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Hopfield networks are iterative procedures able to solve combinatorial optimization problems. New studies regarding algorithm-architecture adequacy are fostered by the re-emergence of hardware implementations of such methods in the form of Ising machines. In this work, we propose an optoelectronic architecture suitable for fast processing and low energy consumption. We show that our approach allows effective optimization relevant to statistical image denoising.

Objectives Tumor-associated antigens (TAAs) are frequently overexpressed in several cancer types. The aim of this study was to investigate the expression of TAAs in breast cancer. Material and methods A total of 250 selected invasive breast cancers including 50 estrogen receptor (ER)-positive (Luminal B like), 50 triple-negative (TN), 50 ER-positive lobular type, 50 ER- and progesterone receptor (PgR)-positive (Luminal A like) and 50 cerbB2-positive breast cancers, were assessed for New York esophageal squamous cell carcinoma-1 (NY-ESO-1), Wilms tumor antigen (WT-1) and PReferentially expressed Antigen of MElanoma (PRAME) antigen expression by immunohistochemistry (IHC). Results A significantly higher expression of cancer testis (CT)-antigens NY-ESO-1 and WT-1 antigen was detected in TN breast cancers compared with ER-positive tumors. NY-ESO-1 overexpression (score 2 + and 3+) assessed by monoclonal and polyclonal antibodies was detected in 9 (18%) TN cancers as compared to 2 (4%) ER-positive tumors (p = 0.002). WT1 over-expression (score 2 + and 3+) was confirmed in 27 (54%) TN tumor samples as compared to 6 (12%) ER-positive (p, Highlights • Tumor-associated antigens are frequently overexpressed in several cancer types, being also associated with poorer patients’ survival outcomes. • Our study confirmed that NY-ESO-1 and WT1 antigens are higher expressed in triple-negative than in other breast cancer subtypes. • Given the limited therapeutic options for triple-negative breast cancer patients, the assessment of WT1 and NY-ESO-1 antigens expression in breast cancer tissue at surgery may allow to identify patients potentially candidate to adjuvant peptide vaccines, alone or in combination with other systemic therapies.

International audience; When the state space dimension increases, the computational burden can become a major challenge for optimal Kalman filtering in Gaussian triplet Markov models (TMMs). In this paper, we introduce a new model order reduction technique applicable to linear time-homogeneous Gaussian TMMs. Taking advantage of the lower state dimension of the resulting approximate model, a low-complexity suboptimal Kalman filter is obtained. The proposed estimator provides complexity reduction without significant accuracy loss and is shown to outperform two classical methods in the case of Markovian process noise.

An optoelectronic Reservoir Computer is proposed and implemented numerically and on physical hardware for early-stage Alzheimer’s disease detection for the first time. The approach yields classification accuracy of 85% surpassing state-of-the-art performances.

International audience; A new lower bound is proposed in this article. Like Levenshtein bound, it relates to the maximum correlation value (autocorrelation and cross-correlation) a set of sequences can achieve. The novelty introduced here is that each sequence is associated with a mismatched filter. The proposed bound is inspired from Levenshtein’s, holds for any set of unimodular sequences and can be applied in both aperiodic and periodic cases. It appears that the obtained expression does not deviate a lot from the (matched) Levenshtein, which indicates that the use of a mismatched filter will not guarantee much better sidelobe performance, as the number fo sequences is significant, contrary to the popular belief.

International audience; We propose a novel estimation procedure for linear time-varying pairwise Markov models (PMM), that is robust to system parameter uncertainties occurring in real-world applications. In order to cope with mismodeling errors and ignorance of noise/initial state statistics, we solve a finite-horizon state estimation problem. The resulting unbiased finite impulse response filter for PMMs (PMM-UFIR) is first derived in batch form and then converted to a recursive Kalman-like form for the sake of complexity reduction. Closed forms for the error covariance matrix of the state estimate are also provided for analytical performance assessment.Numerical results illustrate the effectiveness of the proposed estimation method over Gaussian processes, by showing that the PMM-UFIR is nearly as accurate as (resp. more robust than) optimal filtering under perfect (resp. uncertain) system parameters after tuning the horizon size.

This paper provides a comparative analysis for robustness of the Kalman filter (KF), $H_\infty$ filter derived using the game theory, and unbiased finite impulse response (UFIR) filter, which ignores the noise statistics and initial values. A comparison is provided for Gaussian models by studying the effects of errors and disturbing factors on the bias correction gain. It is shown that the rule of thumb of optimal filtering in terms of accuracy, $\text{UFIR} , typically does not hold in the real-world implying errors in the noise statistics, mismodeling, temporary uncertainties, and difficulties in filter tuning to optimal mode. Under such conditions, the filters are related to each other as $\text{KF} \lessgtr H_\infty . A justification of this statement is provided analytically and confirmed by simulations and experimentally based on two-state polynomial and harmonic models.

