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.
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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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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 binds to 8 ligands (MICA, MICAB, and ULBP1-6) over-expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
Phase I DEPLETHINK study (NCT03466320) evaluates the safety and preliminary efficacy of a single CYAD-01 infusion (inf.) after lymphodepletion with cyclophosphamide and fludarabine in patients with relapsed or refractory (r/r) AML and MDS. A second cycle of 3 CYAD-01 infusions without preconditioning could be administered in absence of progressive disease (PD) following the 1st infusion. Three dose-levels (DLs; 1x108, 3x108 and 1x109 cells/inf.) are evaluated in the dose escalation segment. The first DL is also evaluated at two different intervals between preconditioning and CYAD-01 infusion (T7: seven days interval; T3: three days interval) in order to mitigate for any potential increased toxicity due to the administration of lymphodepletion.
As of end of July 2019, 6 patients (4 AML and 2 MDS) were enrolled in the first 2 cohorts which evaluated DL1 (1x108 cells/inf. at T3 or T7) and 3 patients (3 AML) were enrolled in the cohort 3 evaluating DL2 (3x108 cells/inf. at T3). The blasts in the bone marrow of 8 out of 9 patients ranged between 3% and 48% at baseline. Of the 6 patients treated at DL1 (with lymphodepletion administered up to 7 or 3 days before first CYAD-01 infusion), 3 patients experienced grade (G) 1 toxicity (cytokine release syndrome or CRS and diarrhea), or G2 CRS (uncleaned database). The patient with G2 CRS following the first infusion also experienced G4 CRS and G3 CAR T-cell-related encephalopathy syndrome (CRES) during the second inf. at 3x109 cells/inf. One other patient experienced G1 CRS during the second cycle. At DL2, only 1 patient experienced G1 related AEs (diarrhea and CRS) after the first CYAD-01 infusion. Another patient experienced G3 CRS during the second cycle. All patients recovered with treatment including tocilizumab and, when indicated, steroids.
At DL1, two out of 5 evaluable patients reached a stable disease (SD) at day (d) 36, allowing the initiation of the 2nd cycle. At DL2, one patient out of 3 reached SD. The DEPLETHINK study is currently enrolling at DL3 (T3).
Preliminary correlative studies show that the area under the curve at d36 (AUC D1-D36) after a single infusion of CYAD-01 with prior lymphodepletion is better than without preconditioning. Furthermore, the T3 interval between the preconditioning and CYAD-01 provides better engraftment than the T7 interval.
In conclusion, to date, the results demonstrate the safety and tolerability for CYAD-01 doses 1x108 and 3x108 cells/infusion with a prior lymphodepletion in patients with r/r AML and MDS. The T3 interval was therefore chosen for further CYAD-01 evaluations. The improved persistence of CYAD-01 with lymphodepletion, in particular 3 days before infusion, could lead to improved clinical responses. The study is ongoing and further data will be provided at the meeting.
Al-Homsi:Celyad: Membership on an entity's Board of Directors or advisory committees. Abdul-Hay:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pollyea:Diachii Sankyo: 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, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lequertier:Celyad: Employment. Alcantar-Orozco:Celyad: Employment. Borghese:Celyad: Employment. Lonez:Celyad: Employment. Braun:Celyad: Employment. Renard:Celyad: Employment. Flament:Celyad: Employment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We recently developed a novel chimeric antigen receptor (CAR) T-cell therapy, called CYAD-01 (a.k.a. NKR-2), incorporating the full-length human natural killer receptor NKG2D fused with the ...human CD3 zeta signaling domain, which associates with the adaptor molecule DAP10 to provide co-stimulatory signal upon ligand binding. CYAD-01 is currently evaluated in multiple intravenous administrations in the ongoing THINK study (NCT03018405) in both hematological and solid indications. Classical CAR-Ts has yet to demonstrate positive results in the context of solid tumors. Underlying reasons for this reduced clinical activity include the need to extravasate from the peripheral circulation, infiltrate into the tumor and overcome the hostile immune suppressive tumor microenvironment (TME) to deliver anti-tumor effector responses. To address the challenge related to the difficulty of CAR-T cells to access the site of metastasis, the LINK trial (Locoregional Immunotherapy with NKR-2) has been developed to assess the safety and clinical activity of multiple hepatic transarterial administrations of CYAD-01 treatment (every 2 weeks x 3 infusions) in colorectal cancer patients with unresectable liver metastases (NCT03370198). The hepatic transarterial administration (HTAA) cell therapy may offer the advantage of lower systemic toxicity and higher and more persistent concentration of the infused cells on the TME compared with systemic administration. The difference in blood supply between uninvolved liver parenchyma and metastases may favor CYAD-01 tumor homing. Moreover, based on the potential impact of the CYAD-01 treatment on the host immune system, combined with the tumor antigens spreading induced by its direct anti-cancer cells activity, the CYAD-01 HTAA may boost the adaptive immune response and therefore may control any distant lesion (aboscopal effect). This dose escalation study will use a 3+3 design including 3 dose levels of CYAD-01 (3x108, 1x109 and 3x109 cells per injection) to evaluate the maximum tolerated dose of the CYAD-01 hepatic transarterial administration. Peripheral blood samples, as well as tumor biopsies will be collected to determine systemic CYAD-01 kinetics and within the liver tumor tissues, NKG2D ligand expression and systemic cytokine levels in peripheral blood post-infusion. This study will enroll 12 patients in case of no DLT and is open for recruitment.
