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AROVELLA THERAPEUTICS LTD (ALA) - Killer Cells on a Mission: The iNKT Cell Cancer Therapy Story

• Andrew Musgrave

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Revolutionary cancer therapies are no longer confined to science fiction. Dr. Michael Baker, CEO of Arovella Therapeutics (ASX: ALA), reveals how the company's groundbreaking work with invariant natural killer T-cells (iNKT cells) is transforming cancer treatment through truly off-the-shelf cell therapies.

Traditional cell therapies face significant hurdles – they're expensive, time-consuming to produce, and limited to treating the same patient they're derived from. Arovella's approach elegantly solves these problems. "iNKT cells can be given freely from one person to another," explains Dr. Baker, highlighting their unique ability to bypass rejection issues that plague other immune cell therapies. This revolutionary approach means potentially hundreds of doses can be manufactured in a single run, dramatically improving accessibility and reducing costs.

The clinical promise extends beyond manufacturing advantages. Early studies show iNKT-based therapies may offer improved safety profiles compared to traditional CAR-T, with reduced rates of serious side effects like cytokine release syndrome and neurotoxicity. Arovella's pipeline includes ALA-101 for blood cancers, advancing toward clinical trials in 2026, and ALA-105 targeting solid tumours like gastric and pancreatic cancers – areas with devastating mortality rates and few effective treatments. Their collaboration with the University of North Carolina on IL-12-TM "armoring" technology further enhances these cells' cancer-fighting abilities by increasing their persistence and tumour infiltration.

Ready to witness the next evolution in cancer treatment? Follow Arovella Therapeutics as they advance their pipeline toward clinical trials and potentially reshape how we approach cancer therapy. With recent funding secured and clear strategic direction, they're positioned at the forefront of a therapeutic revolution that could benefit countless cancer patients worldwide.

Andrew Musgrave Host

Welcome to ASX Briefs, where we speak with the leaders from some of the most innovative smaller mid-cap companies listed on the ASX, and today we're joined by Dr Michael Baker, the Chief Executive Officer and Managing Director of Arovella Therapeutics. Arovella is pioneering the development of next-generation off-the-shelf cell therapies to treat both blood cancers and solid tumours using its invariant natural killer T-cell therapy platform. Michael, thanks for joining me today and welcome to the ASX Briefs podcast. 

Michael Baker Guest

Thank you, Andrew, thank you for having me. 

Andrew Musgrave Host

Now, Michael, for investors that may be unfamiliar with Arovella Therapeutics, do you want to provide a brief overview of the company? 

Michael Baker Guest

Absolutely so. Arovella is an ASX listed biotechnology company under the ticker, and we're listed under the ticker ALA, and what we're doing is working on a unique what we call CAR invariant natural killer team which we shortened to CAR-iNKT to make it simpler and we're using that platform to target initially blood cancers, but also building a carefully curated pipeline to target solid tumours. 

Andrew Musgrave Host

Okay Now. Arovella's core platform centres around iNKT cells, so for those unfamiliar, can you explain what makes this cell type so unique and why it's a game changer for off-the-shelf cancer therapies? 

Michael Baker Guest

Yes, I'd be very happy to so, and just stepping back very briefly to provide some context. So the human immune system is one of the most potent killers of things that don't belong in our bloodstream and it's made up of a whole range of immune cells and one of the most well-studied immune cell is called the T cell, and that's when we talk about CAR-T, which some of the audience may be familiar with. That's the T element. It stands for T cell and that's the most well-known soldier of the immune system. 

Now there's also another group called natural killer cells that are also widely studied, and what Arovella actually works on is, as I mentioned a moment ago, it's called the invariant natural killer T cell. Now why we like them and why we think they're unique is they actually have componentry from both T cells and natural killer cells. So, what we like to think of them as is almost like a T cell that can kill quite quickly, like an NK cell, and I know that's a lot of acronyms and so forth in that. But really importantly for us, one of the big features of an iNKT cell is that they can be given freely from one person to another. Now, this is not the case for all other immune cells, and we see that as critical in our quest of having an anti-cancer therapy that can be developed so that it's got a chance of getting widespread adoption and access to this type of therapeutic approach, largely a cell therapy. 

 

 

Andrew Musgrave Host

Okay, and how does Arovella's ALA-101 compare with traditional CAR-T therapies in terms of scalability, safety and clinical promise? 