Off-the-shelf allogeneic CAR T cells derived from healthy donor cells have the potential to overcome many of the issues associated with the time-consuming manufacturing of autologous CAR T cells. However, adoptive transfer of allogeneic T cells carries the risk of graft-versus-host disease (GvHD). Most of the clinical experience with allogeneic CAR T cells is based on gene editing to eliminate T cell receptor (TCR) to mitigate the risk of GvHD. While clearly effective, the downsides of gene editing include multiple manufacturing steps requiring multiple clinical grade reagents, thus extending culture times, which can be associated with T cell exhaustion. As an alternative, we have explored short hairpin RNA (shRNA) as a means to knockdown TCR expression at the mRNA level. This shRNA is co-expressed along with the CAR in a single clinical grade vector, therefore requiring just one step of genetic modification. CYAD-211 is an allogeneic anti-BCMA CAR T that co-expresses a shRNA targeting CD3z which results in reduction of cell surface TCR expression. IMMUNICY-1 is an ongoing open-label Phase 1 trial (NCT04613557) designed to evaluate CYAD-211 in adult patients with refractory or relapsed multiple myeloma (MM) following at least two prior MM regimens. Patients receive non-myeloablative preconditioning (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, for 3 days) followed by a single CYAD-211 infusion in a 3+3 dose escalation design evaluating three dose-levels (DL): 30x10 6, 100x10 6 and 300x10 6 cells/infusion. As of July 29, 2021, nine patients were enrolled across the 3 DLs. Patients had received a median of four prior lines of treatment. Seventy-eight percent of patients were previously exposed to all three major MM drug classes (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibody therapy). Eight patients had prior autologous stem cell transplantation. CYAD-211 was well tolerated. One patient developed grade 1 cytokine release syndrome. Two patients had Grade ≥ 3 hematologic toxicities possibly related to the experimental treatment. Two patients experienced infectious adverse events (1 grade 1 rhinitis and 1 grade 2 upper respiratory infection). There was no neurologic toxicity and no GvHD. There was no dose-limiting toxicity. Eight patients were evaluated for activity per IMWG criteria. Two patients achieved partial response at dose-levels 1 and 2 while 5 patients had stable disease (SD). One patient with an ongoing SD (3 months +) showed evidence of reduction in size of plasmacytomas. Analysis of peripheral blood samples by molecular methods confirmed the engraftment of CYAD-211. All patients had detectable CAR T cells. However, the engraftment was short lasting (3-4 weeks). There was a correlation between the depth of lymphodepletion and engraftment. There was also a dose-response in terms of CYAD-211 kinetics with a level neighboring 8,000 copies of CAR T per microgram of input DNA in patients at DL3. These early data indicate that CYAD-211 is well tolerated with a good safety profile. While further study is required to fully understand the anti-BCMA potency of the CAR used in this trial, the lack of observed GvHD despite engraftment of CYAD-211 provides proof of concept of the safe administration of CAR T using a shRNA-allogeneic platform. The lack of sustained engraftment of CYAD-211 can be explained by rejection of the allogeneic cells by the recovering immune system of the recipient and calls for exploring the role of augmented lymphodepletion. Furthermore, given the ability to include multiple shRNA within the single CAR vector, future strategies will also examine knocking down other molecules that are important in driving immune rejection. Disclosures Al-Homsi: BMS: Other: Independent Medical Education Grant; Daichii Sankyo: Consultancy; Celyad Oncology: Other: Advisory Board. Deeren: Alexion: Consultancy; BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Sanofi: Consultancy, Research Funding; Sobi: Consultancy; Takeda: Consultancy. Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Meuleman: iTeos Therapeutics: Consultancy. Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Abbvie: Consultancy; Jazz: Other: Advisory Board, Speakers Bureau; Servier: Other: Advisory Board, Speakers Bureau. Braun: Celyad Oncology: Current Employment. Lonez: Celyad Oncology: Current Employment. Dheur: Celyad Oncology: Current Employment. Alcantar-Orozco: Celyad Oncology: Current Employment. Gilham: Celyad Oncology: Current Employment. Flament: Celyad Oncology: Current Employment. Lehmann: Celyad Oncology: Current Employment.

While CAR T cell therapy has delivered impressive clinical efficacy in B cell malignancies, similar levels of clinical activity have not been demonstrated in acute myeloid leukemia (AML). One underlying reason for this lack of translation is the relative paucity of validated CAR T targets. Major Histocompatibility Complex Class 1 related proteins MICA and MICB along with the UL16 binding proteins 1-6 (ULBP1-6) are frequently over-expressed on AML and myelodysplastic syndrome (MDS) blasts. The Natural Killer Group 2D (NKG2D) is a single receptor able to bind MICA, MICB and ULBP1-6, thus providing a potentially powerful approach that could be exploited to target this family of targets thereby providing a novel CAR T approach for AML/MDS. Expressing the NKG2D receptor fused to the human CD3z cytoplasmic domain generates a CAR that, when expressed in primary T cells, generates a CAR T product (termed CYAD-01) that showed good anti-tumor activity in preclinical models. In clinical trials, CYAD-01 showed a good tolerability profile but with a disappointing level of clinical activity when combined with cyclophosphamide / fludarabine preconditioning (DEPLETHINK trial, NCT03466320). We hypothesised that the transient expression of MICA/MICB on the CAR T itself may inhibit the activity of the NKG2D CAR through self-targeting and consequent fratricide. We developed a single shRNA able to knockdown both MICA and MICB. Co-expression of this shRNA with the NKG2D CAR generated a second generation CAR T product termed CYAD-02 which was examined in a highly similar AML/MDS patient population and preconditioning regimen as employed in the DEPLETHINK trial. CYAD-02 was evaluated in the the first-in-human CYCLE-1 trial (NCT04167696) in patients with r/r AML/MDS. The dose-escalation phase evaluated three dose-levels (DL) (1x10 8, 3x10 8 and 1x10 9 total cells per infusion), administered as a single infusion after standard preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days) according to a classic 3+3 design. As of July 2021, 11 patients have been treated with CYAD-02 at the different dose-levels (3 at each DL1 and 2 and 5 at DL3). In terms of safety and tolerability, there was no evidence of a differential safety profile of CYAD-02 within the CYCLE-1 trial as compared to that observed in the CYAD-01 clinical trial. Of note, five patients enrolled in all 3 DLs experienced Grade ≥ 3 adverse events (AE) at least possibly related to CYAD-02 (cytokine release syndrome, febrile neutropenia, white blood cell count decreased, infusion related reaction). With respect to clinical activity, seven patients in total achieved stable disease (2 at DL1, 3 at DL2 and 2 at DL3) with 4 demonstrating evidence of transient blast reduction or anti-leukemic activity (decrease of at least 50% of the bone marrow blasts). In addition, two MDS patients at DL3 achieved a marrow complete response. Overall, this suggests dose dependent response to CYAD-02. Furthermore, patients receiving CYAD-02 cells seem to display a greater duration of response and stronger blast reduction as compared to patients who received CYAD-01 in DEPLETHINK. Interestingly, peak engraftment levels were higher for CYAD-02 compared to CYAD-01 at the same dose (DEPLETHINK trial). At DL3, CYAD-02 cells could be readily detected in peripheral blood of 4/5 patients through month 2. In addition, and unlike what is reported in B cell CAR T-cells trials, there was very limited evidence of elevated homeostatic cytokines (IL-7/IL-15) following CyFlu administration with IL-15 not detected in any of the patients and IL-7 showing only a minor increase in 2 patients. The knockdown of MICA/MICB appears to have a positive contribution to the initial clinical activity of CYAD-02 as compared to that achieved with the first generation CYAD-01 CAR T, together with good safety and tolerability. The lack of homeostatic cytokines after preconditioning, likely limiting the engraftment and activity of CAR T cells, may be related to the biology of myeloid malignancies. One approach to further drive the potency of NKG2D-based CAR T cells would likely be armoring the CAR T through using the T cell as a vehicle to secrete cytokines alongside the CAR. Overall, shRNA knockdown technology provides a means to modify CAR T function and here shows that single shRNA can target two independent genes to enhance the phenotype of the CAR Ts. Disclosures Deeren: Alexion: Consultancy; BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Sanofi: Consultancy, Research Funding; Sobi: Consultancy; Takeda: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Alcantar-Orozco: Celyad Oncology: Current Employment. Dheur: Celyad Oncology: Current Employment. Breman: 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.