Citation Format: Nathalie Braun, Alain Hendlisz, Leila Shaza, Michaël Vouche, Vincent Donckier, Philippe Aftimos, Ahmad Awada, Caroline Lonez, Bikash Verma, David E. Gilham, Frédéric F. Lehmann. A phase I study assessing the safety and clinical activity of multiple hepatic transarterial administrations of a NKG2D-based CAR-T therapy CYAD-01, in patients with unresectable liver metastases from colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT134.
Hypochlorite is a powerful oxidant produced by neutrophils to kill invading microorganisms. Despite this important physiological role of HOCl in fighting bacterial infections, no ...hypochlorite-specific stress response has been identified yet. Here, we identified a hypochlorite-responsive transcription factor, YjiE, which is conserved in proteobacteria and eukaryotes. YjiE forms unusual dodecameric ring-like structures in vitro that undergo large DNA-induced conformational changes to form dimers and tetramers as shown by transmission electron microscopy and analytical ultracentrifugation. Such smaller oligomers are predominant in hypochlorite-stressed cells and are the active species as shown by fluorescence anisotropy and analytical ultracentrifugation. YjiE regulates a large number of genes upon hypochlorite stress. Among them are genes involved in cysteine, methionine biosynthesis, and sulfur metabolism (up-regulated) and genes involved in iron acquisition and homeostasis (down-regulated), thus supposedly replenishing oxidized metabolites and decreasing the hypochlorite-mediated amplification of intracellular reactive oxygen species. As a result, YjiE specifically confers hypochlorite resistance to E. coli cells. Thus, to our knowledge, YjiE is the first described hypochlorite-specific transcription factor.
Hypochlorite is strongly bactericidal and used as disinfectant; yet, a response regulator allowing adaptation to the inflicted stress is so far unknown.
The transcription factor YjiE specifically confers hypochlorite resistance and is an atypical dodecameric regulator that undergoes DNA-induced dissociation to dimers and tetramers.
YjiE protects cells from hypochlorite-induced oxidative damage by triggering a specific stress response.
This is the first described hypochlorite-specific regulator.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
CYAD-01 is a T-cell product engineered to express a chimeric antigen receptor (CAR) based on the NKG2D receptor (NKG2D CAR) which binds 8 ligands (MICA/B, ULBP1-6) over-expressed by a ...large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
The phase I THINK study (NCT03018405) evaluated the safety and clinical activity of multiple injections of CYAD-01 infused every 2 weeks, without preconditioning chemotherapy, in 13 relapsed/refractory (r/r) AML and MDS patients. While an encouraging objective response rate according to ELN2017 (AML) or revised IPSS (MDS) and reduction in bone marrow blasts were seen with good safety profile, the responses were short-lived (≤ 3 months - see ASH 2019, poster 3826). To enhance CAR T-cell persistence, we evaluated a weekly dose schedule without preconditioning (THINK study) or the addition of cyclophosphamide and fludarabine (CyFlu) as a preconditioning regimen prior to CAR T-cell infusion (phase I DEPLETHINK study, NCT03466320).
Aim
To further increase persistence and potency of the T-cell product, optimization of the previously used mAb manufacturing process was performed by shortening the duration of production along with modification of PI3K inhibitor. This optimized manufacturing process (termed “OptimAb”) aimed to generate CYAD-01 cells with a higher frequency of early memory T-cells with high cytokine secretion upon activation, as compared to the original “mAb” process.
