Press Release

Kiadis announces new data related to its K-NK cell therapy platform presented today at the ASCO 2020 Virtual Annual Meeting

May 29, 2020 at 8:05 AM EDT
  • A poster presentation (abstract 3025) demonstrates results of multiple FC21-NK infusions in R/R AML patients with CNS disease, treated in an investigator-initiated Phase I/II study
  • An abstract accepted for publication (abstract e15018) presents pre-clinical data demonstrating how a CD38 knock-out of off-the-shelf FC21-NK cells limits NK cell fratricide and enhances the overall activity against multiple myeloma cells in presence of an anti-CD38 antibody
  • An additional poster presentation (abstract TPS7562) describes the clinical trial for the first-in-man assessment of off-the-shelf FC21-NK cells derived from universal allogeneic donors in R/R AML and MDS

Amsterdam, The Netherlands, May 29, 2020 – Kiadis Pharma N.V. (“Kiadis” or the “Company”) (Euronext Amsterdam and Brussels: KDS), a clinical stage biopharmaceutical company, announces that new data supporting the Company’s K-NK cell therapy program will be presented today at the American Society of Clinical Oncology (ASCO) Virtual Annual Meeting. The poster for abstract 3025 presents clinical data of a subset of AML patients with concurrent central nervous system (CNS) disease treated with FC21-NK cells in a Phase I/II study. Abstract e15018 was accepted for publication and presents pre-clinical data that demonstrates how a CD38 knock-out of FC21-NK cells limits NK cell fratricide and enhances the overall activity against multiple myeloma cells in presence of an anti-CD38 antibody. Finally, a poster (abstract TPS7562) summarizes how safety and efficacy for off-the-shelf FC21-NK cells will be investigated in R/R AML and MDS patients in a Phase I clinical trial.

Abstract #3025: CD56bright/CD16bright NK-cell adoptive immunotherapy in patients with concurrent CNS disease and relapsed or refractory (R/R) AML

Patients with R/R AML and concurrent CNS disease rarely respond to chemotherapy and have a dismal prognosis. Adoptive immunotherapy with haploidentical ex vivo-activated/expanded NK cells shows promise in R/R AML, but it was previously unknown whether the blood–brain barrier would represent an obstacle to this approach.

Lucia Silla, MD, PhD, at Hospital de Clínicas de Porto Alegre (HCPA) in Brazil, investigated multiple doses of ex vivo mbIL-21 expanded NK cells (FC21-NK) in patients with R/R AML in combination with FLAG in a Phase I/II study (NCT02809092). In this trial, thirteen AML R/R patients were treated and a subgroup of four of those patients had concurrent CNS disease (from 1.6 to 48 years of age,), including nerve and root disease, chloroma, fungal infection and SNC parenchymal leukemic infiltration. All four patients were heavily pretreated including a prior stem cell transplant. These four patients completed ≥6 FC21-NK infusions (dose per infusion ranged from1 x 106 to 6.6 x 106 cells/kg). All patients showed a response that lasted up to 5.5 months.

Strikingly, CNS responses as indicated by resolution or cellular infiltration of CNS lesions was observed in all four patients. Two patients experienced complete resolution of CNS lesions, one patient had a near complete response and the fourth achieved a 50% reduction of CNS chloromas. Gene expression profiles for FC21-NK cells were examined and showed that key NK cell receptors were all significantly upregulated compared with freshly isolated peripheral blood NK cells. Adverse events considered related to the FC21-NK infusions occurred in three patients, all were manageable. In summary, multiple IV infusions of ex vivo-expanded FC21-NK cells were well tolerated and demonstrated unprecedented CNS responses in patients with R/R AML, demonstrating the potential of FC21-NK cells to traverse the blood brain barrier to mediate a therapeutic anti-leukemic effect in the CNS.