Michael Baker Guest

Absolutely so when we think about the original version of CAR-T and, as I said, I never want to be disparaging of that because it has been phenomenal. We've seen cancer rates where people have been cured in, let's say, 40 to 60% of cases of things like lymphoma and leukemia, which is absolutely fantastic. Now where the challenge sits is precisely around their manufacturing. So, they are essentially made from the raw material of the patient. So, they start with their blood, they genetically modify, and they give them back to those patients. So, this really makes it a bespoke therapy where it's n equals one every time it needs to be manufactured. So, for Arovella's therapy, the idea is we use iNKT cells but we collect them from a healthy donor and by doing that we're actually working with a material that we think is also a better starting point, because from the healthy donors, who are perfectly healthy, their immune cells haven't been beaten up by cancer, chemotherapy and so forth. Now the idea is that when we manufacture, we are able to make in the order of, hopefully, hundreds of doses per manufacturing run, which means every time we manufacture we're actually. We're at a point where this is now scalable. It's not one-to-one and what we've also seen in a range of studies already where iNKT-cells have been used in clinic not by Arovella at this point, but by others that they can freely be given from one human to another and there is no issue of what we call graft versus host disease, and this is the big risk for using T-cells in that same context. 

Now, what we've also seen is there's a couple of well-known side effects that we've observed for CAR-T. One is called cytokine release syndrome. The other one is a neurotoxicity referred to as ICANS, and for the clinical studies that we've seen using CAR iNKT cells, there seems to be a lot less or lowered, reduced rates of CRS and ICANS, which is already alluding to a stronger safety profile. And we haven't seen a lot of clinical studies to date. As I said, the iNKT cell field is still very small. There's only a handful of companies working in the field alongside Arovella. But what we have seen at least in some of the early studies where they have used patient CAR iNKT cells and then gone back to the patient that we've seen interesting or promising clinical data in the form of what we call partial responses or even a complete response in one of the neuroblastoma studies that were published in a nice journal called Nature Medicine. So a lot of promising factors of CAR iNKT cells relative to CAR-T. 

Andrew Musgrave Host

Okay, and you're aiming to start phase one trials for ALA101 in early 2026. So, what are the key milestones you're focused on over the next six to 12 months to enable that? 

Michael Baker Guest

Yeah, that's exactly right. So, aiming to start our phase one quite soon, which is we expect that to be a very big milestone for the company, actually, which is quite exciting. And there's one major item on the checklist for that and that's getting our investigational new drug application accepted, and this is a document that goes to the FDA, so the Food and Drug Administration in the US, and that's a process that's already ongoing. So, we're drafting that document and we're aiming to have that submitted to the FDA and accepted before the end of calendar year 2025. 

So that's quite exciting, and that's certainly the biggest milestone that enables us to start the phase one. Now we will likely take that IND and then use that to start phase one in Australia, and so some of the other activities that we're currently working through at the moment is selecting our clinical research organisation that will be essentially our partner for that study, and then also then working through site selection. So which clinical sites do we want to have involved in the study? And then, once we have the IND accepted, the idea is we have all the ducks in a row and we go off and get what we call ethics approval and then we're in a position where shortly thereafter we're able to start the phase one clinical study through those sites that we've established in Australia, which is quite exciting. 

Andrew Musgrave Host

And the company is also advancing a second candidate, ALA-105, targeting CLDN18.2 for solid tumours. So, what progress have you made on this front and how significant is this opportunity? 

Michael Baker Guest

Yeah, absolutely so. That's a very exciting program for us. So, I'll just step back a little bit. That program is targeting something called CLDN18.2. It is found on the surface of things like gastric cancer, gastroesophageal, pancreatic, some lung, some ovarian cancers, and we licensed a monoclonal antibody sequence from a company called Sparx and what we've been working to do is generate what we call a an apologies for the terminology here, but a short chain variable fragment, or SCFE for short. That's the piece that we then add to our CAR-iNKT cells that would enable us to use the cells to target those particular tumour types. So, we have made great progress in turning that monoclonal antibody into a CAR or chimeric antigen receptor and we've shown some early data on that, using that in what we call. We've used that in CAR T cells, essentially to demonstrate proof of principle. We are aiming to put out some more data on that program quite soon and then the next step following that is to put this into our manufacturing process for our CAR-iNKT cells. 

Now, in terms of opportunity, we do see this as a very large opportunity. 

Gastric cancer is a very high unmet need, and things like pancreatic cancer, if that's locally advanced or metastatic, there's really not much at all for patients that unfortunately are in that situation. So, we think it's a huge opportunity. We know there's only one product approved to date that targets CLDN18.2. It is a monoclonal antibody, so it doesn't have the cytotoxic or cytolytic power of a cell therapy, let's say and that was approved last year in the US and Japan, which validates CLDN18.2 as a target to go after. And in the two phase three studies that led to the approval of that product we saw that it was used as the antibody plus chemotherapy versus chemotherapy alone. The two 500 patient plus phase three studies showed an improvement in survival for the test group of 2.5 months. So why we think that's important is it demonstrates just how desperate we are for new and improved products that target CLDN18.2 and these nasty malignancies, so very excited to get that program moving along into our CAR-iNKT cells and taking that into the future steps of manufacturing and so forth. 