BackgroundThe peptide-based allogeneic chimeric antigen receptor (CAR) T-cell treatment CYAD-101 utilizes an NKG2D receptor that targets eight ligands expressed on tumor cells and non-malignant stromal cells of many cancer types. CYAD-101 also co-expresses a peptide intended to eliminates the potential of graft versus host disease (GvHD). In the phase 1 alloSHRINK study (NCT03692429), CYAD-101 was administered with FOLFOX preconditioning chemotherapy to 15 patients with metastatic colorectal cancer (mCRC). The treatment was well tolerated with no evidence of GvHD, no treatment-related adverse events ≥ Grade 3 and only two patients who presented a cytokine release syndrome grade 1. By contrast, encouraging clinical activity was observed including two partial responses. Evidence of changes in the TCR repertoire and modulation of the cytokine profile four months post-treatment with CYAD-101 were also observed implying that the NKG2D CAR T may also be modulating the immune suppressive environment in patients reflecting that seen in pre-clinical models (ASCO GI 2021 abstract #74).Given the expansion of the T cell repertoire after CYAD-101 therapy, we considered that employing a checkpoint inhibitor to release this expanded T cell population may drive more durable clinical responses beyond that currently seen with the CAR T alone.MethodsThe KEYNOTE-B79 trial evaluates the safety and clinical activity of multiple infusions of CYAD-101, administered post FOLFOX preconditioning chemotherapy, then followed three weeks after CYAD-101 by a pembrolizumab consolidation treatment (200 mg every three weeks for a maximum two years total treatment duration) in microsatellite stable/mismatch-repair proficient mCRC patients with recurrent/progressing disease after at least one metastatic line of therapy which must include FOLFOX chemotherapy.The schedule of administration of three CYAD-101 infusions at the dose 1x109 cells/infusion Q2W post-FOLFOX preconditioning chemotherapy are based on the alloSHRINK study.This sequencing of checkpoint inhibitor at a timepoint after CYAD-101 therapy ensures that the modulated endogenous immune response is enabled by pembrolizumab. This study is not focused on impacting the CAR T cell itself largely since CYAD-101 cells at the time of manufacture show negligible expression of PD-1 and that this sequencing ensures no overlap of potential toxicities that could arise from the CAR T or checkpoint inhibitor therapies.The KEYNOTE-B79 study is planned to be initiated in Q4-2021.Ethics ApprovalThe study was approved by all relevant authorities and submitted to Institution’s Ethics Boards for their approval before study initiation.

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. Figure Disclosures 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.

Background Autologous CAR T-cell therapy targeting the B-cell maturation antigen (BCMA) has shown impressive objective response rates in patients with advanced multiple myeloma (MM). Clinical grade manufacturing of autologous CAR T-cells has limitations including vein-to-vein delivery time delay and potentially sub-optimal immunological capability of T-cells isolated from patients with advanced disease. Allogeneic CAR T-cell products, whereby cells from healthy third-party donors are used to generate an "off-the-shelf" CAR T-cell product, have the potential to overcome some of these issues. To circumvent the primary potential risk of graft-versus-host disease (GvHD) associated with the use of allogeneic T-cells, abrogation of the T-cell receptor (TCR) expression in the CAR T-cells, via gene editing, is being actively pursued. To avoid the potential safety risks and manufacturing challenges associated with gene editing, the allogeneic CYAD-211 CAR T-cell product exploits short hairpin RNA (shRNA) interference technology to down-regulate TCR expression thus avoiding the risk of life-threatening GvHD. Aim The aim is to generate a BCMA-specific allogeneic CAR T-cell product using a non-gene editing approach and study its activity both in vitro and in vivo. CYAD-211 combines a BCMA-specific CAR with a single optimized shRNA targeting the TCR CD3ζ subunit. Downregulation of CD3ζ impairs the TCR expression on the surface of the donor T-cells, preventing their reactivity with the normal host tissue cells and potential GvHD induction. Maintaining all the elements required for the therapy within a single vector (all-in-one vector) provides some significant manufacturing advantages, as a solitary selection step will isolate cells expressing all the desired traits. Results CYAD-211 cells produce high amounts of interferon-gamma (IFN-γ) during in vitro co-cultures with various BCMA-expressing MM cell lines (i.e., RPMI-8226, OPM-2, U266, and KMS-11). Cytotoxicity experiments confirmed that CYAD-211 efficiently kills MM cell lines in a BCMA-specific manner. The anti-tumor efficacy of CYAD-211 was further confirmed in vivo, in xenograft MM models using the RPMI-8226 and KMS-11 cell lines. Preclinical data also showed no demonstrable evidence of GvHD when CYAD-211 was infused in NSG mice confirming efficient inhibition of TCR-induced activation. Following FDA acceptance of the IND application, IMMUNICY-1, a first-in-human, open-label dose-escalation phase I clinical study evaluating the safety and clinical activity of CYAD-211 for the treatment of relapsed or refractory MM patients to at least two prior MM treatment regimens, is scheduled to begin recruitment. IMMUNICY-1 will evaluate three dose-levels of CYAD-211 (3x107, 1x108 and 3x108 cells/infusion) administered as a single infusion after a non-myeloablative conditioning (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days) according to a classical Fibonacci 3+3 design. Description of the study design and preliminary safety and clinical data from the first cohort will be presented at ASH 2020. Conclusion CYAD-211 is the first generation of non-gene edited allogeneic CAR T-cell product based on shRNA technology. The IMMUNICY-1 clinical study seeks to provide proof of principle that single shRNA-mediated knockdown can generate fully functional allogeneic CAR T-cells in humans without GvHD-inducing potential. We anticipate that subsequent generations of this technology will incorporate multiple shRNA hairpins within a single vector system. This will enable the production of allogeneic CAR T-cells in which multiple genes of interest are modulated simultaneously thereby providing a platform approach that can underpin the future of this therapeutic modality. Figure 1 Disclosures Al-Homsi: Celyad: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy; Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Sotiropoulou:Celyad Oncology: Current Employment. Twyffels:Celyad Oncology: Current Employment. Bolsee: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.