Dr. Silla commented, “These data are very encouraging as it shows the ability of NK cells to cross the blood-brain barrier and deliver unprecedented responses in this very difficult-to-treat patient population. The role of ex vivo-expanded FC21-NK cells for use in therapeutic applications for CNS malignancies warrants further investigation.”  

Abstract #e15018: Impact of CD38 Knockout in NK Cells on Daratumumab-mediated Cytotoxicity and Cellular Metabolism.

This abstract describes the results from pre-clinical work performed at Johns Hopkins and Nationwide Children’s Hospital, investigating how the antibody dependent cell cytotoxicity (ADCC) effect of Daratumumab in multiple myeloma (MM) cells could be enhanced by infusing expanded NK cells. Daratumumab is a monoclonal antibody targeted towards CD38 and its efficacy may wane as depletion by Daratumumab of CD38high NK cells during therapy limits overall ADCC, in a process called ‘fratricide’. The current research investigated whether CD38 knockout (CD38KO) NK cells from healthy donors, generated via Cas9 RNPs and expanded ex vivo with mbIL-21 Feeder Cell (FC21), increased the overall ADCC anti-tumor effect upon combination with Daratumumab.

Knockout efficiency was 81.9 ± 6.9% (mean ± SD, N = 5). Very low off-target gene modification effects were seen by whole genome sequencing. When compared to paired CD38 wild type (CD38WT) NK cells, CD38KO NK cells showed lower co-NK cell conjugation (2.57% vs. 11.85%, N = 3, p = 0.04), less fratricide (97.3% vs. 54.2%, mean viability, N = 3, p = 0.01), and superior persistence in mice (18.16% vs. 0.42%, mean frequency in blood, N = 5, p < 0.01) in the presence of  Daratumumab. Additionally, CD38KO NK cells exhibited enhanced ADCC against all tested MM cell lines and primary samples including CD38 cell lines and primary MM cells from a patient with disease relapse on Daratumumab.

In summary, proof of concept is presented that adoptive CD38KO NK cell therapy has the potential to maximize the efficacy of Daratumumab against multiple myeloma. Further investigation into the role of metabolic reprogramming of CD38KO NK cells is warranted.

Abstract #TPS7562: A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Off-the-Shelf, Natural Killer Cells for Relapse/Refractory Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS)

A major requirement for adoptive NK cell immunotherapy is obtaining sufficient cell numbers, having them readily available for patients, and ensuring alloreactivity for anti-leukemic effect. This Phase I trial (NCT04220684), sponsored by Ohio State University and supported by Kiadis, will address these obstacles investigating the safety of FC21 expanded off-the-shelf (OTS), universal donor-derived NK cells for relapsed/refractory AML and MDS patients.

The primary objective of the study is to establish the safety of OTS FC21-NK cells for the induction of remission in patients with R/R AML and MDS. After FLAG chemotherapy, patients with primary refractory AML, relapsed AML or MDS, aged ≥18 to ≤80 years with a Karnofsky or Lansky Performance Scale ≥70, will receive six doses of OTS FC21-NK cells (thrice weekly for two weeks). The recommended Phase II dose will be determined in a 3+3 design (dose levels: 1 x 107 cells/kg; 3 x 107 cells/kg; 1 x 108 cells/kg). Additional endpoints include clinical responses, tolerability and translational research. Enrolment of this study has started, and the aim is to include up to 56 patients in the dose determination and expansion phase.

Andrew Sandler, Chief Medical Officer of Kiadis, commented, “This investigator-initiated Phase I trial is aimed to provide further confirmation that cell therapies with expanded off-the-shelf NK cells from universal donors have the potential to safely treat R/R AML and MDS. We look forward to Dr. Vasu and the OSU team enrolling their first patients.”                  

