Takeaways From Phase 1 Trial of RTX-240 in Solid Tumors: Alexander I. Spira, MD, PhD, FACP

Video

Alexander I. Spira, MD, PhD, FACP, research institute director with Virginia Cancer Specialists Research Institute, discusses the examination of RTX-240 in a phase 1 trial (NCT04372706) with solid tumors, presented recently at the 2022 AACR Annual Meeting.

This video was originally published on OncLive.com.

RTX-240, an allogeneic off-the-shelf cell therapy in development by Rubius Therapeutics, is currently being evaluated in a phase 1 trial (NCT04372706) for solid tumors. In data presented recently at the 2022 American Association for Cancer Research (AACR) meeting, the agent elicited some responses and prolonged stable disease, according to clinical investigator Alexander I. Spira, MD, PhD, FACP, research institute director with Virginia Cancer Specialists Research Institute and clinical assistant professor at Johns Hopkins.

In a video interview, Spira shared the key takeaways from the AACR presentation and also discussed next steps for RTX-240, including exploring combination treatment alongside pembrolizumab.

The below transcript has been edited for clarity and length.

CGTL: Can you provide some background on RTX-240? How does it work and how is it unique?

Spira: One of the challenges that we know about cellular therapies is both they’re [difficult to] mak[e], they're all kind of personalized, so they take a lot of time to make. There is obviously a huge expense in that...As well as, of course, of the toxicity. Most of the current cellular therapies such as CAR T and allogeneic therapies require hospitalization, a lot of chemotherapy, with very real toxicity and morbidity, so there's a huge desire to come up with a new generation that is both easier, less toxic, and, as we like to say, off-the-shelf, so you can rapidly administer it to patients without this long uptake period.

And that's where RTX 240 comes in. It's rather unique…it's actually a red cell therapy, and the key thing to think about red blood cells is that they don't replicate. So what they've been engineered to do, and these are engineered red blood cells taken from donor cells [from] donor banks, is that they've been engineered to express, in this case, 4-1BBL and IL-15 TP. And the idea here is to use different aspects of the immune system to engage cancer cells and effectively attack them. It's done differently than the typical cellular therapies, which [are] given on a one-time basis; this will be given repeatedly. But of course, most notably, it's off-the-shelf and doesn't necessarily have to be personalized.

CGTL: From the research conducted to date, what has been observed thus far?

Spira: The idea with these cells is that these are supposed to engage NK and T cells, and they've seen some clear evidence of engaging that on the preclinical models, as well as some of the biopsy specimens obtained. In the phase 1 clinical study, and remember, this is a phase 1 clinical study, first-in-human, multiple tumor types, heavily pretreated, some evidence of activity, meaning stabilization of disease, possibly some improvement, again—holding cards close to the chest, not wanting to get too excited—but there's some preliminary evidence of efficacy. The idea now is to take it to patients in earlier lines of therapy, as well as possibly combined with other checkpoint inhibitors such as pembrolizumab or whatever else may come down the pike.

CGTL: What were the primary objectives of the phase 1 trial presented at AACR, and what did patient eligibility look like?

Spira: This [was] very broad…multiple different tumor types were allowed into the clinical study, very heavily pretreated [patients]. These are patients clearly without any options and it's a phase 1 study so the main goals of this were really to explore dose-finding, as well as preliminary evidence of efficacy. One of the important things was getting a lot of biopsies to really look at the preclinical models and see how that matched up with the patients’ specimen. So that was an important end point to look at activity, but really, very broad patient enrollment, [and] really first trying to figure out the dose and then expanding as we get to the higher doses to see what level of efficacy we're able to find. There was also, interestingly, an [acute myeloid leukemia] cohort that I think has previously been reported as well, so looking at multiple different tumor types here.

CGTL: What were some of the primary efficacy findings from the phase 1 trial presented at AACR?

Spira: Some of the key findings, just very high level, of the RTX-240 study presented AACR was some evidence of efficacy, so some prolonged stable disease, what looks like some responses as well. We're able to get to a MTD and come up with a recommended phase 2 dosing as well, which we'll use now going forward. Most importantly, I think it's proof of concept that we're able to give it, not a lot of toxicity, and certainly, obviously, [there’s] a long way between here and…an approved drug, but really showing that this is a viable concept. And not only is [it] a viable concept, but we have good biomarkers to show that [it’s] really doing what you expect it to do, so proof of principle.

CGTL: Have any toxicity concerns been raised so far?

