Results from the Completed Dose-Escalation of the Hematological Arm of the Phase I Think Study Evaluating Multiple Infusions of NKG2D-Based CAR T-Cells As Standalone Therapy in Relapse/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients

CYAD-01 cells are engineered T-cells expressing a chimeric antigen receptor (CAR) based on the natural full-length human natural killer group 2D (NKG2D) receptor fused to the intracellular domain of CD3ζ. NKG2D receptor binds to 8 ligands (MICA/B, ULBP1-6) expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The hematological arm of the Phase I THINK study (NCT03018405) evaluates the safety and clinical activity of multiple CYAD-01 infusions (inf) without any prior preconditioning chemotherapy in r/r AML, MDS and multiple myeloma (MM) patients (pts). Three dose levels (DL) were evaluated: 3x108, 1x109 and 3x109 T-cells/inf. The first cycle of the treatment consists of 3 CYAD-01 infusions every 2 weeks and a potential 2nd cycle of 3 CYAD-01 infusions every 2 weeks if the patient is not in progressive disease (PD) at the end of the 1st cycle. Additional cohorts evaluate DL2 and DL3 following a denser treatment schedule for the 1st cycle of treatment, with the first 3 CYAD-01 infusions administered every week. As of end of July 2019, 16 pts were enrolled in the dose-escalation segment of the hematological cohort with the initial schedule (CYAD-01 infusions every 2 weeks) for 1st cycle, now completed. In total (uncleaned database), 7 pts experienced grade (G) 3/4 treatment-related adverse events (AEs). Cytokine release syndrome (CRS) occurred in 7 pts with only 2 pts at DL2 who experienced G3 CRS and 1 pt who experienced G4 CRS at DL3 reported as a dose-limiting toxicity (DLT). All CRS AEs resolved with early tocilizumab treatment. No treatment-related neurotoxicity AEs have been observed. Out of the 10 AML/MDS pts who received at least 3 CYAD-01 infusions and were assessed for clinical activity, 4 showed overall response (OR) at Day 29 of which 1 complete remission (CR) with partial hematologic recovery (CRh) for > 21 months in a r/r AML pt at DL1, 2 CR with incomplete hematologic recovery (CRi) for 1 month in AML pt at DL1 and DL3, and 1 marrow CR (mCR) for 1 month in an MDS pt at DL3. 2 AML pts at DL2 had stable disease (SD) for ≥ 3 months with bone marrow (BM) blast percentage decrease. Two other AML pts in DL3 achieved SD for at least 2 months. 2 AML pts did not have evidence of clinical response. The 2 evaluable MM pts did not show evidence of clinical response. As of end of July 2019, 8 pts were enrolled in cohorts with the dense schedule (4 in DL2 and 4 in DL3). Recruitment at 3x109 T-cells/inf. is still ongoing and is expected to be completed by the time of presentation. At DL2 (uncleaned database), only 1 pt out of 4 experienced a study treatment-related G4 AE (infusion related reaction). The 3 other pts experienced G1 or 2 study treatment-related AEs, with 3 pts who experienced G1/2 CRS. One AML pt reached a stable disease at the Day 32 tumor evaluation. At DL3, 2 out of 4 currently enrolled pts experienced study treatment related G3 AE (CRS) after their first CYAD-01 infusion. One of these G3 CRS was reported as a dose-limiting toxicity. Altogether, results obtained to date demonstrate an encouraging safety and tolerability profile of CYAD-01 without preconditioning chemotherapy in pts with r/r hematological malignancies. Encouraging anti-leukemic activity was observed in 6 out of 13 (46%) evaluable r/r AML/MDS pts in the THINK study, presenting relevant decrease in BM blasts. Four objective responses (1 CRh, 2 CRi, 1 mCR) were observed with the initial schedule. At DL2, the denser schedule did not modify the safety profile while increasing the area under the curve of CYAD-01 peripheral blood levels, which could suggest a possible impact on clinical activity at DL3, results expected by the time of presentation. Disclosures Sallman: Celyad: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Awada:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EISAI: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genomic Health: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ispen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Lonez:Celyad: Employment. Lequertier:Celyad: Employment. Alcantar-Orozco:Celyad: Employment. Braun:Celyad: Employment. Flament:Celyad: Employment.

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Association of MHC Class I Chain-Related Gene a (MICA) Polymorphisms with Allogeneic Hematopoietic Cell Transplantation Outcomes in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-112745 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2075-2075

Author(s):

Sagar S. Patel ◽

Betty K. Hamilton ◽

Lisa Rybicki ◽

Dawn Thomas ◽

Arden Emrick ◽

...

Keyword(s):