Results
As compared to the previous mAb manufacturing process, the OptimAb manufacturing process generates a product that secretes higher levels of IFN-γ upon co-culture with tumor cells and contains a higher frequency of CD62L+ T-cells in vitro, characteristic of an early memory phenotype. In an in vivo aggressive AML (THP-1) model, CYAD-01 OptimAb displayed a strong improvement in long-term anti-tumor activity as compared to the CYAD-01 mAb at the same dose chosen to have a minimal anti-tumor activity (stress-test dose, see figure).
Based on these results, both THINK and DEPLETHINK clinical studies were amended to evaluate the OptimAb process. As of August 2020, 5 patients have been treated with multiple infusions of the OptimAb CYAD-01 as standalone treatment at the dose of 3x108 cells/infusion in the small expansion segment of the THINK study. 7 patients were treated with a single infusion of OptimAb CYAD-01 administered after a CyFlu preconditioning in the dose-escalation segment at the doses of 3x108 cells/infusion or 1x109 cells/infusion in the DEPLETHINK study. To date, the results demonstrate the safety and tolerability for CYAD-01 OptimAb with or without a prior lymphodepletion in patients with r/r AML and MDS.
Preliminary data of the clinical and pharmacokinetics evaluation of CYAD-01 manufactured with the improved OptimAb process, as compared with the mAb process at the same dose, in two Phase I studies will be provided at the time of presentation.
Conclusion/summary
The autologous CYAD-01, a first generation NKG2D CAR T-cell product is currently investigated in r/r AML/MDS patients, a difficult to target disease due in part to the absence of truly AML-specific surface antigens, its rapid clinical progression and the absence of disease control by the CyFLu preconditioning. CYAD-01 manufactured using an optimized process, OptimAb, aims to improve CAR T-cell persistence and clinical responses. The data analysis of the same CAR-T product with different manufacturing processes, with or without preconditioning chemotherapy, will provide the medical community with clinical and scientific insights to guide the future of this therapeutic modality.
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Sallman:Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Al-Homsi:Celyad: Membership on an entity's Board of Directors or advisory committees. Pollyea:Janssen: Consultancy; 47: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Syndax: Consultancy; Syros: Consultancy; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Celgene/BMS: Consultancy; Agios: Consultancy; Glycomimetics: Other. Wang:Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Jazz Pharmaceuticals: Consultancy. Demoulin:Celyad Oncology: Current Employment. Sotiropoulou:Celyad Oncology: Current Employment. Alcantar-Orozco:Celyad Oncology: Current Employment. Breman:Celyad Oncology: Current Employment. Dheur:Celyad Oncology: Current Employment. Braun:Celyad Oncology: Current Employment. Lonez:Celyad Oncology: Current Employment. Gilham:Celyad Oncology: Current Employment. Flament:Celyad Oncology: Current Employment. Lehmann:Celyad Oncology: Current Employment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CYAD-01 is an autologous chimeric antigen receptor (CAR) T-cell product based on the natural killer (NK) group 2D (NKG2D) receptor, which binds eight ligands that are overexpressed in a wide range of ...haematological malignancies but are largely absent on non-neoplastic cells. Initial clinical evaluation of a single infusion of CYAD-01 at a low dose in patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, and multiple myeloma supported the feasibility of the approach and prompted further evaluation of CYAD-01. The aim of the present study was to determine the safety and recommended phase 2 dosing of CYAD-01 administered without preconditioning or bridging chemotherapy.
The multicentre THINK study was an open-label, dose-escalation, phase 1 study for patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, or multiple myeloma, after at least one previous line of therapy. Patients were recruited from five hospitals in the USA and Belgium. The dose-escalation segment evaluated three dose levels: 3 × 10
(dose level one), 1 × 10
(dose level two), and 3 × 10
(dose level three) cells per infusion with a 3 + 3 Fibonacci study design using a schedule of three infusions at 2-week intervals followed by potential consolidation treatment consisting of three additional infusions. The occurrence of dose-limiting toxicities post-CYAD-01 infusion was assessed as the primary endpoint in the total treated patient population. The trial was registered with ClinicalTrials.gov, NCT03018405, and EudraCT, 2016-003312-12, and has been completed.