Kiadis contacts

Kiadis:
Maryann Cimino, Sr. Manager, Corporate Affairs
Tel: +1 (617) 710-7305
m.cimino@kiadis.com

 
Optimum Strategic Communications:
Mary Clark, Supriya Mathur, Hollie Vile
Tel: +44 203 950 9144
David Brilleslijper (Amsterdam)
Tel: +31 610 942 514
kiadis@optimumcomms.com

Dutch Translation/Nederlandse vertaling

Kiadis nv ('Kiadis'), een biofarmaceutisch bedrijf dat zich toelegt op klinisch onderzoek, kondigt aan dat vandaag, op de virtuele jaarlijkse bijeenkomst van de American Society of Clinical Oncology (ASCO), nieuwe gegevens zullen worden bekendgemaakt ter ondersteuning van het K-NK-celtherapieprogramma van de onderneming. De poster voor abstract 3025 presenteert klinische gegevens van een subgroep van AML-patiënten met gelijktijdige ziekte van het centrale zenuwstelsel (CZS), behandeld met FC21-NK-cellen in een fase I/II studie. Abstract e15018 werd voor publicatie goedgekeurd. Het document presenteert preklinische gegevens die aantonen hoe een CD38-knock-out van FC21-NK-cellen de NK-cel fratricide beperkt en de algemene activiteit tegen myeloomcellen in aanwezigheid van een anti-CD38-antilichaam verbetert. Tot slot vat een poster (abstract TPS7562) samen hoe de veiligheid en werkzaamheid voor direct beschikbare FC21-NK-cellen bij patiënten met R/R AML en MDS zullen worden onderzocht in een klinische fase 1-studie.

Abstract #3025: CD56bright/CD16bright NK-cell adoptive immunotherapy in patients with concurrent CNS disease and relapsed or refractory (R/R) AML

Patiënten met R/R AML en gelijktijdige CZS-ziekte reageren zelden op chemotherapie en hebben een sombere prognose. Adoptieve immuuntherapie met haplo-identieke ex vivo geactiveerde/geëxpandeerde NK-cellen is veelbelovend bij R/R-AML, maar het was voordien niet bekend of de bloed-hersenbarrière een obstakel zou vormen voor deze aanpak.

Lucia Silla, MD, PhD, van het Hospital de Clínicas de Porto Alegre (HCPA) in Brazilië, onderzocht meerdere doses ex vivo mbIL-21 geëxpandeerde NK-cellen (FC21-NK) bij patiënten met R/R AML in combinatie met FLAG in een fase I/II-studie (NCT02809092). In dit onderzoek werden dertien R/R AML-patiënten behandeld en een subgroep van vier van deze patiënten had gelijktijdig een CZS-ziekte (van 1,6 tot 48 jaar oud), zoals zenuw- en wortelziekte, chloroom, schimmelinfectie en parenchymale leukemische infiltratie van het CZS. Elk van de vier patiënten was vooraf al zwaar behandeld, onder meer met een eerdere stamceltransplantatie. Deze vier patiënten kregen de volledige ≥6 FC21-NK-infusies (de dosis per infusie varieerde van 1 x 106 tot 6,6 x 106 cellen/kg). Alle patiënten vertoonden een respons die tot 5,5 maanden duurde.

Opvallend is dat reacties van het CZS zoals aangegeven door resolutie of cellulaire infiltratie van CZS-letsels werden waargenomen bij alle vier de patiënten. Bij twee patiënten werd een volledige resolutie van de CZS-letsels vastgesteld, één patiënt had een nagenoeg volledige respons en de vierde bereikte een 50% reductie van chloromen in het CZS. De genexpressieprofielen voor FC21-NK-cellen werden onderzocht en hieruit bleek dat alle belangrijke NK-celreceptoren significant werden gestimuleerd in vergelijking met pas geïsoleerde perifere NK-cellen uit bloed. Bij drie patiënten waren er bijwerkingen waarvan werd aangenomen dat ze verband hielden met de FC21-NK-infusies. Al deze bijwerkingen waren beheersbaar. Samengevat werden meerdere IV-infusies van ex vivo geëxpandeerde FC21-NK-cellen goed verdragen en resulteerden ze in een nooit geziene respons van het CZS bij patiënten met R/R-AML. Dit toont aan dat FC21-NK-cellen het potentieel bieden om de bloed-hersenbarrière te passeren en een therapeutisch antileukemisch effect te mediëren in het CZS.

