxia in vitro, maintaining the barrier function of the epithelial monolayer. Intrarenal administration in vivo of 8-pCPT-2′-O-Me-cAMP also reduced renal failure in a mouse model for ischemia-reperfusion injury. This was accompanied by decreased expression of the tubular cell stress marker clusterin-α, and lateral expression of β-catenin after ischemia indicative of sustained tubular barrier function. Our study emphasizes the undervalued importance of maintaining tubular epithelial cell adhesion in renal ischemia and demonstrates the potential of pharmacological modulation of cell adhesion as a new therapeutic strategy to reduce the extent of injury in kidney disease and transplantation

CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

Abstract Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don't eat me" signal to suppress macrophage phagocytosis. Overexpression of CD47 serves as a mechanism of immune surveillance evasion, and is associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Methods This is an ongoing multicenter, Phase 1a/1b dose-escalation and expansion trial of TTI-622 (NCT03530683). Based on a modified 3+3 scheme, dose escalation proceeded through 8 dose levels ranging from 0.05 to 18 mg/kg weekly dosing in patients with refractory or relapsed (r/r) lymphomas. Testing of every two and three week schedules of single agent TTI-622 at doses up to 24 mg/kg is ongoing. Safety monitoring includes clinical laboratories and assessments of adverse events (AEs) based on CTCAE v 4.03. Results As of April 12, 2021, 42 patients (18M/24F) with a median age of 67 years (range 24-86) have received dose levels of 0.05−18 mg/kg weekly TTI-622. Lymphoma histologies enrolled include diffuse large B-cell lymphoma (DLBCL; n=19), cutaneous T-cell lymphoma - mycosis fungoides (CTCL-MF; n=6), peripheral T-cell lymphoma (PTCL; n=6), Hodgkin lymphoma (HL; n=5), and follicular lymphoma (FL; n=4). Additional histologies with single patients only accounted for the remaining 2 patients. Disease stages at entry have been III or IV in 38 patients and median prior systemic therapies of 3 (range 1-9) have been received, including CAR-T and HSCT in 9 and 10 patients, respectively. One additional patient with Erdheim-Chester disease initially diagnosed as lymphoma is included in the safety analysis only. Treatment-related AEs have occurred in 20 (47%) patients; most AEs have been Grade 1 or 2 and reversible. The most frequent treatment-related AEs include thrombocytopenia (n=9, 21%), neutropenia (n=5, 12%), and anemia and fatigue (n=4 each, 9%). Related adverse events of Grade ≥ 3 intensity include thrombocytopenia (n=2, 5%; 1 each Grade 3 &amp; 4), neutropenia (n=4, 9%; all Grade 3), and anemia (n=1, 2%; Grade 3). These Grade 3 and 4 hematologic events occurred in dose levels ranging from 0.8 to 18 mg/kg without apparent dose relationship. Mild to moderate platelet decreases seen in the majority of patients generally occurred on dosing days and recovered quickly to baseline levels. Preliminary PK results suggest dose-dependent increases in exposure following both single and repeated TTI-622 infusions. A total of 27 patients were response-evaluable at dose levels ≥0.8 mg/kg at the time of the data-cut. Objective responses have been achieved in 9 patients, including 2 complete responses (CR) - 1 in DLBCL (0.8 mg/kg) and 1 in CTCL (18 mg/kg) - and 7 partial responses (PR) - 2 in CTCL (both 8 mg/kg), 2 in PTCL (2 and 12 mg/kg), 2 in DLBCL (4 and 18 mg/kg), and 1 in FL (8 mg/kg). Initial responses were achieved at the first disease assessment (week 8) in all 9 responders. In the dose range of 0.8-18 mg/kg, objective responses occurred in 33% (9/27) of response-evaluable patients. At the time of the data cut-off 4 responders were active on treatment; both patients with CR, ongoing 22+ months (0.8 mg/kg) and 12 weeks on an every three week dosing schedule (18 mg/kg). Two patients with PR were ongoing 18 weeks (12 mg/kg) and 11 weeks (18 mg/kg). Conclusions Results to date in patients with r/r lymphomas indicate that weekly doses of single agent TTI-622 up to 18 mg/kg are well tolerated. TTI-622 has shown activity in r/r lymphoma with objective responses across a broad dose range (0.8-18 mg/kg), in highly pre-treated patients, across multiple histologies, and with onset of action consistently observed at the first response assessment at Week 8. The study is ongoing evaluating single agent TTI-622 in every two and three week schedules. Updated data including additional patients will be presented at the conference. Based on these results demonstrating promising single-agent activity as well as good tolerability, TTI-622 is currently being investigated in combination regimens in a range of hematologic malignancies. Disclosures Patel: Xencor: Research Funding; Velos Bio: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Millenium/Takeda: Research Funding; MEI Pharma: Consultancy, Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Juno Pharmaceuticals: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Fate Therapeutics: Research Funding; Curis, Inc: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Aptevo Therapeutics: Research Funding; Abbvie: Consultancy. Zonder: Amgen: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Caelum Biosciences: Consultancy; Intellia: Consultancy; Regeneron: Consultancy; Alnylam: Consultancy. Lesokhin: pfizer: Consultancy, Research Funding; Genetech: Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy; bristol myers squibb: Research Funding; Serametrix, Inc: Patents &amp; Royalties; Trillium Therapeutics: Consultancy; Behringer Ingelheim: Honoraria. von Keudell: Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Research Funding; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; BMS: Research Funding; Janssen: Research Funding. Lai: Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ramchandren: curis: Research Funding; seattle genetics: Consultancy, Research Funding; MERCK: Consultancy, Research Funding; pharmacyclics: Consultancy, Research Funding; BMS: Consultancy; Trillium: Research Funding. Catalano: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lin: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Uger: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Petrova: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Molloy: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Bruns: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. </jats:sec