Spira: So far, in terms of looking at toxicity, not really much of anything, so no major concerns whatsoever. One of the things people were concerned about is hemolysis and breaking down the red cell product, obviously, but it's not a ton of red blood cells and we did not see significant hemolysis. Overall, not really many immune-related adverse events either, so incredibly well-tolerated.

CGTL: Part of the phase 2 trial will investigate RTX-240 in combination with pembrolizumab. What's the rationale in combining RTX-240 with that agent?

Spira: The question is obviously why to combine with checkpoint inhibitors? I think a lot of oncology research is now because you can, because they're very well-tolerated as you see. We're almost hard pressed to find a trial that doesn't try a PD-L1 or PD-1 inhibitor. But I think there is a little bit of a scientific rationale here as well, of course, in that you're looking at 2 different aspects of the immune system. So how do you make a cold tumor hot? How do you attack things from multiple aspects? And clearly, as you think about a development path, as you think about things down the road, such as first-line lung cancer, they'll have to be combined with another drug because that's where we are right now. And most importantly, we don't think, at least now. [that] there's going to be a lot of overlapping toxicity, meaning that you can combine the 2 together. So a couple of reasons… One, both scientifically, and two, a practical rationale a s we get these drugs closer to approval, we hope.

Alexander I. Spira, MD, PhD, FACP

Alexander I. Spira, MD, PhD, FACP

CGTL: What are the next steps in the development of RTX-240?

Spira: I think a couple of things from that standpoint. One is, what is going to be the efficacy in a less heavily pretreated population? That's the fundamental question. [In] what tumor types do we take it forward? I think there's a plan to take it forward in lung right now. But what are the tumor types down the road? No. 2, this is also a unique platform, right? It's not just RTX-240. And Rubius, the company that's making this, actually has a couple of trials already, because you have a platform, right? So you have the red blood cells, but now you can transfect with multiple different targets. There’s one for HPV-positive tumors, there's another one being done right now also in phase 1 escalation...So there's a lot of different things you can do, not only in terms of RTX-240, but with this platform as well. Kind of like, as I like to say, antibody-drug conjugates, you can mix and match and do multiple different things so it gets to be exciting. But first things first, let's see some activity.

CGTL: If ultimately approved, how do you see RTX-240 fitting into the treatment landscape in the future?

Spira: Like most things…we think…what's the path to development? Second-line is, of course, the first area of development because that's where most drugs are developed. But obviously, there's some thoughts, what can you do in first-line, right? Because these are patients…if it doesn't have a lot of toxicity, although we've made a lot of headway in terms of first-line response rates…there's still room for improvement. So how do we improve on that, as well as of course, in the second-line, and I think that'll be the developmental question, as we see how things play out with larger phase 2 studies.

CGTL: What is the take-home message for clinicians?

Spira: In terms of take-home messages regarding RTX-240, I actually want to take a bigger 30,000-foot view. There's been a lot of time and energy put on cellular therapies and cellular therapies have not panned out as we'd like them to…because of the delay in making them. There are some great studies out there, but they require a huge amount of expense, work, and time, and sometimes as you try and get this personalized therapy, solid tumor patients don't have that time. And we have not had any home runs. Right now, there's been some hints of activity, but I think we would all agree that in the solid tumor world, the data has not been as good as the hematologic malignancies.

For all those reasons, I think we need a new platform. From my standpoint, the most exciting thing is what things can be done off-the-shelf that we can get to patients rapidly, [that are] less of an expense, that we don't have to wait for these personalized therapies that also have a different mechanism of action and, most importantly, may work.

CGTL: Are there any other cell therapy products in development that you are excited about and would like to discuss?

Spira: In terms of other things and where Rubius is going, they have a couple of other exact things based on this platform. They have one for HPV-positive tumors, and they have another immune stimulant as well, both in early phase 1 clinical studies. They're doing what we kind of expected [and] using this red cell platform and, as you can figure out how to scale up, you can literally come up with any mechanism of action. So one is, how much better is that going to be? You can put PDL on these drugs and see if it can stimulate using PDL therapies, or is it really going to be guided for newer therapies or in combination as well? It’s literally, as I said, you can mix and match and come up with any sort of thing based upon what you find. You can imagine things such as even acting as an antibody-drug conjugate...Instead of using an ABC, putting the antibody in the cell surface and doing it that way as well, so there's a host of things that you can do. Obviously, it'll depend on how many red cells you can administer, the mass, how it gets to the tumors, etc., but it's really a very interesting concept. Hopefully, [it’ll] be the next generation of cellular therapies, which is what we need.

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