Cellterapier har botat vissa blodcancerformer, men mot solida tumörer, som står för ungefär 90 procent av den globala cancerbördan, har de kommit till korta. Två problem står i vägen. Nyttan har varit svår att överföra från blodcancer, och varje dos tillverkas fortfarande på beställning för en enskild patient, en batch i taget. Zellunas svar är en allogen off-the-shelf-plattform inom TCR-NK: naturliga mördarceller från friska donatorer som försetts med en tumörspecifik T-cellsreceptor, förtillverkade i hundratals doser från en och samma batch och frysta tills de behövs.
Efter övergången till klinisk utveckling har Zelluna nu behandlat sina två första patienter i ZIMA-101. Rekryteringen löper enligt plan och de inledande säkerhetsobservationerna har varit uppmuntrande. I juni i år tilldelades bolaget ett anslag på 16 miljoner NOK från Norges forskningsråd till stöd för ZIMA-101. När bolaget nu förbereder nästa steg i doseskaleringen ska det färska anslaget på ytterligare 15,6 miljoner NOK från samma råd stödja arbetet med att öka skalbarheten i tillverkningen ytterligare och sänka produktionskostnaderna. Den långsiktiga ambitionen är att göra TCR-NK-terapier tillgängliga för fler patienter med solida tumörer.
Första kliniska data från plattformen
Zelluna behandlade den första patienten i ZIMA-101 den 13 juli vid The Christie NHS Foundation Trust i Storbritannien, med ZI-MA4-1, världens första MAGE-A4-riktade TCR-NK-terapi som når klinik. I augusti granskade studiens oberoende dataövervakningskommitté (IDMC) den patientens säkerhetsdata och gav klartecken till fortsatt rekrytering, utan att några dosbegränsande toxiciteter noterats.
En andra patient behandlades efter kvartalets utgång, och en tredje planeras under fjärde kvartalet för att slutföra dosnivå 1. Vid de två brittiska klinikerna, The Christie och The Royal Marsden, har fler än 30 patienter screenats för uttryck av HLA-A2 och/eller MAGE-A4 inom de fyra målindikationerna: äggstockscancer, icke-småcellig lungcancer av skivepiteltyp, synovialt sarkom och huvud- och halscancer.
Avläsningen är ännu begränsad men, enligt bolaget, uppmuntrande. Blodprover tyder på en cellkinetik i linje med förväntningarna, tillsammans med tidiga förändringar i cirkulerande proinflammatoriska immunmarkörer efter infusion. Under förutsättning att dosnivå 1 slutförs utan anmärkning och klarar en förnyad säkerhetsgranskning räknar Zelluna med att genomföra dosnivå 2, med en tre gånger högre celldos, med start under första kvartalet 2027 och slutförande tidigt under andra kvartalet.
Utanför den egna studien pekar bolaget på en komplett respons som forskare vid MD Anderson Cancer Center rapporterat hos en tungt förbehandlad myelompatient som fått en annan TCR-NK-terapi, något bolaget tolkar som ett externt stöd för biologin, trots att det gäller en annan sjukdom och en annan aktör.
En skalbar och kostnadseffektiv tillverkning
De NOK 15,6 miljoner som Norges forskningsråd beviljade den 4 november är icke-utspädande och kommer via rådets program för innovationsprojekt i näringslivet (IPN), med förbehåll för slutliga avtalsförhandlingar. Det kommer utöver junianslaget på NOK 16 miljoner från samma råd.
Pengarna är helt inriktade på tillverkningen: att få ut fler patientdoser ur varje donator och ytterligare pressa kostnaden per dos. En off-the-shelf-modell når patienter i stor skala bara om varje batch kan tillverkas tillräckligt billigt för att behandla många av dem.
Det arbetet pågår redan. Bolaget har nyligen slutfört en första inledande tillverkningskörning hos en ny kontraktstillverkare. Enligt bolaget är det ett viktigt steg mot att överföra tillverkningsprocessen till en ny produktionsanläggning, och som visar att processen kan flyttas mellan anläggningar.
Bredare pipeline än MAGE-A4
ZI-MA4-1 är huvudkandidaten, men den är en del av en bredare TCR-NK-pipeline. Zelluna screenar AI-konstruerade TCR-kandidater mot KKLC1, ett prekliniskt validerat mål vid solida tumörer som enligt bolaget kompletterar MAGE-A4 i de tumörer det når, och bolaget har ett PRAME-program i tidigare fas.