Between Feb 6, 2017, and Oct 9, 2018, 25 patients were registered in the haematological dose-escalation segment. Seven patients had manufacturing failure for insufficient yield and two had screening failure. 16 patients were treated with CYAD-01 (three with multiple myeloma and three with acute myeloid leukaemia at dose level one; three with acute myeloid leukaemia at dose level two; and six with acute myeloid leukaemia and one with myelodysplastic syndromes at dose level three). Median follow-up was 118 days (IQR 46-180). Seven patients (44%) had grade 3 or 4 treatment-related adverse events. In total, five patients (31%) had grade 3 or 4 cytokine release syndrome across all dose levels. One dose-limiting toxicity of cytokine release syndrome was reported at dose level three. No treatment-related deaths occurred, and the maximum tolerated dose was not reached. Three (25%) of 12 evaluable patients with relapsed or refractory acute myeloid leukaemia or myelodysplastic syndromes had an objective response. Among responders, two patients with acute myeloid leukaemia proceeded to allogeneic haematopoietic stem-cell transplantation (HSCT) after CYAD-01 treatment, with durable ongoing remissions (5 and 61 months).
Treatment with a multiple CYAD-01 infusion schedule without preconditioning is well tolerated and shows anti-leukaemic activity, although without durability outside of patients bridged to allogeneic HSCT. These phase 1 data support the proof-of-concept of targeting NKG2D ligands by CAR T-cell therapy. Further clinical studies with NKG2D-based CAR T-cells are warranted, potentially via combinatorial antigen targeted approaches, to improve anti-tumour activity.
Celyad Oncology.
▪
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.
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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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that prevent the unspecific aggregation of proteins. So far, Hsp26 was the only unambiguously identified member of the sHsp ...family in Saccharomyces cerevisiae. We show here that the sHsp system in the cytosol of S. cerevisiae consists of two proteins, Hsp26 and Hsp42. Hsp42 forms large dynamic oligomers with a barrel‐like structure. In contrast to Hsp26, which functions predominantly at heat shock temperatures, Hsp42 is active as a chaperone under all conditions tested in vivo and in vitro. Under heat shock conditions, both Hsp42 and Hsp26 suppress the aggregation of one‐third of the cytosolic proteins. This subset is about 90% overlapping for Hsp42 and Hsp26. The sHsp substrates belong to different biochemical pathways. This indicates a general protective function of sHsps for proteome stability in S. cerevisiae. Consistent with this observation, sHsp knockout strains show phenotypical defects. Taken together, our results define Hsp42 as an important player for protein homeostasis at physiological and under stress conditions.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
NKG2D is a receptor with specificity for a broad range of stress ligands expressed on the majority of tumors (MICA, MICB and ULBP1-6). In vivo preclinical studies in acute myeloid leukemia ...(AML), ovarian, multiple myeloma (MM) and pancreatic cancer models all showed potent efficacy of T cells engrafted with a NKG2D Chimeric Antigen Receptor (CAR) indicating the possible effectiveness of CYAD-01 (a.k.a NKR-2) in the clinic. To evaluate the susceptibility of several malignancies to NKG2D ligand targeting in a clinical setting, and the safety of CYAD-01, an open-label phase I THINK (THerapeutic Immunotherapy with NKR-2, NCT03018405) trial was initiated. CYAD-01 was administered three successive times with 2-week intervals, and without prior lymphodepletive conditioning, in refractory or relapsed patients with different metastatic solid tumors and hematological malignancies (AML/MDS and MM), which failed from standard treatments. The study was designed to have two segments. The first dose escalation segment (3+3 design) includes three dose levels: 3x108, 1x109 and 3x109 CYAD-01 per injection, in both solid and hematological arms. The second, open-label phase I expansion segment of the study will evaluate the recommended dose in each tumor type. By December 2017, within the solid tumor arm, 4 patients had received three CYAD-01 administrations at dose-level 1 and three patients had received three CYAD-01 administrations at dose-level 2 and completed the safety period with no DLT occurrence. Within the hematologic arm, two AML patients and 1 MM patient have received the three CYAD-01 administrations at dose-level 1 and completed the safety period with no dose-limiting toxicity (DLT) occurrence. One relapsed AML patient to salvage CLAG-M chemotherapy reached a morphologic leukemia-free state (MLFS) after the CYAD-01 treatment, and resolution of symptoms with improved hematopoiesis at 3 months follow up at which time he started conditioning therapy for allo-HSCT. At 3 months post allo-HSCT, the patient is in complete remission with 100% donor chimerism. Interestingly, even at this early stage of the evaluation, there is variation in the phenotype of the CYAD-01 cells (e.g. CD4/CD8 ratio) and an early observation of a relative increase in the systemic levels of SDF-1 and RANTES in the patient who achieved MLFS. In summary, we report the first objective response to CAR-T in r/r AML using CYAD-01 without preconditioning chemotherapy and with no significant toxicities, highlighting the potential of targeting NKG2D ligands in AML.