Board Of Directors ◽

Binding Affinity ◽

Myeloid Leukemia ◽

Research Funding ◽

Somatic Mutations ◽

Hematopoietic Cell Transplantation ◽

Advisory Committees ◽

Post Transplant ◽

Transplant Outcomes ◽

Nkg2d Receptor

Abstract Background MHC class I chain-related gene A (MICA) is a polymorphic ligand of the natural killer (NKG2D) receptor on immune effector cells. The activating NKG2D receptor controls immune responses by regulating NK cells, NKT cells and γδ-T cells. Dimorphisms at sequence position 129 of the MICA gene confers varying levels of binding affinity to NKG2D receptor. MICA previously has been associated with post-allogeneic hematopoietic cell transplantation (alloHCT) outcomes including graft-versus-host-disease (GvHD), infection, and relapse. However, it is unclear how MICA interacts with cytogenetic and somatic mutations in regards to these outcomes in acute myeloid leukemia (AML). Methods We conducted a single center, retrospective analysis of adult AML patients in first or second complete remission (CR1, CR2), who underwent T-cell replete matched related or unrelated donor alloHCT. Analysis was limited to those who had MICA data available for donors and recipients. In addition to cytogenetic risk group stratification by European LeukemiaNet criteria (Döhner H, et al, Blood 2016), a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms at the MICA-129 position have previously been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Fine and Gray or Cox regression was used to identify the association of MICA and outcomes with results as hazard ratios (HR) and 95% confidence intervals (CI). Results From 2000 - 2017, 131 AML patients were identified meeting inclusion criteria. Median age at transplant was 54 years (18-74), with 98% Caucasian. Disease status at transplant included 78% CR1 and 22% CR2. Cytogenetic risk stratification showed 13% of patients as favorable, 56% as intermediate, and 31% as adverse-risk. The five most common somatic mutations were FLT3 (15%), NPM1 (14%), DNMT3A (11%), TET2 (7%), and NRAS (6%). 60% of patients had a related donor. A myeloablative transplant was performed in 84% of patients and 53% had a bone marrow graft source. The most common conditioning regimen used was busulfan/cyclophosphamide (52%). 12% of patients were MICA mismatched with their donor. The distribution of donor MICA-129 polymorphisms were 41% V/V, 53% M/V, and 6% M/M. In univariable analysis, donor-recipient MICA mismatch tended to be associated with a lower risk of infection (HR 0.49, CI 0.23-1.02, P=0.06) and grade 2-4 acute GvHD (HR 0.25, CI 0.06-1.04, P=0.06) but was not associated with other post-transplant outcomes. In multivariable analysis, donor MICA-129 V/V was associated with a higher risk of non-relapse mortality (NRM) (HR 2.02, CI 1.01-4.05, P=0.047) (Figure 1) along with increasing patient age at transplant (HR 1.46, CI 1.10-1.93, p=0.008) and the presence of a TET2 mutation (HR 6.00, CI 1.77-20.3, P=0.004). There were no differences between the V/V and the M/V+M/M cohorts regarding somatic mutational status, cytogenetics and other pre-transplant characteristics and post-transplant outcomes. With a median follow-up of 65 months for both cohorts, 45% vs. 49% of patients remain alive, respectively. The most common causes of death between the V/V and the M/V+M/M cohorts was relapse (38% vs. 62%) and infection (31% vs. 8%), respectively. Conclusion While previous studies have demonstrated associations of somatic mutations and cytogenetics with survival outcomes after alloHCT for AML, we observed mutations in TET2 and the V/V donor MICA-129 polymorphism to be independently prognostic for NRM. Mechanistic studies may be considered to assess for possible interactions of TET2 mutations with NK cell alloreactivity. The weaker binding affinity to the NKG2D receptor by the V/V phenotype may diminish immune responses against pathogens that subsequently contribute to higher NRM. These observations may have implications for enhancing patient risk stratification prior to transplant and optimizing donor selection. Future investigation with larger cohorts interrogating pre-transplant AML somatic mutations with MICA polymorphisms on post-transplant outcomes may further elucidate which subsets of patients may benefit most from transplant. Disclosures Nazha: MEI: Consultancy. Mukherjee:Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; BioPharm Communications: Consultancy; Bristol Myers Squib: Honoraria, Speakers Bureau; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; LEK Consulting: Consultancy, Honoraria; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Advani:Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy; Novartis: Consultancy. Carraway:Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau. Gerds:Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria.

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Phase 1/2 Study of Nexi-001 Donor-Derived Multi-Antigen Specific CD8+ T Cells for the Treatment of Relapsed Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Transplantation

Blood ◽

10.1182/blood-2021-152419 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4819-4819

Author(s):

Monzr M. Al Malki ◽

Sumithira Vasu ◽

Dipenkumar Modi ◽

Miguel-Angel Perales ◽

Lucy Y Ghoda ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Board Of Directors ◽

Cd8 T Cells ◽

Research Funding ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees ◽

Over Time

Abstract Patients who relapse after allogeneic HCT have a poor prognosis and few effective treatment options. Responses to salvage therapy with donor lymphocyte infusions (DLI) are driven by a graft versus leukemia (GvL) effect. However, relapses and moderate to severe graft versus host disease (GVHD) are common. Therapies that increase the GvL effect without inducing GVHD are needed. The NEXI-001 study is a prospective, multicenter, open-label phase 1/2 trial designed to characterize the safety, immunogenic, and antitumor activity of the NEXI-001 antigen specific T-cell product. This product is a donor-derived non-genetically engineered therapy that consists of populations of CD8+ T cells that recognize HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. These T cells consist of populations with key memory phenotypes, including stem-like memory, central memory, and effector memory cells, with a low proportion (<5%) of potentially allogeneic-reactive T-naïve cells. Patients enrolled into the first cohort of the dose escalation phase received a single infusion of 50 million (M) to 100M cells of the NEXI-001 product. Bridging anti-AML treatment was permitted during the manufacture of the cellular product with a wash-out period of at least 14 days prior to lymphodepletion (LD) chemotherapy (intravenous fludarabine 30 mg/m 2 and cyclophosphamide 300 mg/m 2) that was administered on Days -5, -4, and -3 prior to the infusion of the NEXI-001 product up to 72 hours later (Day1). Lymphocyte recovery to baseline levels occurred as early as three days after the NEXI-001 product infusion with robust CD4 and CD8 T cell reconstitution after LD chemotherapy. NEXI-001 antigen specific T cells were detectable in peripheral blood (PB) by multimer staining and were found to proliferate over time and to traffic to bone marrow. The phenotype composition of detectable antigen specific T cells at both sites was that of the infused product. T-cell receptor (TCR) sequencing assays revealed T cell clones in the NEXI-001 product that were not detected in PB of patients tested at baseline. These unique clones subsequently expanded in PB and bone marrow (BM) and persisted over time. Neutrophil recovery, decreased transfusion burden of platelets and red blood cells, and increased donor chimerism were observed. Decreases in myeloblasts and reduction in the size of an extramedullary myeloid sarcoma were suggestive of clinical activity. One patient, a 23-year- old with MRD+ disease at baseline, received two doses of 200M NEXI-001 cells separated by approximately 2 months. Following the first infusion, antigen specific CD8+ T cells increased gradually in PB to 9% of the total CD3+ T cell population just prior to the second infusion and were found to have trafficked to bone marrow. By Day 2 following the second infusion, which was not preceded by LD chemotherapy, the antigen specific CD8+ T cells again increased to 9% of the total CD3+ T cell population in PB and remained at ≥5% until the end of study visit a month later. The absolute lymphocyte count increased by 50% highlighting continued expansion of the NEXI-001 T cells. These cells also maintained significant Tscm populations. Treatment related adverse events, including infusion reactions, GVHD, CRS, and neurotoxicity (ICANS), have not developed in these patients who have received 50M to 200M T cells of the NEXI-001 product either as single or repeat infusions. In conclusion, these results show that infusion of the NEXI-001 product is safe and capable of generating a cell-mediated immune response with early signs of clinical activity. A second infusion is associated with increasing the level of antigen specific CD8+ T cells and their persistence in PB and BM. TCR sequencing and RNA Seq transcriptional profiling of the CD8+ T cells are planned, and these data will be available for presentation during the ASH conference. At least two cycles of 200M NEXI-001 cells weekly x 3 weeks of a 4-week cycle is planned for the next dose-escalation cohort. Early data suggest that the NEXI-001 product has the potential to enhance a GvL effect with minimal GVHD-associated toxicities. Disclosures Al Malki: Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy. Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Modi: MorphoSys: Membership on an entity's Board of Directors or advisory committees; Seagen: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Perales: Sellas Life Sciences: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Merck: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; MorphoSys: Honoraria; Kite/Gilead: Honoraria, Other; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Medigene: Honoraria; NexImmune: Honoraria; Cidara: Honoraria; Nektar Therapeutics: Honoraria, Other; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other. Edavana: Neximmune, Inc: Current Employment. Lu: Neximmune, Inc: Current Employment. Kim: Neximmune, Inc: Current Employment. Suarez: Neximmune, Inc: Current Employment. Oelke: Neximmune, Inc: Current Employment. Bednarik: Neximmune, Inc: Current Employment. Knight: Neximmune, Inc: Current Employment. Varela: Kite: Speakers Bureau; Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v118.21.768.768 ◽