Bakom pipelinen ligger ett konceptpatent som täcker hela TCR-NK-fältet, beviljat i USA och Europa samt ytterligare territorier, vilket bolaget beskriver som en ovanlig position som får verkligt värde om huvudkandidaten visar sig fungera i klinik.
Q&A med vd
BioStock ställde några frågor till vd Namir Hassan om steget in i klinik, det nya tillverkningsanslaget, doseskaleringen och vad bolagets tidiga data behöver visa.
Patient recruitment is often a challenge in early-stage cell therapy trials. How is recruitment progressing in ZIMA-101, and what gives you confidence in the momentum going forward?
– Recruitment is progressing on track, and we’re encouraged by the strong engagement from our clinical sites and investigators.
– One of the important aspects of recruitment in a targeted cell therapy trial like ours is identifying patients who meet the relevant biological and clinical eligibility criteria. Our therapy targets patients who are HLA-A2 positive and whose tumours express MAGE-A4. Together, these biological criteria are met by approximately one in five patients, although the proportion varies depending on the cancer type.
– Against this background, we’ve now screened more than 30 patients for HLA-A2 and/or MAGE-A4 expression across our four target indications. This is helping us identify potential patients not only to complete Dose Level 1, but also to support recruitment as we progress into Dose Level 2.
– With two patients treated and the third planned for this quarter, our immediate focus is completing Dose Level 1 and preparing for dose escalation. The screening activity and strong engagement we’re seeing from our clinical sites give us confidence in the recruitment momentum as we move towards higher dose levels.
Dose Level 1 is almost complete and Dose Level 2 means a threefold higher cell dose. How should investors read that step up, and what would tell you the platform is doing what you hoped as the dose rises?
– Dose Level 1 is primarily about establishing initial safety and tolerability, and we’re encouraged by the observations so far, with no dose-limiting toxicities reported to date.
– Progressing to Dose Level 2 represents an important next step, as we will be administering a threefold higher dose of our TCR-NK cells, subject to completion of the first cohort and a favourable independent safety review.
– Importantly, we continue to follow patients treated at Dose Level 1, collecting clinical and translational data, including tumour imaging assessments as patients reach the relevant timepoints. We’re particularly interested in understanding how our TCR-NK cells behave following infusion, looking for biological evidence of their activity and, ultimately, any signs of anti-tumour effects.
– As we progress through dose escalation and continue following treated patients, we expect to build a more comprehensive picture of the safety and therapeutic potential of ZI-MA4-1.
You report early changes in circulating pro-inflammatory immune markers after infusion. What do you most want the translational data to show before you reach the higher dose levels?
– There are really two aspects to our translational programme. The first is understanding what’s happening in the peripheral blood, and the second is understanding what’s happening inside the tumour itself.
– In the blood, we’re looking at how our TCR-NK cells behave following infusion, but also for changes in immune markers that might suggest the immune system is being activated and potentially responding to tumour cell killing. We’ve already observed some early changes in circulating pro-inflammatory immune markers, although it’s too early to determine their significance.
– Through tumour biopsies, we’re looking for evidence that our TCR-NK cells are reaching the tumour and, importantly, whether there are signs that they’re actively engaging and killing cancer cells.
– I sometimes think of this as putting together the pieces of a puzzle. Each observation gives us a clue about what might be happening inside the patient. By bringing together the findings from the blood, the tumour biopsies and the clinical assessments, we can start to build a picture of the biological effects of our therapy, potentially even before we see measurable tumour responses on imaging.
– It’s still early, but this is precisely why we’ve built such a comprehensive translational programme alongside our clinical study.
The complete response reported at MD Anderson came from a different disease and a different developer. How much does an external TCR-NK result like that shape how you think about ZI-MA4-1?
– I think this is a very encouraging development for the TCR-NK field.
– What makes this result particularly interesting is that it provides early clinical evidence that combining the targeting precision of a T-cell receptor with the natural killing capabilities of an NK cell can deliver meaningful anti-tumour activity in a patient.
– Of course, this was a different TCR-NK therapy targeting a different antigen and treating a different cancer. Nevertheless, it is an important development because it provides independent clinical support for the underlying TCR-NK approach, which until recently had largely been supported by preclinical evidence.