Citation Format: David A. Sallman, Jason B. Brayer, Xavier Poire, Tessa Kerre, Philippe Lewalle, Eunice S. Wang, Bikash Verma, Eytan Breman, Marco Davila, Nathalie Braun, Caroline Lonez, David E. Gilham, Frédéric F. Lehmann. The THINK clinical trial: Preliminary evidence of clinical activity of NKG2D chimeric antigen receptor T cell therapy (CYAD-01) in acute myeloid leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT129.
Introduction:
CYAD-01 is a chimeric antigen receptor T-cell (CAR-T) product based on the receptor NKG2D which demonstrated anti-tumor efficacy through different mechanisms of action in numerous ...preclinical models. A comprehensive clinical program was developed with the aim to define the optimal CYAD-01 treatment in acute myeloid leukemia (AML).
Methods:
The ongoing Phase I THINK trial (NCT03018405) evaluates multiple CYAD-01 injections in 2 parallel cohorts: one in patients (pt) with metastatic solid tumors and the other one in relapsing/refractory hematological malignancies. 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 at 2 weeks apart. As of July 30, 2018, 12 pts in the THINK hematological cohort (8 AML, 3 MM and 1 MDS) have been enrolled at the 3 DLs without prior preconditioning. No dose-limiting toxicity occurred. We evidenced promising anti-leukemic activity with 42% ORR in r/r AML with 5/7 pts having clinical benefit. Based on the initial data generated into the THINK study, two additional Phase I clinical trials have been developed to evaluate 3 DLs (1x108, 3x108 and 1x109 cells per injection) post preconditioning regimen or in association with standard of care (SoC).
The DEPLETHINK study (NCT03466320) aims at evaluating the CYAD-01 treatment administered after a cyclophosphamide and fludarabine preconditioning regimen to r/r AML patients. The preconditioning chemotherapy should (i) favor the expansion and engraftment of CYAD-01, (ii) increase NKG2D ligand expression on tumor cells and (iii) help to overcome the strong immunosuppressive microenvironment.
The EPITHINK study (EudraCT 2018-000745-39) aims at assessing the safety of the CYAD-01 treatment administered concurrently with SoC 5-azacytidine treatment in treatment-naïve AML pts ineligible for intensive treatment. Similar to the preconditioning treatment, the epigenetic treatment could contribute to favor engraftment of CYAD-01 cells and increase target antigen expression while better controlling the disease progression of patients early in the treatment.
Results:
Description of the study design and preliminary clinical data from the first cohorts of the EPITHINK and DEPLETHINK studies will be presented. The preliminary data in term of CYAD-01 engraftment kinetics, NKG2D ligand expression (including blasts and soluble ligands), and the kinetics of cytokine induction will be correlated with the concurrent treatment (preconditioning or epigenetic treatment) versus the stand alone therapeutic approach.
Conclusions:
We have demonstrated the feasibility and safety of multiple injections of CYAD-01 without preconditioning chemotherapy (THINK). Preliminary safety, activity and correlative science data will be presented according a prior preconditioning (DEPLETHINK) and concurrent administration with SoC epigenetic treatment (EPITHINK).
Sallman:Celgene: Research Funding, Speakers Bureau. Kerre:BMS: Consultancy; Celgene: Consultancy, Research Funding; Celyad: Consultancy. Wang:Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; 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; Jazz: Speakers Bureau. Selleslag:Kiadis Pharma: Other: Financial support for study-related issues. Beguin:Kiadis Pharma: Consultancy. Al-Homsi:Celyad: Membership on an entity's Board of Directors or advisory committees. Dekker:Celyad: Employment. Breman:Celyad: Employment. Sotiropoulou:Celyad: Employment. Snykers:Celyad: Employment. Braun:Celyad: Employment. Lonez:Celyad: Employment. Verma:Celyad: Employment. Lehmann:Celyad: Employment, Honoraria, Patents & Royalties; GSK: Patents & Royalties. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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