Andrew Musgrave Host

Okay, and just looking at the manufacturing, the company has developed a semi-automated, clinic-ready manufacturing process. So, what advantages does this give you from a cost and speed to clinic perspective, particularly in a competitive field like cell therapy? 

 

 

Michael Baker Guest

Excellent question and I think I'll probably address that slightly in reverse. So, where we are now, as I said, we've established the manufacturing process for our lead product, ALA-101, which we're aiming to take into clinic early next year. Now, I guess, where we see the benefit there is it's more not around getting into clinic per se, because we have had to spend quite a lot of time optimising that manufacturing process to get to this point. Where we see the benefit for that program is really the commercial end. So assuming we get good data and that does progress into later stage clinical trials and beyond, we do think that having the ability to scale is really important for cell therapies in the sector broadly, and just reminding everybody that for the original CAR-T we're still back at, we make one dose for every single patient, which is quite complex logistically. So, when we talk about the manufacturing process itself, we do think the advantages we will derive in terms of speed to clinic and cost will actually be when we start integrating new CARS or missiles to target a range of different cancer types. 

Andrew Musgrave Host

Okay, and looking at partnerships, you formed a research collaboration with the University of North Carolina around your IL-12-TM armouring technology. So, what potential does this technology have in overcoming the tumour microenvironment in solid cancers? 

Michael Baker Guest

So, it's fascinating actually. 

So what we've been looking at more broadly and there was a very nice publication last year from the same group actually, that developed the IL-12-TM technology, the armouring technology and that was published in a very prestigious journal called Nature Medicine and what they were able to show is that when they compared CAR-iNKTs versus CAR-T in a range of solid tumours, that the CAR-iNKT outperformed. 

And they went on to demonstrate mechanisms for why this was the case, one of them being the ability for iNKT cells to influence the tumour microenvironment. So when we talk about our armouring through the IL-12-TM, what we know from some of the earlier studies for that particular technology is it increases the total number of CAR-iNKT cells in the bloodstream, and when they published that work, it showed that CAR-iNKT cells, including IL-12-TM, there was approximately 10 times more CAR-iNKT cells in the bloodstream of mice versus those that lacked it at four weeks. So why that's important is it tells us that by incorporating that technology into our programs, we can expect to have more CAR-I NKT cells which are capable of then taking on and killing more tumour cells. So, we think that's tremendously exciting. But already noting that CAR-iNKT cells have been shown to infiltrate tumours, we now believe there's also a very good argument for the fact that they will shape the tumour microenvironment and it's the IL-12-TM that will actually enhance their number and persistence, potentially, so again excited to build that technology into our solid tumour programs. 

Andrew Musgrave Host

Now touching on the financials. Following your $15 million capital raise earlier this year, you've indicated you're funded to generate early clinical data. So how do you plan to manage capital allocation between ALA-101 and your newer pipeline programs? 

Michael Baker Guest

So certainly, the focus will continue to be ALA-101, and that is the primary focus of the company, which is, as we discussed, getting our IND filed, accepted and then commencing Phase 1 to start generating clinical data for that program. So, we'd expect that to take a higher proportion of our capital at this point. But, as I said, we've got some very exciting, carefully curated solid tumour pipeline programs coming forward and we do expect to be in a position where we can fund those to stages where we're close to having IND submitted and so forth. The beauty of those programs from that point of view is that even though we think they're tremendously exciting, they are slightly earlier stage, which does also mean that the capital input is far lower than what we see for something that's about to go into clinic and beyond. So capital allocation certainly will be highest for ALA-101, but we're not looking to slow down on the generation of our pipeline programs either. 

Andrew Musgrave Host

Okay, and finally, looking ahead over the next 12 to 18 months, what would you consider a successful year for Arovella, both in clinical progress and corporate development? 

Michael Baker Guest

Yes, I think the number one is ALA-101 IND accepted, phase one commenced and starting to generate clinical data. So, we're obviously very excited to see what that looks like in patients with lymphoma and leukemia. And, on our solid tumour front, certainly getting proof of concept data and animal models which demonstrates that these are doing what we want them to do in a range of cancer types, potentially gastric and pancreatic cancer. And then on the commercial front, we do have a very, very clear focus on in-licensing new missiles. So not just our CD19 targeting car or CLDN18.2, but other CARS, and we do have two under option already from Baylor College of Medicine. So, if our due diligence checks out for those particular CARS and we're happy with them, then we'd expect to have a few updates commercially as well and expansion of the pipeline. So, a lot to look forward to in the next year. 

Andrew Musgrave Host

Okay, Michael. Well, it's been great to chat. Thanks for coming on the podcast today and giving us an update on where the company is at, and we look forward to further updates from Arovella in the coming months. 

Michael Baker Guest

My pleasure, Andrew. Thank you again. 

Andrew Musgrave Host

That concludes this episode of ASX Briefs. Don't forget to subscribe and we look forward to catching you on our next episode.