– For Zelluna, our focus is now on building our own clinical evidence in solid tumours. We have already made the important transition into treating patients, and as we progress through dose escalation and continue collecting clinical and translational data, we have an opportunity to explore whether we can translate the promise of TCR-NK biology into meaningful benefit for patients with solid cancers
MAGE-A4 already has one approved therapy and PRAME programmes are in late-stage development. Where does an allogeneic, off-the-shelf approach give you room against the autologous T-cell therapies already on that ground?
– I think the progress made with autologous TCR-T therapies is extremely encouraging for the field. In particular, the approval of a MAGE-A4-targeting therapy provides important clinical validation of the target and demonstrates that engineered T-cell therapies can deliver meaningful benefit to patients with solid tumours.
– For Zelluna, we’re not looking to replicate these therapies, but to build on that progress with a differentiated approach.
– One of the major challenges with autologous cell therapies is that they require an individual manufacturing process for every patient. This creates complexity, cost and potentially significant waiting times, particularly for patients with rapidly progressing cancers.
– Our off-the-shelf TCR-NK approach is designed to overcome some of these limitations. By manufacturing multiple patient doses from a single healthy donor in advance, we have the potential to offer a more readily available and scalable treatment.
– We also believe the biology offers important differentiation. By combining the precision of TCR-mediated tumour recognition with the innate killing capabilities of NK cells, our approach has the potential to recognise and kill cancer cells through two complementary mechanisms. This could be particularly valuable in solid tumours, where tumour heterogeneity and loss of target antigen can limit the effectiveness of targeted therapies. We’re now beginning to explore these potential advantages clinically
– Ultimately, the opportunity is not simply to develop another cell therapy, but to make these potentially transformative treatments available to a much broader population of patients. Of course, we first need to demonstrate the safety and clinical activity of our own approach, and that is precisely what ZIMA-101 is designed to investigate
The new grant targets more doses per donor and a lower cost per dose. In concrete terms, where does your manufacturing cost stand today, and how far could this project move it?
– One of the key advantages of our off-the-shelf TCR-NK approach is the potential to manufacture multiple patient doses from a single healthy donor, rather than having to manufacture a separate product for every patient.
– We have already established a clinical manufacturing process, and our focus now is on further improving its efficiency and scalability. The new grant will support further developments to the process designed to increase the number of doses we can produce from each donor while further reducing the cost per dose.
– Our longer-term ambition is to bring manufacturing costs towards €2,000–€5,000 per dose at commercial scale, which we believe is achievable through further process optimisation and manufacturing efficiencies.
– Of course, the overall manufacturing cost of treating a patient will also depend on the number of doses required, which is something we are continuing to evaluate through clinical development.
– Ultimately, we believe that combining off-the-shelf availability with low manufacturing costs could be a major advantage in making cell therapies accessible to a much broader population of patients with solid tumours.
Zelluna began developing its TCR-NK platform in earnest in early 2020, taking it from an initial idea to treating its first patients. Having led the programme through this journey, what are you watching most closely as it moves through dose escalation?
– We began developing our TCR-NK platform in earnest in early 2020, so seeing the first patients treated is an important milestone for everyone who has contributed to the programme.
– Over the past several years, we’ve built the scientific foundation, developed the manufacturing process and generated the preclinical evidence needed to bring this approach into patients. We’re now at the exciting stage where we can begin to understand how the therapy behaves in humans.
– There are really three things I’m watching closely. First, continued safety and tolerability as we increase the dose. Second, the translational evidence, particularly whether we can begin to see signs that our TCR-NK cells are reaching tumours and exerting biological effects. And third, of course, the clinical outcomes, looking for early indications of anti-tumour activity as we accumulate more patient experience.
– What excites me most is that we’re now moving from scientific promise towards clinical evidence. We know that developing new cell therapies for solid tumours is challenging, but we believe our approach has the potential to make a meaningful difference for patients.
– The coming stages of clinical development will be important in helping us understand just how much of that potential we can realise.
Innehållet i BioStocks nyheter och analyser är oberoende men BioStocks verksamhet är i viss mån finansierad av bolag i branschen. Detta inlägg avser ett bolag som BioStock erhållit finansiering från.