Investigational CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 serves as a mechanism of immune surveillance evasion, and is found to be associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Methods TTI-622-01 is an ongoing multicenter, Phase 1 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of TTI-622 in adult patients with relapsed/refractory (R/R) lymphoma (NCT03530683). Based on a modified 3+3 scheme, weekly doses are escalated through pre-planned dose levels ranging from 0.05 to 8 mg/kg. The observation period for dose limiting toxicity (DLT) is the initial 3 weeks of treatment. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) based on CTCAE v 4.03. Blood samples are collected for PK analysis and assessment of receptor occupancy on normal peripheral T cells. Disease assessments are performed per Lugano criteria every 8 weeks within the first 6 months, every 3 months up to two years, and every 6 months thereafter until the end of treatment. Results As of the July 16, 2020 cutoff, 25 patients (12M/13F) with a median age of 68 years (range 24-86) have received dose levels of 0.05−8 mg/kg with testing at 8 mg/kg ongoing. Patients with the following histologies have been enrolled: diffuse large B-cell lymphoma (DLBCL; n=13), Hodgkin lymphoma (n=5), follicular lymphoma (FL; n=2), peripheral T-cell lymphoma (PTCL; n=2), cutaneous T-cell lymphoma with CD30 negative large cell transformation (CTCL-LCT, n=2), and mantle cell lymphoma (n=1). Disease stages at entry have been III or IV in 23 patients; patients had received a median of 3 (range 1-9) prior systemic therapies including CAR-T in 5 patients and HSCT in 6 patients. Treatment-related AEs have been reported in 12 (48%) patients. Most AEs have been grade 1 or 2. The most frequent treatment-related AEs include thrombocytopenia (n=4; 1 grade ≥3), neutropenia (n=3; 3 grade ≥3) and fatigue (n=3; 0 grade ≥3). Grade 4 thrombocytopenia occurred in 1 patient in the 8 mg/kg cohort and accounted for the only DLT and treatment-related serious AE reported to date. This event that occurred on Day 8 was not associated with bleeding and resolved within 1 day after prophylactic platelet transfusion. Mild to moderate platelet decreases seen in the majority of patients generally occurred on dosing days and recovered quickly to baseline levels. No other grade ≥3 thrombocytopenia have been observed in the 4 other DLT evaluable patients dosed with 8 mg/kg to date. Preliminary PK results suggest dose-dependent increases in exposure following both single and repeated TTI-622 infusions. PD results indicate that end-of-infusion CD47 receptor occupancy (RO) is above 60% at doses ≥2 mg/kg and that RO is more sustained with TTI-622 doses ≥1 mg/kg compared to lower doses. Objective responses have been achieved in 5 patients, including 1 complete response (CR) in DLBCL (0.8 mg/kg) and 4 partial responses (PR) in PTCL (2 mg/kg), DLBCL (4 mg/kg), CTCL-LCT and FL (8 mg/kg). Initial responses were achieved at the first disease assessment (week 8) in all 5 responders including initial PR in the patient who subsequently achieved CR at week 36 (See Figure 1). In the dose range of 0.8-8 mg/kg, objective responses occurred in 31% (5/16) of patients with ≥1 post-treatment response assessment (See Table 1). Two of 4 response evaluable patients in the ongoing 8 mg/kg cohort achieved a PR, and 2 other patients have been on treatment for &amp;lt;8 weeks. Conclusions Results to date from this ongoing Phase 1 study in patients with R/R lymphomas indicate that weekly doses of TTI-622 up to 4 mg/kg are well tolerated with dose-dependent increases in exposure and RO. TTI-622 has shown activity in R/R lymphoma with objective responses across a broad dose range (0.8-8 mg/kg) and in multiple histologies. The study is currently evaluating the 8 mg/kg dose level. Disclosures Patel: Pharmacyclics: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Kite: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy. Ramchandren:Seattle Genetics, Sandoz-Novartis, Pharmacyclics/Janssen, Bristol-Myers Squibb: Consultancy; Merck, Seattle Genetics, Janssen, Genentech: Research Funding. Lesokhin:Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents &amp; Royalties; Takeda: Consultancy, Honoraria. von Keudell:Pharmacyclics: Research Funding; Genentech: Research Funding; Bayer: Research Funding. Cheson:Symbio: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; TG Therapeutics: Speakers Bureau; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Kite: Consultancy; Parexel: Consultancy. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Catalano:Trillium Therapeutics Inc.: Current Employment. Lin:Trillium Therapeutics Inc.: Current Employment. Uger:Trillium Therapeutics Inc.: Current Employment. Petrova:Trillium Therapeutics Inc.: Current Employment. Roberge:Trillium Therapeutics Inc.: Current Employment. Shou:Trillium Therapeutics Inc.: Current Employment. Iyer:Target Oncology: Honoraria; Seattle Genetics, Inc.: Research Funding; Rhizen: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Spectrum: Research Funding; Merck: Research Funding; Afffimed: Research Funding. </jats:sec