Chimeric antigen receptor-T cells (CAR-Ts) are an exciting new cancer treatment modality exemplified by the recent regulatory approval of two CD19-targeted CAR-T therapies for certain B cell malignancies. However, this success in the hematological setting has yet to translate to a significant level of objective clinical responses in the solid tumor setting. The reason for this lack of translation undoubtedly lies in the substantial challenges raised by solid tumors to all therapies, including CAR-T, that differ from B cell malignancies. For instance, intravenously infused CAR-Ts are likely to make rapid contact with cancerous B cells since both tend to reside in the same vascular compartments within the body. By contrast, solid cancers tend to form discrete tumor masses with an immune-suppressive tumor microenvironment composed of tumor cells and non-tumor stromal cells served by abnormal vasculature that restricts lymphocyte infiltration and suppresses immune function, expansion, and persistence. Moreover, the paucity of uniquely and homogeneously expressed tumor antigens and inherent plasticity of cancer cells provide major challenges to the specificity, potency, and overall effectiveness of CAR-T therapies. This review focuses on the major preclinical and clinical strategies currently being pursued to tackle these challenges in order to drive the success of CAR-T therapy against solid tumors., SCOPUS: re.j, info:eu-repo/semantics/published

74 Background: CYAD-101 is a first-in-class, non-gene edited allogeneic CAR T-cell product that combines the broad breadth of tumor targeting of the NKG2D-based chimeric antigen receptor (CAR) with a peptide-based approach that controls graft versus host disease (GvHD). NKG2D binds eight ligands commonly over-expressed across many tumors while the co-expressed T-cell receptor (TCR) inhibitory (TIM) peptide interferes with signaling by the endogenous TCR. A bank of CYAD-101 cells was produced from a single donor and evaluated in the AlloSHRINK phase 1 study (NCT03692429) in patients with unresectable metastatic colorectal cancer (mCRC). Methods: Three CYAD-101 infusions, each administered following a FOLFOX standard cycle as preconditioning chemotherapy, were tested in a 3+3 dose-escalation study (dose-levels (DL): 108, 3x108 and 109 T-cells per infusion) in patients with relapsed/refractory mCRC who progressed after previous treatment with oxaliplatin-based chemotherapy, with or without irinotecan-based chemotherapy. Results: Fifteen patients (pts) were enrolled (3 pts at DL-1, 3 pts at DL-2, 9 pts at DL-3). No dose-limiting toxicity (DLT), Grade ≥ 3 related adverse events or GvHD were reported after any of the CYAD-101 infusions, thus confirming the overall good safety profile of CYAD-101 post FOLFOX. Encouraging anti-tumor activity was observed with 2 confirmed partial responses (PR), including one response in a KRAS mutated patient. In addition, 9 pts achieved stable disease (SD), with 7 SD lasting at least 3 months. The median progression-free survival in this heavily pre-treated population was 3.9 months (95% CI). Whilst engraftment of the CYAD-101 cells was observed after each infusion, the relative level of systemic cytokines appeared to be primarily modulated by cell dose with some suggestion that the magnitude of modulation might be associated with clinical response. Interestingly, preliminary analysis of the T-cell repertoire identified some evidence of TCR diversity after therapy in the patient showing the most durable partial response. Conclusions: These clinical results demonstrate the safety and tolerability of a fist-in-human non-gene edited allogeneic CAR T-cell treatment with early promising anti-tumor activity in advanced mCRC pts. Preliminary translational analysis present intriguing observations that the modulation of systemic cytokine levels may be associated with dose which is uncommon in CAR T-cell therapies reported to date while limited T-cell clonal diversification in the best responding patient underscores the likely central role of the adoptively transferred T-cell in driving therapeutic response in this particular patient. Extension cohort evaluating CYAD-101 following other preconditioning chemotherapy is expected to be initiated end 2020. Clinical trial information: NCT03692429.