2011 ◽

Vol 118 (21) ◽

pp. 768-768 ◽

Cited By ~ 17

Author(s):

Joseph G. Jurcic ◽

Todd L. Rosenblat ◽

Michael R. McDevitt ◽

Neeta Pandit-Taskar ◽

Jorge A. Carrasquillo ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Clinical Activity ◽

Bone Marrow Blast ◽

Elimination Kinetics ◽

Advisory Committees ◽

Dose Levels

Abstract Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDevitt:Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg:Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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A Phase 1/1b Safety Study of Prgn-3006 Ultracar-T™ in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2020-139417 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-17

Author(s):

David A. Sallman ◽

Hany Elmariah ◽

Kendra L. Sweet ◽

Chetasi Talati ◽

Asmita Mishra ◽

...

Keyword(s):

T Cells ◽

Gene Transfer ◽

Board Of Directors ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Car T Cells ◽

Car T

Background: Therapeutic options for relapse or refractory (r/r) acute myeloid leukemia (AML) and hypomethylating agent (HMA) failure higher risk myelodysplastic syndrome (MDS) pts are limited with median overall survival of < 6 months. Consequently, novel therapies are urgently needed. CD33 is highly expressed on most myeloid leukemia stem cells with lesser expression on normal hematopoietic stem cell populations and minimal non-hematopoietic expression making CD33 a leading target in chimeric antigen receptor therapy (CAR-T) development for myeloid malignancies. However, additional barriers of CAR-T development in myeloid malignancies include long manufacturing period, expansion of CAR-T cells and potential toxicity related to on-target, off-tumor toxicity. Scientific Rationale: Current CAR-T cells utilize viral vectors for gene transfer and subsequent lengthy ex vivo expansion at centralized manufacturing facilities, which is costly and leads to cell product that is exhausted and short lived in vivo. Time is of the essence for pts with rapidly progressing disease such as r/r AML and the prolonged interval between apheresis to product infusion with current CAR-T cell therapies can be a disadvantage. Although allogeneic "off-the-shelf" products allow for rapid administration, challenges remain with rapid rejection. Precigen has developed UltraCAR-T platform to overcome these limitations by utilizing an advanced non-viral gene delivery system and a rapid, decentralized manufacturing process. UltraCAR-T cells are manufactured overnight at medical center's cGMP facility using patient's autologous T cells and administered back to patient only one day after gene transfer with no need for ex vivo expansion. PRGN-3006 UltraCAR-T cells co-express CD33 CAR, membrane bound IL-15 (mbIL15) and a kill switch. Preclinical studies have demonstrated that the expression of the mbIL15 on UltraCAR-T cells leads to maintenance of preferred stem-like memory phenotype (TSCM). Superior efficacy of UltraCAR-T cells was demonstrated in an aggressive murine xenograft model of AML where a single administration of PRGN-3006, only one day after gene transfer, showed significantly higher expansion and persistence; effectively eliminated tumor burden; and significantly improved overall survival compared to traditional CD33 CAR-T cells lacking mbIL15 expression (Blood (2019) 134(S1): 2660). Study Design: The PRGN-3006 UltraCAR-T cells are currently being evaluated in a Phase 1/1b first-in-human dose escalation/dose expansion clinical trial (NCT03927261). The study population includes adult pts (≥ 18 years) with relapsed or refractory AML and HMA failure higher risk MDS or chronic myelomonocytic leukemia (CMML) with ≥ 5% blasts. Pts who have relapsed post allogeneic stem cell transplant are allowed if > 3 months out from transplant without evidence of active graft versus host disease and off immunosuppression for 6 weeks. Key inclusion criteria include an absolute lymphocyte count ≥ 0.2k/µL, KPS > 60%, absence of other active malignancy within 1 year of study entry, daily corticosteroid dose < 10mg of prednisone daily, adequate organ function and a backup allogeneic donor should bone marrow aplasia occur. Hydroxyurea is allowed for cytoreduction with cessation 3 days prior to apheresis/infusion but can be reinitiated post-infusion. To test the hypothesis that expression of mbIL15 on PRGN-3006 cells is sufficient to promote CAR-T cell expansion and persistence, study subjects will receive PRGN-3006 infusion either without prior lymphodepletion (Cohort 1) or following lymphodepleting chemotherapy (Cohort 2 with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 days -5 to -3). Up to 5 dose levels are planned in dose escalation. All subjects will be followed for adverse events, CAR-T-related toxicities, disease response and PRGN-3006 cell expansion and persistence in blood and bone marrow compartments. In addition, the mechanisms of safety and effectiveness of PRGN-3006 cells will be evaluated with correlative assays of specific immune response pathways. Currently, the study is in the dose escalation phase and has cleared the lower dose level while demonstrating successful manufacturing of UltraCAR-T cells. Additionally, multi-center expansion of the trial is in progress. Disclosures Sallman: Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Sweet:Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Talati:Astellas: Speakers Bureau; Jazz: Speakers Bureau; AbbVie: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Lankford:Precigen, Inc.: Current Employment. Chan:Precigen, Inc.: Current Employment, Current equity holder in publicly-traded company. Shah:Precigen, Inc.: Current Employment; Intrexon Corporation: Current equity holder in publicly-traded company. Padron:BMS: Research Funding; Novartis: Honoraria; Kura: Research Funding; Incyte: Research Funding. Komrokji:Novartis: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Geron: Honoraria; BMS: Honoraria, Speakers Bureau. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sabzevari:Precigen, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Compass Therapeutics: Current equity holder in publicly-traded company. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