Long Term Outcome After Low Dose TBI Based Conditioning Hematopoietic Stem Cell Transplantation (HSCT) From Related and Unrelated Donors for Older Patients with AML

Abstract Abstract 2030 HSCT after reduced or minimal intensity conditioning is increasingly used to treat AML patients not eligible for conventional HSCT. Short term outcome has been reported frequently and risk factors have been identified; long term results still await in depth evaluation. We report here 5 years follow up results from a prospective phase II study conducted by two AML study groups in Europe. Patients were recruited from AML protocols HOVON/SAKK AML 43 and the OSHO AML 1997 study. The regimen consisted of fludarabine (FLU), 30 mg/m2/d on days −4, −3, and −2, 2 Gy TBI on day 0 (the day of HSCT) with mycophenolate mofetil, [15 mg/kg p.o. b.i.d. from 5 hours after HSCT to day +40], and cyclosporine, [CSP; 6.25 mg/kg p.o. bid from day –3 to day +180] after HSCT. Cyclosporine was adjusted to trough levels and reduced according to a predetermined tapering schedule and donor type. A total of 96 patients were recruited between 5/2002 and 8/2005 in the study. Age was median 62 (range 40 – 74) years, 54 patients were male (56%) and 73 patients (76%) had de novo AML. The remission status on entry was CR1 in 83 (86%) patients and CR2 in 13 (14%). Of the 96 patients, 20% had high risk cytogenetics and SCT was performed a median of 75 days after chemotherapy. There were no statistical differences in the above described characteristics except for more secondary AML (p=0.04) and more CR2 patients (p=0.07) among the 59 unrelated SCT (61%) as compared to the 37 related SCT (39%). Graft rejection at two years was observed in 6% of the patients. Absence of chronic GvHD was diagnosed in 40% and limited chronic GvHD in 29% of the patients, with no difference between related and unrelated SCT. Probability of overall survival (OS) at 6 years with a median follow up of 64 (49–92) months reaches a plateau after 5 years at 0.33±0.05 and was not significantly better in CR1 than in CR2. However, there was a trend towards better OS at 6 years for unrelated 0.41±0.11 as compared to related 0.29±0.07 SCT (p=0.08) in CR1 only. This difference was significant for disease free survival (DFS) (0.48±0.09 unrelated vs 0.27±0.06 related; p=0.04), the major reason being a higher relapse rate in related as compared to unrelated SCT (0.62±0.08 vs 0.40±0.09). The overall non-relapse mortality at 6 years was 0.21±0.05. We conclude that OS and DFS reach a stable plateau from 5 years after SCT to more than 8 years after SCT. In CR1 patients, DFS is superior after unrelated as compared to related SCT. Accordingly, strategies designed to decrease relapse, especially after related SCT, have already been implemented in the ongoing protocols. The preferential use of unrelated rather than related donors may be beneficial and should be considered in future protocols. Disclosures: Off Label Use: Transplantation in elderly patients. </jats:sec

Celebration in the park (image)

http://deepblue.lib.umich.edu/bitstream/2027.42/61040/1/2701.pd