Introduction Treatment of non-small cell lung cancer (NSCLC) is an important and often unmet medical need regardless of the disease stage at the time of first diagnosis. Antigen-specific immunotherapy may be a feasible therapeutic option if tumor associated antigens (TAAs) that can be targeted by the patient's immune system are identified. The study objective (NCT01837511) was to investigate the expression rates of MAGE-A3 and PRAME in tumors from East Asian NSCLC patients, and the associations between TAA expression and clinico-pathologic patient characteristics. Methods Archived formalin-fixed paraffin-embedded tumor tissue specimens were tested for MAGE-A3 and PRAME expression by quantitative reverse transcription polymerase chain reaction. Exploratory analyses of the impact of patient and tumor characteristics on antigen expression were performed by multivariate logistic regression analyses. Results A total of 377 specimens were tested and a valid expression result was obtained for 86.5% and 92.6% for MAGE-A3 and PRAME , respectively. Of the specimens with valid test results, 26.4% expressed MAGE-A3 , 49.9% PRAME , 20.0% both and 57.5% expressed at least one TAA. The same pattern of associations between antigen expression and patient and tumor characteristics was found for both TAAs: higher rates of antigen-positive tumors were found in squamous cell carcinomas compared to adenocarcinomas, and for smokers compared to non-smokers. Conclusions Expression of MAGE-A3 and PRAME suggests an association with tumor histology and the patient's smoking status. The rates of TAA-positive tumors found in these East and South East Asian NSCLC patients indicate that both antigens may serve as targets for antigen-specific immunotherapies.

International audience; We consider cooperative communications between a source and a destination node with the help of two relays. In order to overcome the half-duplex constraint, the amplify-and-forward two-path relaying protocol is used. We adopt orthogonal frequency-division multiplexing modulation to combat frequency- selective channels and asynchronous reception at the destination node. In this paper, we develop a coherent receiver architecture suitable for unknown block fading channels. A factor graph representing the joint a posteriori probability of the coded symbols and the channels in the frequency domain is introduced. Then, we derive a Bayesian inference algorithm based on message-passing over the factor graph. The resulting iterative receiver maintains low-complexity, based on the interaction between an off-the-shelf soft-input soft-output decoder and a newly introduced per-subcarrier processor for two-path relaying channel estimation and symbol detection. Simulation results show that the proposed solution maintains the full diversity order, even with a limited number of training blocks

In this paper, we develop a reliable bandwidth-efficient solution for coherent reception in networks prone to self-interference. Our primary focus is on orthogonal-frequency-division-multiplexing (OFDM)-based amplify-and-forward (AF) two-way relaying, where each source node suffers from reradiation of its own signal. An important issue is the superposition of the desired and interfering signals, which makes the channel estimation task difficult, particularly for varying channel coefficients. To address this challenging problem, we introduce a factor graph model of the estimation and detection problem at hand. Exploiting the conditional independence between unknown variables in the factor graph, an efficient message-passing algorithm, which performs joint Bayesian channel estimation, self-interference mitigation, and decoding, is derived. Simulation results show that the performance of the proposed method is close to that given by perfect knowledge of the channel for the target and interfering signals, even with limited training overhead.

We consider a transmission system, where the emitted symbols are subject to unknown nonlinear intersymbol interference. Several methods have been proposed in the literature to mitigate the degradation introduced by such channels. However, the problem of nonlinear channel identification in the presence of carrier phase noise has not been addressed previously.In this paper, we derive an iterative receiver structure to detect the transmitted symbols, jointly with phase and channel estimation. At each iteration, the channel parameters are refined based on the expectation-maximization (EM) approach. Also, a pseudo maximum-likelihood (pseudo-ML) carrier recovery, operating in a decision-directed mode, re-estimates the time-varying phase at each iteration. The proposed technique is semi-blind, since a short training sequence is needed to initialize the phase and channel coefficients properly.We show that the proposed scheme allows symbol detection performances close to the genie-aided detector with data-aided channel coefficient estimation. Moreover, a theoretical analysis of the residual phase error confirms that coherent detection in the presence of strong phase noise is achieved. Numerical simulations are presented for systems with severe nonlinear distortions, including satellite communications with nonlinear amplifiers and coherent optical fiber transmissions. HighlightsEM parameter estimation of nonlinear channels with equalization and carrier recovery.Only a small number of known pilot symbols are required.Application to satellite links with HPA and dispersion managed optical fibers.

Background T-cells engineered to express a chimeric antigen receptor (CAR) based on the NKG2D receptor (NKG2D CAR) targeting the 8 NKG2D ligands (MICA/B, ULBP1-6) over-expressed by a large variety of malignancies have been developped to treat patients, including patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Previously, CYAD-01, the first generation of NKG2D CAR T-cell products, was evaluated in several Phase I clinical trials and showed initial signals of objective clinical responses in patients with r/r AML and MDS, albeit with short durability. Preclinical data have shown that NKG2D ligands MICA and MICB are transiently upregulated on activated CAR T-cells, and target-dependent killing of CAR T-cells post-infusion can potentially occur, leading to short in vivo persistence. In an effort to increase the persistence and potency of the NKG2D CAR T-cells, CYAD-02 was developed as a next-generation product using a non-gene editing approach to silence the expression of MICA and MICB. Aim MICA and MICB were down-regulated by inserting a single optimized short hairpin RNA (shRNA) targeting both MICA and MICB within the NKG2D CAR construct. This next-generation NKG2D CAR T-cell product is manufactured with the OptimAb process, resulting in CAR T-cells with a higher frequency of early memory T-cells secreting high levels of cytokines upon activation, and is referred to as CYAD-02. Results As compared to CYAD-01, CYAD-02 cell expansion in vitro was 3-fold increased. In an in vivo AML model, CYAD-02 showed 10-fold higher engraftment 1 week after injection and improved anti-tumor activity as compared to CYAD-01 manufactured with the initial mAb process. This led to a 2.6-fold increase of mouse survival as compared to CYAD-01 in a stress-test aggressive AML model where the dose of CYAD-01 was titrated down for minimal activity (figure). The first-in-human study evaluating CYAD-02, the CYCLE-1 study (NCT04167696), has been initiated in early 2020 in patients with r/r AML/MDS. The study evaluates three dose-levels of CYAD-02 (1x108, 3x108 and 1x109 cells/infusion), administered as a single infusion after non-myeloablative preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days, CyFlu) according to a classical Fibonacci 3+3 design. As of August 2020, 6 patients have been treated with CYAD-02 at the dose of 1x108 or 3x108 cells/infusion. To date, the results demonstrate the safety and tolerability for CYAD-02 in patients with r/r AML and MDS with no dose-limiting toxicity observed. The study is currently enrolling at 1x109 cells/infusion. The CYAD-02 safety profile and preliminary clinical activity data together with the pharmacokinetics evaluation from the complete dose escalation segment will be provided at the time of presentation. Conclusion/summary The CYAD-02 is the first autologous CAR T-cell product based on the non-gene edited shRNA technology used to treat patients. This next generation NKG2D CAR T-cell product is currently investigated in the CYCLE-1 Phase I study in r/r AML/MDS patient population, 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. Both the anti-MICA and MICB shRNA hairpin and the OptimAb manufacturing process for CYAD-02 aim to improve CAR T-cell persistence and clinical responses. Figure Disclosures Lin: Mateon Therapeutics: Research Funding; Aptevo: Research Funding; Abbvie: Research Funding; Ono Pharmaceutical: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Jazz: Research Funding; Astellas Pharma: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Celyad: Research Funding; Genetech-Roche: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Prescient Therapeutics: Research Funding; Pfizer: Research Funding. Demoulin:Celyad Oncology: Current Employment. Fontaine: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.