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Transcriptomic Features of Immune Exhaustion and Senescence Predict Outcomes and Define Checkpoint Blockade-Unresponsive Microenvironments in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-145854 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 223-223

Author(s):

Sergio Rutella ◽

Jayakumar Vadakekolathu ◽

Francesco Mazziotta ◽

Stephen Reeder ◽

Tung On Yau ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Checkpoint Blockade ◽

Newly Diagnosed ◽

Advisory Committees ◽

Immune Exhaustion

Abstract Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Reinstating immunological control of AML is highly desirable to eradicate chemotherapy-resistant clones and provide long-term disease control. We recently identified bone marrow (BM) microenvironmental transcriptomic profiles that stratify patients with newly diagnosed AML into an immune-infiltrated and an immune-depleted subtype and that refine the accuracy of survival prediction beyond that afforded by current prognosticators (Vadakekolathu J et al., 2020). We have also shown that CD8 + T cells from patients with AML exhibit features of immune exhaustion and senescence (IES), including heightened expression of killer cell lectin-like receptor subfamily G member 1 (KLRG1) and B3GAT1 (encoding CD57) (Knaus H et al., 2018). Whether deranged T-cell functions affect the likelihood of responding to antitumor therapy, including immune checkpoint blockade (ICB), is an outstanding question in AML. In the current study, we analyzed 183 BM samples collected longitudinally at time of AML onset, response assessment and disease relapse from multiple cohorts of patients with AML treated with standard-of-care induction chemotherapy, and from 33 elderly AML patients with newly diagnosed or chemotherapy-refractory/relapsed AML treated with azacitidine, and the PD-1 checkpoint inhibitor pembrolizumab (NCT02845297). Primary patient specimens and associated clinical data were obtained via informed consent in accordance with the Declaration of Helsinki on research protocols approved by the Institutional Review Boards of the participating Institutions. RNA (150-200 ng) was extracted from BM aspirates and was processed on the nCounter FLEX analysis system (NanoString Technologies, Seattle, WA) using the PanCancer Immune profiling panel, as previously published (Vadakekolathu J et al., 2020). The correlation between transcriptomic features of IES, clinical characteristics, therapeutic response and patient outcome was validated using publicly available RNA-sequencing and NanoString data from 1,698 patients with AML, including samples from the TCGA-AML (n=147 cases), Beat-AML Master Trial (n=264 cases, of which 240 with survival data and 195 with chemotherapy response data) and Children's Oncology Group (COG)-TARGET AML series (n=145 cases). We initially showed that, compared with their non-senescent CD8 +CD57 -KLRG1 - counterpart, senescent CD8 +CD57 +KLRG1 + T cells are functionally impaired in terms of their ability to effect AML-blast killing mediated by an anti-CD33/CD3 bi-specific T-cell engager antibody construct (kindly provided by Amgen, USA; effector/target [E/T] ratio = 1:5). We then used gene set enrichment analysis (GSEA) to derive a transcriptomic signature of IES encompassing natural killer (NK)-cell and stem-like CD8 + T-cell markers, and showed that IES states correlate with lymphoid infiltration, adverse-risk molecular lesions (TP53 and RUNX1 mutations), experimental gene signatures of leukemia stemness (LSC17 score; Ng et al., 2016) and poor outcome in response to standard induction chemotherapy (Fig. 1A). In independent validation cohorts of children and adults with AML, the IES score was higher at baseline in patients with primary induction failure (following a standard 2 cycles of chemotherapy) compared with complete remission, increased in post-chemotherapy BM specimens, and predicted survival with greater accuracy than the ELN cytogenetic risk classifier (Fig. 1B). In the immunotherapy setting, high IES scores at baseline defined a checkpoint blockade-unresponsive AML tumor microenvironment and correlated with significantly shorter overall survival (9.1 versus 15.56 months in patients with high and low IES scores, respectively; HR = 3.32 (95% CI = 1.19-9.25); log-rank P = 0.021; Fig. 1C). Finally, the IES-related gene set also predicted for long-term outcomes and objective responses, based on RECIST criteria, to single-agent nivolumab or pembrolizumab, or combination anti-PD-1 + anti-CTLA-4, in 106 patients with melanoma (PRJEB23709 and GSE93157 series), a tumor type known to derive durable clinical benefit from ICB (Fig. 1D). Our findings encourage the pursuit of immune senescence reversal as a strategy to functionally reinvigorate T cells and could inform the delivery of ICB and other T cell-targeting immunotherapies to patients who are likely to benefit. Figure 1 Figure 1. Disclosures Radojcic: Syndax Pharmaceuticals: Research Funding; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Allakos: Membership on an entity's Board of Directors or advisory committees. Minden: Astellas: Consultancy. Tasian: Aleta Biotherapeutics: Consultancy; Gilead Sciences: Research Funding; Kura Oncology: Consultancy; Incyte Corporation: Research Funding.