Dr. Silla merkte op: “Deze gegevens zijn zeer bemoedigend omdat ze aantonen dat NK-cellen in staat zijn om de bloed-hersenbarrière te passeren en een nooit geziene respons te veroorzaken in deze zeer moeilijk te behandelen patiëntenpopulatie. De rol van ex vivo geëxpandeerde FC21-NK-cellen voor gebruik in therapeutische toepassingen voor maligniteiten in het CZS verdient nader onderzoek.”

Abstract #e15018: Impact of CD38 Knockout in NK Cells on daratumumab-mediated Cytotoxicity and Cellular Metabolism.

Deze samenvatting beschrijft de resultaten van preklinisch onderzoek uitgevoerd in het Johns Hopkins and Nationwide Children’s Hospital, waarbij werd nagegaan hoe het ADCC-effect (antibody dependent cell cytotoxicity) van daratumumab in myeloomcellen (multipel myeloom, MM) kan worden versterkt door infusie van geëxpandeerde NK-cellen. Daratumumab is een monoklonaal antilichaam gericht op CD38 en de werkzaamheid ervan kan afnemen naarmate de depletie van CD38hoge NK-cellen door daratumumab tijdens de behandeling de totale ADCC beperkt in een proces dat 'fratricide' wordt genoemd. In de huidige studie wordt onderzocht of de CD38 knock-out (CD38KO) van NK-cellen van gezonde donoren, gegenereerd via Cas9 RNP’s en ex vivo geëxpandeerd met mbIL-21 feeder cel (FC21), het totale antitumorale effect van ADCC na combinatie met daratumumab verhoogde.

De effectiviteit van de knock-out bedroeg 81,9 ± 6,9% (gemiddelde ± SD, N = 5). 'Whole genome sequencing' bracht zeer geringe off-targeteffecten in de vorm van genmodificatie aan het licht. In vergelijking met gepaarde CD38 wild type (CD38WT) NK-cellen vertoonden CD38KO NK-cellen een lagere co-NK-celconjugatie (2,57% vs. 11,85%, N = 3, p = 0,04), minder fratricide (97,3% vs. 54,2%, een gemiddelde levensvatbaarheid, N = 3, p = 0,01) en superieure persistentie bij muizen (18,16% vs. 0,42%, gemiddelde frequentie in bloed, N = 5, p < 0,01) in aanwezigheid van daratumumab. Bovendien vertoonden CD38KO NK-cellen een verhoogde ADCC tegen alle geteste MM-cellijnen en primaire monsters, waaronder CD38-cellijnen en primaire MM-cellen van een patiënt met een ziekterelaps onder daratumumab.

Samengevat wordt een proof-of-concept geleverd dat adoptieve CD38KO NK-celtherapie het potentieel heeft om de werkzaamheid van daratumumab tegen multipel myeloom te maximaliseren. Verder onderzoek naar de rol van metabole herprogrammering van CD38KO NK-cellen is gewettigd.

Abstract #TPS7562: A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Off-the-Shelf, Natural Killer Cells for Relapse/Refractory Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS)
Belangrijke vereisten voor adoptieve immuuntherapie met NK-cellen is het verkrijgen van voldoende celaantallen die direct beschikbaar zijn voor patiënten en het bekomen van alloreactiviteit voor een antileukemisch effect. Deze fase I-studie (NCT04220684), gesponsord door Ohio State University en ondersteund door Kiadis, zal deze obstakels aanpakken door de veiligheid van geëxpandeerde direct beschikbare (off-the-shelf of OTS) FC21 NK-cellen van universele donoren te onderzoeken voor patiënten met recidiverende/refractaire AML en MDS.