3032 Background: In contrast to autologous CAR-T cell therapies, allogeneic donor-derived CAR-T cells can be banked and used in a timely fashion overcoming the critical time delay of just in time autologous cell manufacture. CYAD-101 is an allogeneic CAR-T that uses a non-gene edited peptide-based technology (TIM) to control graft versus host disease (GvHD) combined with a NKG2D-based CAR. Pre-clinical studies confirmed that CYAD-101 maintained CAR-directed anti-tumor activity in the absence of the induction of GvHD. Clinical grade CYAD-101 cells were produced for the phase 1 alloSHRINK trial (NCT03692429). Methods: A bank of clinical grade CYAD-101 cells was generated through two production runs using a single donor apheresis. Together, the bank generated > 53 billion CYAD-101 cells suitable for the entire dose escalation segment and short expansion phase of the trial (15 patients in total). Both runs showed high consistency with the CYAD-101 product generated composed mainly of CD4+ T cells (>85%) with a transduction level of > 92%, low relative expression of CD69/CD25 and largely absent expression levels of PD-1/LAG-3. The CYAD-101 cells were predominantly (>80%) CD45RA−/ CD62L−/ CD27− suggestive of an effector memory T cell population. Results: Upon co-culture with target K562 cells, CYAD-101 readily produced IFN-γ that was blocked by a NKG2D blocking antibody confirming specificity of the CAR. CYAD-101 cells showed in vitro cytotoxicity against tumor cells and produced an array of Th1 (IFN-γ, IL-2 and TGF-β) and Th2 (IL-4, IL-5) cytokines. Importantly, minimal IFN-γ was produced upon TCR stimulation while stimulation with a non-TCR mitogen (PMA + ionomycin) lead to high levels of IFN-γ. Together, these data show that clinical grade CYAD-101 cells were able to functionally respond through the CAR but showed minimal TCR-driven activation. Fifteen refractory metastatic CRC patients who had previously failed at least one line of oxaliplatin—containing therapy were treated with three doses of CYAD-101 cells given on Day 3 of three successive FOLFOX chemotherapy cycles. Updated clinical results continue to demonstrate an encouraging clinical activity (2 patients with partial response and 9 with stable disease) and the absence of GvHD in the context of CYAD-101 cell engraftment. Conclusions: These early clinical results demonstrate the safety and tolerability of a non-gene edited predominantly CD4+ CAR-T therapeutic approach. The initial observations of clinical activity in metastatic CRC patients warrants the continued development of this therapy. Clinical trial information: NCT03692429 .

International audience; We propose a Bayesian framework for the problem of multi-user dectection in the context of an unknown and time-varying number of active users. In this paper, we combine orthogonal frequency-division multiplexing modulation with multi-antenna reception to mitigate both the asynchronism and frequency-selectivity of the wireless medium. We develop a method for user identity and data detection with joint channel parameter estimation, performed on a per-OFDM block basis to account for a highly dynamic random-access channel. Based on a factor graph approach, we derive an inference algorithm based on message-passing resulting in an iterative code-aided receiver. We show that a suitable Gaussian approximation leads to a complexity that increases only linearly with the maximum number of users. Computer simulations show that the proposed iterative receiver has a low probability of erroneous activity detection, while maintaining a high antenna diversity order for active users

Purpose This study assessed clinical activity, safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with MAGE-A3-positive metastatic melanoma. Patients and methods In this open-label, multicentre, uncontrolled, Phase II study (ClinicalTrials.gov NCT00896480),patients received ≤24 doses of MAGE-A3 immunotherapeutic (4-cycle schedule). At screening, two skin lesions were biopsied for MAGE-A3 expression analysis and presence/absence of a previously identified gene signature (GS) associated with favourable clinical outcome. Clinical activity was assessed in terms of clinical response, time-to-treatment failure (TTF) and progression-free survival (PFS). Adverse events (AEs) and serious AEs (SAEs) were recorded. MAGE-A3-specific immune responses were assessed. Clinical activity and immunogenicity were analysed overall and separately in patients with 2/2 (GS+/+), 1/2 (GS+/-) or 0/2 (GS-/-) biopsies presenting GS. Results Of 49 screened patients, 32 had MAGE-A3-positive tumours; 24 (8 GS+/+, 8 GS+/-, 8 GS-/-) were treated. Two complete (GS+/+ patients) and two partial responses (one GS+/+, one GS+/-) were reported; of note, one of the two complete responses was unlikely to be related to the study treatment. Median TTF and PFS were 14.8 and 7.2 months for GS+/+, 2.3 and 2.8 months for GS+/- and 2.4 and 2.9 months for GS-/- patients. Three grade 3 AEs and two SAEs unrelated to treatment were reported. All patients were seropositive for MAGE-A3 antibodies on vaccination with no differences between the different GS profiles. MAGE-A3-specific CD4+ and CD8+ T cell immunogenicity was detected; 12/16 (75.0%) of patients presented CD4+ T cell responses. Conclusion Treatment with MAGE-A3 immunotherapeutic showed signs of clinical activity in GS+/+ patients. Treatment was well tolerated and immunogenic. No differences in immune responses according to GS status were observed. Trial registration number NCT00896480 (Results).