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CC-122 Dosing on a Novel Intermittent Schedule Mitigates Neutropenia and Maintains Clinical Activity in Subjects with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.1494.1494 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1494-1494 ◽

Cited By ~ 3

Author(s):

Cecilia Carpio ◽

Loïc Ysebaert ◽

Raúl Cordoba ◽

Armando Santoro ◽

José Antonio López-Martín ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Clinical Activity ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Background: CC-122, a first in class PPM™ pleiotropic pathway modifier, has anti-tumor activity against B cell lymphomas. The molecular target of CC-122 is cereblon (CRBN) and CC-122 promotes ubiquitination of lymphoid transcription factor Aiolos in a CRBN-dependent manner, leading to its degradation in Diffuse Large B Cell Lymphoma (DLBCL) tumor tissue and immune cells. CC-122 also depletes Ikaros, which is expressed in immature stages of myeloid differentiation and regulates early neutrophil differentiation (Blood 101:2219 2003). Following establishment of CC-122 3mg daily (QD) as the maximum tolerated dose (MTD) on a continuous schedule (Blood 122:2905 2013), subjects with advanced lymphoma, myeloma, and select solid tumors were enrolled in parallel expansion. In DLBCL subjects, CC-122 treatment demonstrated promising clinical efficacy, however, dose reductions due to neutropenia were frequent with the QD schedule (Blood 124:3500 2014). Therefore, a second cohort of DLBCL subjects was enrolled to evaluate the tolerability and clinical activity of intermittent schedules. Methods: Subjects with relapsed/refractory DLBCL were enrolled in parallel dose escalation of CC-122 given orally at 4mg or 5mg on two intermittent schedules. CC-122 given 21/28 days was tested based on lenalidomide experience. In order to model a second schedule, human bone marrow CD34+ cells were cultured for two weeks in SCF, Flt3L and G-CSF for expansion towards granulocytic lineage followed by 6 days with media plus G-CSF for neutrophil maturation.CC-122 0.5 uM was added continuously or on a 5 out of 7 day (5/7d) schedule. Myeloid maturation stages were measured 14 days later by CD34, CD33 and CD11b flow cytometry. Continuous exposure to CC-122 led to reversible myeloid maturation arrest and 90% decreased mature neutrophils compared to vehicle, whereas, CC-122 exposure for 5/7d resulted in only 50% decreased mature neutrophils. Based on this rationale, CC-122 given 5/7d was selected as the second intermittent schedule tested in DLBCL. Results: As of June 25, 2015, 22 subjects with relapsed/refractory DLBCL were enrolled in the 2nd cohort; all were evaluable for safety, 16 were efficacy evaluable (EE) as of the cutoff date. The median age was 60 years and 54% were male. The median time since diagnosis was 14 months and all subjects were ECOG 0-1. For subjects treated with CC-122 4mg 21/28 days (N=3), there were no dose limiting toxicities (DLTs) in cycle 1, however, all subjects required dose reduction due to neutropenia and therefore this dose level was considered a non-tolerated dose (NTD). For subjects treated with CC-122 on a 5/7 days schedule, the NTD was at 5mg due to 2 DLTs in 2 of 5 subjects (grade 3 febrile neutropenia and grade 3 pneumonitis). CC-122 4mg was the MTD on 5/7d and was selected for ongoing expansion in up to 50 subjects (N=14 as of cutoff date). There were no DLTs in 12 DLT-evaluable subjects. Median relative dose intensity achieved for 4mg 5/7d vs 3mg QD was 99% vs 79%. The most common (≥ 10%) related adverse events (AEs) were neutropenia (36%), constipation (29%), asthenia (21%) and grade 3/4 related AEs were neutropenia (36%) and lipase elevation (14%). In addition, drug-related serious AEs included pneumonia, neck pain, and respiratory failure. AEs were an uncommon cause of discontinuation (7%, n=14). Response rates for the EE DLBCL subjects treated at 5mg 5/7d (N=3), 4mg 5/7d (N=10), and 3mg QD (N=22) was 67% (2 PR), 30% (1CR, 2 PR) and 23% (1CR, 4PR), respectively. Aiolos protein levels in peripheral T cells was measured by flow cytometry pre (baseline) and 5 hours post dosing on C1D1, C1D10 and C1D22. The median % change Aiolos levels at each of these visits were -47, -28 and -52%, respectively, indicating that Aiolos degradation occurs throughout the cycle. In addition, the median increase from baseline in cytotoxic memory T cells and helper memory T cells at cycle 1 day 22 in peripheral blood samples was 580% and 76%, respectively. Conclusion: In an in vitro myeloid differentiation assay, myeloid maturation arrest by CC-122, possibly due to Ikaros degradation, can be partially bypassed with a 2 day drug holiday. From a clinical standpoint, exploration of intermittent dosing confirmed that 5/7d schedule mitigates neutropenia-related dose reductions and improves CC-122 clinical activity in relapse/refractory DLBCL patients. Of note, the immunomodulatory effects of CC-122 are maintained on the 5/7d schedule. Disclosures Carpio: Celgene: Research Funding. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with anti-tumor activity against B cell lymphomas.. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Santoro:Celgene: Research Funding. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Celgene: Research Funding; Roche: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Gharibo:Celgene: Research Funding. Rasco:Asana BioSciences, LLC: Research Funding; Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Damian:Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Carrancio:Celgene: Research Funding. Gandhi:Celgene: Employment, Equity Ownership. Pourdehnad:Celgene: Employment, Equity Ownership. Ribrag:Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase I/II Study to Investigate the Safety and Clinical Activity of the Protein Arginine Methyltransferase 5 Inhibitor GSK3326595 in Subjects with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130337 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2656-2656 ◽

Cited By ~ 2

Author(s):

Justin M. Watts ◽

Terrence J Bradley ◽

Amber Thomassen ◽

Andrew M. Brunner ◽

Mark D. Minden ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Myeloid Leukemia ◽