De belangrijkste doelstelling van de studie is het aantonen van de veiligheid van OTS FC21-NK-cellen voor het induceren van remissie bij patiënten met R/R AML en MDS. Na FLAG-chemotherapie zullen patiënten met primaire refractaire AML, recidiverende AML of MDS in de leeftijd van ≥18 tot ≤80 jaar met een Karnofsky of Lansky Performance Scale ≥ 70 zes doses OTS FC21-NK-cellen (drie keer per week gedurende twee weken) krijgen. De aanbevolen fase II-dosis wordt bepaald in een 3+3-opzet (dosisniveaus: 1 x 107 cellen/kg; 3 x 107 cellen/kg; 1 x 108 cellen/kg). Bijkomende onderzoeksdoelen zijn klinische respons, verdraagbaarheid en translationeel onderzoek. De inschrijvingen voor deze studie zijn gestart en het doel is tot 56 patiënten op te nemen in de dosisbepalings- en uitbreidingsfase.

Andrew Sandler, Chief Medical Officer van Kiadis, licht toe: “Deze door onderzoekers gestarte fase I-studie heeft als doel opnieuw te bevestigen dat celtherapieën met geëxpandeerde direct beschikbare NK-cellen van universele donoren het potentieel bieden om R/R AML en MDS veilig te behandelen. We kijken uit naar het moment waarop dr. Vasu en het OSU-team hun eerste patiënten inschrijven.”      

Dit persbericht vormt een vertaling van het gepubliceerde Engelstalige persbericht. Bij eventuele verschillen is de tekst van het Engelstalige persbericht altijd bepalend.

About Kiadis’ K-NK-Cell Therapies
Kiadis’ NK-cell programs consist of off-the-shelf and haplo donor cell therapy products for the treatment of liquid and solid tumors as adjunctive and stand-alone therapies. 

The Company’s NK-cell PM21 particle technology enables improved ex vivo expansion and activation of anti-cancer cytotoxic NK-cells supporting multiple high-dose infusions. Kiadis’ proprietary off-the-shelf NK-cell platform is based on NK-cells from unique universal donors. The Kiadis off-the-shelf K-NK platform can make NK-cell therapy product rapidly and economically available for a broad patient population across a potentially wide range of indications.

Kiadis is clinically developing K-NK003 for the treatment of relapse/refractory acute myeloid leukemia. The Company is also developing K-NK002, which is administered as an adjunctive immunotherapeutic on top of HSCT and provides functional, mature and potent NK-cells from a haploidentical family member. In addition, the Company has pre-clinical programs evaluating NK-cell therapy for the treatment of solid tumors. 

About Kiadis
Founded in 1997, Kiadis is building a fully integrated biopharmaceutical company committed to developing innovative therapies for patients with life-threatening diseases. With headquarters in Amsterdam, the Netherlands, and offices and activities across the United States, Kiadis is reimagining medicine by leveraging the natural strengths of humanity and our collective immune system to source the best cells for life.

Kiadis is listed on the regulated market of Euronext Amsterdam and Euronext Brussels since July 2, 2015, under the symbol KDS. Learn more at www.kiadis.com.

Forward Looking Statements
Certain statements, beliefs and opinions in this press release are forward-looking, which reflect Kiadis’ or, as appropriate, Kiadis’ officers’ current expectations and projections about future events. By their nature, forward-looking statements involve a number of known and unknown risks, uncertainties and assumptions that could cause actual results, performance, achievements or events to differ materially from those expressed, anticipated or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, regulation, competition and technology, can cause actual events, performance, achievements or results to differ significantly from any anticipated or implied development. Forward-looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, Kiadis expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or projections, or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither Kiadis nor its advisers or representatives nor any of its subsidiary undertakings or any such person’s officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the anticipated or implied developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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