Background aims Adoptive cell therapy employing natural killer group 2D (NKG2D) chimeric antigen receptor (CAR)-modified T cells has demonstrated preclinical efficacy in several model systems, including hematological and solid tumors. We present comprehensive data on manufacturing development and clinical production of autologous NKG2D CAR T cells for treatment of acute myeloid leukemia and multiple myeloma ( ClinicalTrials.gov Identifier: NCT02203825). An NKG2D CAR was generated by fusing native full-length human NKG2D to the human CD3ζ cytoplasmic signaling domain. NKG2D naturally associates with native costimulatory molecule DAP10, effectively generating a second-generation CAR against multiple ligands upregulated during malignant transformation including MIC-A, MIC-B and the UL-16 binding proteins. Methods CAR T cells were infused fresh after a 9-day process wherein OKT3-activated T cells were genetically modified with replication-defective gamma-retroviral vector and expanded ex vivo for 5 days with recombinant human interleukin-2. Results Despite sizable interpatient variation in originally collected cells, release criteria, including T-cell expansion and purity (median 98%), T-cell transduction (median 66% CD8+ T cells), and functional activity against NKG2D ligand-positive cells, were met for 100% of healthy donors and patients enrolled and collected. There was minimal carryover of non–T cells, particularly malignant cells; both effector memory and central memory cells were generated, and inflammatory cytokines such as granulocyte colony-stimulating factor, RANTES, interferon-γ and tumor necrosis factor-α were selectively up-regulated. Conclusions The process resulted in production of required cell doses for the first-in-human phase I NKG2D CAR T clinical trial and provides a robust, flexible base for further optimization of NKG2D CAR T-cell manufacturing.

International audience; Digital signal processing for fiber nonlinearity com- pensation is a key enabler for the ever-increasing demand for higher data rates in coherent optical transmissions. A major challenge of existing techniques is that the fiber nonlinear coefficient needs to be scaled properly during compensation in order to reach the achievable signal quality increase. We solve this problem using a low-complexity algorithm adaptively optimizing a metric based on the soft-decision bitwise demodulator used for modern FEC decoders. An analytical model shows that the proposed scheme converges to the optimal scaling factor with a predictable precision, that is validated by numerical results

NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain. Four dose levels (1 × 106–3 × 107 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3+ T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell–related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the ≥ grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell–expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro, but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity.

Celyad recently initiated several clinical trials with the CYAD-01 product, a natural killer group 2D (NKG2D)-based chimeric antigen receptor (CAR), in both solid and hematologic tumor types. This review discusses the unique properties of CYAD-01, expecting to provide a new paradigm to fight against solid tumors.

Background We assessed safety, immunogenicity and clinical activity of recombinant MAGE-A3 antigen combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) in association with dacarbazine in patients with metastatic melanoma. Methods In this open-label, phase I/II, uncontrolled multicentre trial conducted in Belgium and France, patients with MAGE-A3-positive melanoma received up to 24 doses of MAGE-A3 immunotherapeutic (four cycles) coadministered with eight doses of dacarbazine. Adverse events (AE) were recorded until 31 days postvaccination, and serious AEs (SAE), until 30 days following the last dose. MAGE-A3-specific antibodies were measured by ELISA. Clinical activity of MAGE-A3 immunotherapeutic was assessed in patients positive/negative for previously identified gene signature (GS) associated with clinical outcome. Results Forty-eight patients were enrolled and treated (32 GS+, 15 GS−, 1 unknown GS status); two patients completed the study. All patients reported AEs, the most common were ‘general disorders and administration site conditions’ (94%). Treatment-related AEs were reported by 85% of patients; the most common was pain at injection site (38%). Sixteen SAEs were reported by 21% of patients; two were considered as treatment related (neutropenia and thrombocytopenia; grade 4). Postdose 4, all patients were seropositive for MAGE-A3-specific antibodies, with a geometric mean titre of 2778.7 ELISA units (EU)/mL (95% CI 1638.3 to 4712.8). One complete and three partial responses were reported (only in GS+ patients). Median overall survival was 11.4 months for GS+ and 5.3 months for GS− patients. Conclusion Although this trial shows poor results compared with the new results with checkpoint inhibitors, it gives an interesting insight in rapidly developing fields like combinations of immunotherapy and chemotherapy, new generation vaccines and the use of gene profile as a predictive marker. Trial registration number NCT00849875.

Digital self-interference cancellation is a major challenge for orthogonal frequency division multiplexing full-duplex transmissions. Therefore, reliable estimation of both the signal-of-interest and the self-interference channel, becomes the limiting factor in a mobile radio context. In this letter, improved estimation of the time-varying channels is obtained by solving the problem jointly with self-interference cancellation and decoding using a factor graph approach. Taking advantage of the per-subcarrier structure of message-passing, a low-complexity receiver is obtained. Our semianalytical and numerical results show the superiority of the proposed scheme over state-of-the art self-interference cancellation methods under limited pilot overhead.