Research Funding ◽

Mrna Splicing ◽

Clinical Activity ◽

Employment Equity ◽

Advisory Committees ◽

Myeloid Malignancies ◽

Equity Ownership

Background Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme responsible for symmetric arginine dimethylation of multiple proteins that impact cell proliferation. Its substrates include proteins involved in mRNA splicing, signal transduction, gene transcription, and DNA repair. PRMT5 overexpression occurs in many cancers and correlates with poor prognosis. GSK3326595 is a potent, specific, and reversible inhibitor of PRMT5 that inhibits proliferation and induces cell death in a broad range of solid and hematologic tumor cell lines. It also exhibits potent anti-tumor activity in vivo in animal models, including in preclinical models of myeloid malignancies. One mechanism of action of GSK3326595 is via inhibition of cellular mRNA splicing and upregulation of tumor suppressor function. Mutations in splicing factors are frequent in myeloid malignancies (including approximately 40% of patients with myelodysplastic syndrome [MDS], and over 60% of patients with chronic myelomonocytic leukemia [CMML]), and further inhibition of mRNA splicing via GSK3326595 may lead to a synthetic lethal phenotype specifically in splicing mutant disease. Study 208809 is the first trial of a PRMT5 inhibitor in participants with myeloid malignancies. Methods Study 208809 is a Phase I/II study to evaluate the safety, tolerability, and clinical activity of GSK3326595 monotherapy in participants with relapsed and refractory MDS, CMML, and hypoproliferative acute myeloid leukemia (AML) that has evolved from an antecedent MDS. Part 1 will identify a tolerated dose and establish preliminary evidence of efficacy in this population. At the end of Part 1, if pre-specified criteria are met, then the study will be expanded with three additional Parts that will be opened in parallel. Part 2A is a Phase II randomized comparison of monotherapy GSK3326595 versus investigator's choice of best available care in participants with relapsed and refractory MDS, CMML, and hypoproliferative AML. Part 2B is a single-arm investigation of safety and efficacy of GSK3326595 plus 5-azacitidine in participants with newly diagnosed high-risk MDS. Part 2C is a single-arm investigation of the safety and efficacy of monotherapy GSK3326595 in participants with relapsed or refractory AML whose tumors harbor mutations in components of the pre-mRNA splicing machinery. All participants enrolled in this study have a diagnosis of MDS, CMML, or AML, with enrollment into each cohort as defined above. Participants are adults with adequate organ function as defined in the protocol. Prior allogeneic transplant is permitted. There are no required biomarkers for enrollment to Parts 1, 2A, and 2B, though central confirmation of pre-mRNA splicing factor mutations will be performed to stratify participants for overall analysis. Enrollment to Part 2C is limited to participants with splicing factor mutations. It is estimated that a maximum of 302 participants will be enrolled in the study, divided as follows: Approximately 41 participants in Part 1, approximately 192 participants in Part 2A, approximately 41 participants in Part 2B, and approximately 28 participants in Part 2C. In Part 1, the primary endpoint is clinical benefit rate, as defined as the percentage of participants achieving a complete remission, complete marrow remission, partial remission (PR), stable disease lasting at least 8 weeks, or hematologic improvement, as per standard criteria. In Part 2A, the primary endpoint is overall survival. In Part 2B and Part 2C, the primary endpoint is overall response rate (ORR), defined as the percentage of participants achieving a PR or better. Samples are collected to evaluate symmetric dimethylated arginine (SDMA), the enzymatic product of PRMT5. This has been demonstrated to be a pharmacodynamic marker of PRMT5 inhibition in plasma and tumor tissue. In addition, participants will be stratified based on the presence or absence of spliceosome mutations and analyzed separately to evaluate the effect of these mutations on clinical activity. As of 1 August 2019, recruitment is ongoing across six centers in the United States and Canada; ten participants have been enrolled, all into Part 1. ClinicalTrials.gov identifier: NCT03614728 Study is funded by GlaxoSmithKline Disclosures Watts: Takeda: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Brunner:Novartis: Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Papadantonakis:Agios: Consultancy, Honoraria. Abedin:Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria. Baines:GlaxoSmithKline: Employment, Equity Ownership. Barbash:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties, Research Funding. Gorman:GlaxoSmithKline: Employment, Equity Ownership. Kremer:GlaxoSmithKline: Employment, Equity Ownership. Borthakur:Cantargia AB: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agensys: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding.

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Remissions in Relapse/Refractory Acute Myeloid Leukemia Patients Following Treatment with NKG2D CAR-T Therapy without a Prior Preconditioning Chemotherapy

Blood ◽

10.1182/blood-2018-99-111326 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 902-902 ◽

Cited By ~ 8

Author(s):

David A Sallman ◽

Tessa Kerre ◽

Xavier Poire ◽

Violaine Havelange ◽

Philippe Lewalle ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Research Funding ◽

Clinical Activity ◽

Advisory Committees ◽

Car T ◽

Ligand Expression ◽

Acute Myeloid

Abstract Introduction: CYAD-01 is a chimeric antigen receptor T-cell (CAR-T) product based on the receptor NKG2D with specificity for a broad range of ligands (MICA, MICB and ULBP1-6) expressed on most tumors. In vivo preclinical studies showed long-term anti-tumor activity of CYAD-01, whilst not only targeting tumor cells but also cells from the tumor neo-vasculature and immunosuppressive environment in the absence of pre-conditioning therapy. Methods: Exploiting this unique mode of action of CYAD-01, the THINK trial (NCT03018405) is an open-label Phase I study assessing the safety and clinical activity of multiple CYAD-01 administrations without prior preconditioning in 2 parallel cohorts: one in patients (pt) with metastatic solid tumors and the other one in hematological malignancies, including relapsing/refractory (r/r) acute myeloid leukemia (AML), multiple myeloma (MM) and myelodysplastic syndrome (MDS). The dose escalation segment of the study evaluates 3 dose levels (DL; 3x108, 1x109 and 3x109 cells per injection) of one cycle of 3 CYAD-01 administration with 2-weeks intervals. The study has been amended at the stage of DL-2 to authorize a second cycle of 3 CYAD-01 administrations in case of no progressive disease after 2 months. Results: As of July 31, 2018, 12 pts in the hematological cohort (8 AML, 3 MM and 1 MDS) have been enrolled at the 3 DLs (6 pts in DL-1, 3 in DL-2 and 3 in DL-3) without prior preconditioning. Median age was 64 (range 29-83) and median number of prior therapies was 3. DL-3 (3 pts) has been fully accrued as of data cutoff. Over 34 injections, 5 pts experienced grade (G) 3/4 treatment-related AEs: in DL-1, one pt experienced G3 lymphopenia and a second pt experienced G4 lymphopenia and G4 pneumonitis in DL-2, one pt experienced G3 lymphopenia and G3 thrombocytopenia and two other pts experienced G3 cytokine release syndrome (CRS). Treatment related AEs occurring in ≥ 1pt include pyrexia, CRS, hypoxia, lymphopenia, fatigue and nausea. CRS occurred in 5 pts, three G1/2 and two G3 AEs, with rapid resolution to appropriate treatment including tocilizumab. No neurotoxicity AEs have been observed to date. Out of the 8 r/r AML pts enrolled, 7 were response evaluable (2 at DL-1, 3 at DL-2 and 2 at DL-3). The third DL-3 pt has just initiated the first cycle of CYAD-01 treatment. Overall response rate in r/r AML pts was 42% (3/7 patients) with 1 complete remission with partial hematologic recovery (CRh) in DL-1 and 2 CR with incomplete marrow recovery (CRi; 1 in DL-1 and 1 in DL-3). All responding pts achieved response by day 29 (i.e. after 2 CYAD-01 administrations). The AML pt with CRh in DL-1 was bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT) on day +97 post CYAD-01 and is in durable complete molecular remission (CRMRD-) for more than 1 year (ongoing). The two other responding pts had CRi for 1 month. Two other AML patients at DL-2 had clinical benefit/disease stabilization with hematologic improvement and bone marrow blasts decrease: one pt for 3 months and with a decrease from 24% to 10% and the second pt for at least 4 months (ongoing) and with a decrease from 9.8% to 5.5%. The first patient in CRh had a relative increase in the systemic levels of SDF-1, RANTES and MCP-1 which correlated with the timing of injections. CYAD-01 engraftment kinetics, NKG2D ligand expression (including blasts and soluble ligand expression), and the kinetics of cytokine induction will be correlated with patient's responses. The 3 MM and the MDS pt, all in DL-1, did not present any sign of clinical activity. Conclusions: We have demonstrated the feasibility and safety of multiple injections of CYAD-01 without preconditioning chemotherapy. We evidenced promising anti-leukemic activity with 42% ORR in r/r AML with 5/7 pts having clinical benefit. Rates of G3/4 CRS were low and manageable. Updated safety, activity and correlative science data of the complete dose-escalation segment will be presented. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. Kerre:Celyad: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dekker:Celyad: Employment. Snykers:Celyad: Employment. Sotiropoulou:Celyad: Employment. Breman:Celyad: Employment. Braun:Celyad: Employment. Lonez:Celyad: Employment. Verma:Celyad: Employment. Lehmann:GSK: Patents & Royalties; Celyad: Employment, Honoraria, Patents & Royalties.

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Ameli-01: Phase I, Open Label Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Expansion, Persistence and Clinical Activity of UCART123 (allogeneic engineered T-cells expressing anti-CD123 chimeric antigen receptor), Administered in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-138984 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Gail J. Roboz ◽

Daniel J. DeAngelo ◽

David A. Sallman ◽

Monica L. Guzman ◽

Pinkal Desai ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Committees ◽

Grant Support ◽

Car T ◽

Dose Levels ◽

Acute Myeloid

Background: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an incidence that increases with age, and a generally poor prognosis. The prognosis remains especially grim for those who are older, have secondary AML, or relapsed or refractory (R/R) disease, in which 5-year OS is 5-10%. Therefore, novel therapeutic approaches are needed. CD123(IL3Rα) is a cell surface target that is expressed on normal, committed hematopoietic progenitor cells, and a variety of hematological neoplasms, including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). UCART123 is genetically modified, allogeneic ("off-the-shelf"), anti-CD123 CAR T cell product candidate in which the TCR alpha constant gene is disrupted to reduce the risk of GvHD, and the CD52 gene is disrupted to permit the use of alemtuzumab for selective and prolonged host lymphodepletion. Also, the CAR is co-expressed with a suicide mechanism (RQR8), which can be activated by using rituximab. In vitro data have demonstrated that UCART123 efficiently targets primary AML cells, with minimal effect on normal progenitors. Also, in PDX mouse models of AML, UCART123 cells can eliminate tumor cells in vivo, prevent relapse, and improve survival; in a competitive BM/AML PDX model, UCART123 cells demonstrated preferential targeting of AML blasts (Guzman; Blood 2016). Methods: AMELI-01 is a phase 1, multi-center clinical trial of UCART123 that employs an mTPI design to evaluate the safety, tolerability and preliminary anti-leukemia activity of UCART123 in patients (pts) with R/R AML. Additional objectives include determination of the MTD; characterization of the expansion, trafficking and persistence of UCART123; assessment of cytokine, chemokine and CRP levels after UCART123 infusion; and assessment of immune cell depletion, reconstitution and immune response. Dose escalation will include up to 28 pts. The dose expansion portion follows a Simon 2-stage design and will enroll up to an additional 37 pts. Eligible pts must be ≤ 65 years of age with R/R AML, adequate organ function, a confirmed donor for potential back-up stem cell transplantation, and no ongoing > G1 toxicity from prior treatment. Pts with APL, prior gene or cellular therapy, > 1 allogeneic SCT, or those with a clinically relevant CNS disorder (including CNS leukemia) are not eligible. Pts receive a lymphodepletion (LD) regimen of either fludarabine and cyclophosphamide (FC) or fludarabine, cyclophosphamide plus alemtuzumab (FCA) starting on Day -5, followed by an infusion of UCART123 at one of 5 dose levels on Day 0. Pts are evaluated for the presence of dose-limiting toxicities (DLT) during a 28-day observation period, which extends to 42 days in the setting of marrow aplasia and/or persistent clinically significant cytopenias without residual AML. DL1 has cleared safety without DLT, and enrollment at the next dose levels are proceeding. ClinicalTrials.gov Identifier: NCT03190278 Monica L. Guzman, et al; Allogeneic TCRα/β Deficient CAR T-Cells Targeting CD123 Prolong Overall Survival of AML Patient-Derived Xenografts. Blood 2016; 128 (22): 765. doi: https://doi.org/10.1182/blood.V128.22.765.765 Disclosures Roboz: Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Amgen: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Shire: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Autolos: Consultancy; Incyte Corporation: Consultancy; Agios: Consultancy. Sallman:Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Guzman:SeqRx: Honoraria; Cellectis: Research Funding. Kantarjian:Delta Fly: Honoraria; Novartis: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; BioAscend: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Immunogen: Research Funding; Aptitute Health: Honoraria. Konopleva:Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; Agios: Research Funding; Amgen: Consultancy; Sanofi: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Ablynx: Research Funding; AbbVie: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Calithera: Research Funding; Cellectis: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Esteva:Cellectis: Current Employment. Garton:Cellectis: Current Employment. Backhouse:Cellectis: Current Employment. Galetto:Cellectis: Current Employment. Brownstein:Cellectis: Current Employment. Pemmaraju:Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Pacylex Pharmaceuticals: Consultancy.