Introduction NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3 signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. Methods and analysis This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3×10 8, 1×10 9 and 3×10 9 NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. Ethics approval and dissemination Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals. Trial registration number NCT03018405, EudraCT 2016-003312-12; Pre-result., SCOPUS: ar.j, info:eu-repo/semantics/published

This paper outlines a proposition of a framework optimizing the communication scheme from the physical part of the transmitters to the data gathered at the receiver in a wireless sensor network. We propose a coding scheme able to take into account the correlation between measurements obtained by the sensors. This scheme consists of joint distributed source encoding and linear network coding. Several coding strategies are compared. (1) linear source coding, based on the low density generator matrix (LDGM) codes, where the compression process is performed by every sensor independently (2) distributed source coding, where the correlation between sources is taken into account, without cooperation between sensors. The compression ratios costs are evaluated analytically for each strategy, with respect to the communication costs between the nodes of the network. The results show a significant improvement in terms of compression rate and distortion compared to linear source encoding.

International audience; We present a method for joint decode-and-forward physical layer network coding in two-way relay networks. The two source nodes send their packets simultaneously over time-varying channels to a relay node, then the relay broadcasts the received superimposed packets to the source nodes using network coding. The nodes use trellis coding for the sake of error correction and multi-antenna equipments to combat multipath fading. A challenging multiple access problem occurs at the relay node, which performs joint channel estimation and decoding for the individual source packets. We design message passing algorithms based on factor-graphs to solve this problem. The relay has two separate modules that perform channel estimation and decoding for the packets received from each source node. The interference generated by the other source node is taken into account by exchanging messages between the two modules.

Purpose Active immunization against the tumor-specific MAGE-A3 antigen is followed by a few but impressive and durable clinical responses. This randomized phase II trial evaluated two different immunostimulants combined with the MAGE-A3 protein to investigate whether a more robust and persistent immune response could be associated with increased clinical benefit. Patients and Methods Patients with MAGE-A3–positive stage III or IV M1a melanoma were randomly assigned to receive the MAGE-A3 protein combined either with AS02B or with AS15 immunostimulant. Clinical end points were toxicity and rates of objective clinical responses, progression-free survival (PFS), and overall survival (OS). Results Seventy-five patients were treated, with 36 eligible patients per arm. Both treatments were well tolerated. In the AS15 arm, four objective responses were observed (three complete responses and one partial response) versus one partial response in the AS02B arm. In the AS15 and AS02B arms, the PFS rates after 6 months were 25% and 14%, respectively; and the median OS times were 33 months and 19.9 months, respectively, with a median observation period of 48 months. Antibodies against MAGE-A3, found in all patients, showed three-fold higher titers in the AS15 arm. The anti–MAGE-A3 cellular response was also more pronounced in the AS15 arm. Conclusion In the MAGE-A3+AS15 arm, clinical activity was higher and the immune response more robust. Therefore, the AS15 immunostimulant was selected for combination with the MAGE-A3 protein in phase III trials.

Purpose The MAGE-A3 protein is expressed in approximately 35% of patients with resectable non–small-cell lung cancer (NSCLC). Several immunization approaches against the MAGE-A3 antigen have shown few, but often long-lasting, clinical responses in patients with metastatic melanoma. Patients and Methods A double-blind, randomized, placebo-controlled phase II study was performed assessing clinical activity, immunologic response, and safety following immunization with recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) in completely resected MAGE-A3–positive stage IB to II NSCLC. The primary end point was disease-free interval (DFI). Results Patients were randomly assigned to either MAGE-A3 immunotherapeutic (n = 122) or placebo (n = 60). After a median postresection period of 44 months, recurrence was observed in 35% of patients in the MAGE-A3 arm and 43% in the placebo arm. No statistically significant improvement in DFI (hazard ratio [HR], 0.75, 95% CI, 0.46 to 1.23; two-sided P = .254), disease-free survival (DFS; HR, 0.76; 95% CI, 0.48 to 1.21; P = .248), or overall survival (HR, 0.81; 95% CI, 0.47 to 1.40; P = .454) was observed. Corresponding analysis after a median of 70 months of follow-up revealed a similar trend for DFI and DFS. All patients receiving the active treatment showed a humoral immune response to the MAGE-A3 antigen, although no correlation was observed with outcome. No significant toxicity was observed. Conclusion In this early development study with a limited number of patients, postoperative MAGE-A3 immunization proved to be feasible with minimal toxicity. These results are being investigated further in a large phase III study.

International audience; This paper deals with the local optimization of the periodic or aperiodic ambiguity functions of a set of complex sequences by using a gradient method. This optimization aims to locally minimize the cross-ambiguity and the auto-ambiguity functions of a family of sequences for Multi-Static Primary Surveillance Radar (MSPSR) systems. The optimization of the ambiguity functions is done by an optimized gradient. An extension is also presented for controlling both the spectrum and the ambiguity functions.

International audience; This paper deals with the local optimization of the periodic or aperiodic ambiguity function of a complex sequence by using a gradient method on the phases. It is shown that efficient equations are obtained for those gradient calculations.

This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 A mu g) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations

Purpose The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. Results 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. Conclusions The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. Trial registration number NCT01149343, Results.

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.

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.

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.

International audience; In GPS navigation, distortion of the delay and phase of the received signal due to multipath propagation can degrade seriously the position estimation. In some applications such as aircraft landing, detecting the occurrence of multipath can be as important as mitigating its effect on the pseudodistance. This paper proposes deterministic particle filtering for joint multipath detection and navigation parameter estimation. The efficiency of the proposed method is illustrated by numerical simulations

International audience; Wireless sensor networks (WSN) are specially distributed sensors deployed for the purpose of sensing and monitoring physical or environmental conditions. Sensor measurements in WSN usually suffer from both random errors (noise) and systematic errors (bias). This poses a major problem in the end application, as the data from the network become progressively uninformative

International audience; This paper deals with the selection of some waveforms family sets for use in Active Multi-Static Primary Surveillance Radar (MSPSR). The selection takes into account the correlation properties, the ambiguity function properties, the Peak to Average Power Ratio (PAPR) reduction, the cardinality and the diversity of each set. According to these criteria, the application of spreading codes in the MSPSR context is investigated.