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Targeting Tyrosine Kinase Receptors

Blood ◽

10.1182/blood.v122.21.sci-25.sci-25 ◽

2013 ◽

Vol 122 (21) ◽

pp. SCI-25-SCI-25

Author(s):

Michael Deininger

Keyword(s):

Tyrosine Kinase ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Hematologic Malignancies ◽

Clinical Activity ◽

Third Generation ◽

Advisory Committees ◽

Disease Evolution ◽

Flt3 Mutations

Abstract Protein tyrosine kinases (PTKs) regulate cell growth and other key functions. Constitutive PTK activation by somatic mutations, overexpression, or abnormal upstream signaling is characteristic of many cancers, including hematologic malignancies, providing a rationale for therapeutically targeting PTKs with small molecules. Imatinib, an ATP-competitive inhibitor of BCR-ABL1, the PTK causal to chronic myeloid leukemia (CML), established a paradigm for tyrosine kinase inhibitors (TKIs) as cancer therapeutics. Although a relatively weak inhibitor, imatinib is effective in most patients with chronic phase CML (CML-CP), while responses are transient in blastic phase (CML-BP). Point mutations in the BCR-ABL1 kinase domain have emerged as a major mechanism of drug resistance. The more potent second-generation TKIs – dasatinib, nilotinib, and bosutinib – induce deeper and faster responses and are active against many imatinib-resistant mutants, with the exception of T315I in the gatekeeper position of the catalytic site. This problem was addressed with ponatinib, a third-generation TKI covering all single BCR-ABL1 mutants, including T315I. Ponatinib has excellent clinical activity in CML-CP patients who failed other TKIs, while responses in CML-BP are short-lived. Some patients fail ponatinib due to BCR-ABL1 compound mutations, suggesting even third-generation TKIs cannot completely prevent mutational escape by the disease-initiating kinase. Another unsolved problem is that TKIs fail to efficiently target CML stem cells, leading to recurrence of active leukemia upon discontinuation. Despite these shortcomings, TKIs have completely changed the face of CML. Unfortunately, repeating this success in other hematologic malignancies has been challenging, likely reflecting differences in disease biology as much as suboptimal design of early compounds. CML-CP represents one extreme of the spectrum, where a single genetic lesion is sufficient to produce the phenotype and the hierarchy of hematopoietic differentiation is maintained. The situation is different in acute myeloid leukemia (AML) with activating FLT3 mutations. Not only these AML cases have mutations in other genes, they typically acquire FLT3 mutations late during disease evolution, implying that the disease-initiating clone will be impervious to FLT3 inhibition. Progress has been made through successive development of more potent TKIs with improved pharmacology, leading to quizartinib. It is clear, however, that FLT3 inhibitors cannot be used as single agents if there is a curative intent and the same may be true for JAK2 inhibitors in myelofibrosis. The first approved JAK2 inhibitor, ruxolitinib, dramatically improves symptoms, but has yet to demonstrate a significant impact on the malignant clone and is certainly not curative. It remains to be seen whether this reflects the fact that JAK2 activation is not the disease–initiating event, lack of inhibitor specificity towards the mutant JAK2 kinase, or other undesirable off-target effects that may be overcome with improved drugs. A completely new chapter was opened with ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of chronic lymphocytic leukemia (CLL). BTK is essential for signal transduction from the B-cell receptor (BCR). No activating mutations in BTK have been identified in lymphoma or CLL, but constitutive BCR signaling is critical to CLL cell survival in the microenvironment. Early studies show excellent clinical activity in patients with advanced CLL, although many responses are incomplete; much like the imatinib responses in late CML-CP. Ibrutinib may have a similarly profound effect upon CLL as imatinib on CML, but perhaps also similar limitations, such as the inability to eradicate residual leukemia; this of course needs to be tested in frontline studies. TKIs have had a significant albeit uneven impact upon treatment paradigms in hematologic malignancies. Future progress will involve optimizing compounds in terms of potency, selectivity, and pharmacokinetics. Allosteric inhibitors may add to the armamentarium. From the target perspective, it is likely that most activated kinase alleles have been discovered and the focus should shift to identification of disease-critical unmutated kinases. Lastly, identifying synthetically lethal inhibitor combinations will be critical to fully exploit the potential of TKI therapy. Disclosures: Deininger: BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity’s Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CELGENE: Research Funding; GENZYME: Research Funding; INCYTE: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GILEAD: Research Funding.

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