CD70: How Does ALLO-316 Eliminate or Destroy Malignancies in the TRAVERSE Trial? Samer Srour, MB ChB, MS

CD70: How Does ALLO-316 Eliminate or Destroy Malignancies in the TRAVERSE Trial? Samer Srour, MB ChB, MS

By Samer Srour, MB ChB, MSs

So the ALLO-316 is, it’s very novel agent to treat, kidney cancer and hopefully will expand to other cancers. It’s first of all, it’s take CAR T-cell Therapy antigen receptor, T-cell engineered treatment. The CAR T-cell therapy is groundbreaking right now and practice changing for those similar malignancies. We have FDA approved products for these malignancies. We are trying to pass on on this success for these solid tumors. And that’s where it comes to idea to use the same concept, the T-cell therapy in kidney cancer and other solid tumors to that extent, the ALLO-316 the action is simply like any other CAR T-cell product approved in these malignancies. First, you have to identify the perfect target that you want to attack with those CAR T-cell products. In this novel study, we have CD70 as a target CD70 it’s highly expressed in kidney cancer patients. So the CD70 is an importanttarget for CAR T-cell therapy for several reasons. Number one, it’s highly expressed in kidney cancer with very low or no expression in normal tissues. Number two, CD70 is known to suppress the tumor microenvironment for the, which helps the cancer progress and spread more and be more aggressive. So targeting CD70 has is an ideal target for these reasons. So the ALLO-316 is very novel, it’s one of the first in human studies to target this CD70. And also it has unique genetic edits. The ALLO-316 to make it first expands further and persistmore. And then also has some safety switch, for instance, we knocked out the CD52, which allows us to use monoclonal antibodies on those 6647, and that allows us, when we add that CD52, allows us to improve the persistence of the CAR T-cell therapy. This is, again, allogeneic off shelf, it’s not auto autologous. So having a good lymphodepletion to allow the allogeneic product to persist for manga period is very important. So that’s very unique for this construct, and we also knocked out the TRAC gene, which allows our to prevent Graft-versus-host disease (GVHD). So those automated healthy cells will not cause problems for the patients. And we have a safety switch, which is a CD20, mutual on the construct. So if we get to see any excessive toxicity we are able to use obviously two antibody, like Hydrox to slow down or eliminate the excessive CAR cells. So it’s very unique by ALLO-316CAR T-cell product. And this was the first inhuman to explore this agent on patients on need for this, patients who have relapse kidney cancer.

What is the primary objective of the TRAVERSE trial, and how will the data collected be used to evaluate the safety and efficacy of ALLO-316?

So, like any other phase 1 clinical trial, the primary objectives is usually to assist safety and tolerability of the, investigator, investigational agent. So in this study, our primary objective was to assist safety and tolerability. The secondary points were to assist any problem anti-tumor activity and to look for the pharmacokinetics and cell kinine of the ALLO-316 and or for the ALLO-647 anti CD52 macro antibodies. Now to that extent we have treated so far. We have a growth 20 patients on this early phase 1 clinical trial, 19 patients infused with the ALLO-316 CAR T-cell and those 19 were assist for safety and we did not see any safety signals so far outside what we see in the auto autologous CAR T-cell, the ones or already commercially available. This was very encouraging for us, I just, for instance, if we look at come of these, you know, specific toxicities, how many we see in these malignancies, CRS, or cytokine release syndrome. We saw like 58% of our patients had it. All of them except one were low gradeCRS and were very manageable. As far as, the secondary objectives and the anti-tumor activity, in the context of a phase 1 clinical trial at very low dose levels.  I would like to highlight this study is still accruing patients. And right now most of these patients are talking about, are in the first and second dose levels, we have four dose levels of this study. And in that context, we have seen very encouraging early, anti-tumor activity results. If we take the patients of CD70 positive kidney cancer. And again, this construct, targets the CD70 on these patients, the disease control rate was 100% for these patients. And the objective response rate which mean partial response or more, was 30% in the context of a early phase study or heavily pretreated patients, these are very encouraging results for us.

Can you discuss the patient population enrolled in the TRAVERSE trial and how their disease progression is being monitored throughout the study?

For these 19 patients who were infused the study, if you look at the baseline demographics, the median lines of therapy were three, which means those patients have failed already, three standard therapies in prior clinical trials along with that. And as an example to tell you how much these patients in need for novel treatments, they’re heavily pretreated. For instance, close to 70-75% of these patients, they have been exposed to two different immunotherapy agents, checkpoint inhibitors, and hence if you look at this patient population historically prognosis like eventually most of these patients, they will die unfortunately from their disease.

And to that extent, if you look at our data where we, they were given like only one infusion of ALLO-316, these patients, and if you look at the 10 patients who have CD70 expression achieving a 100% disease control rate, which means those patients, they did have some shrinkage of their tumor, but not enough to say they have partial response. And with median progression survival likeability over, with durability of responses over 5 months and objective response rate of 30% for these heavily protected patients. We are very encouraged with theseresults. The median follow up is still 7 to 8 months. It’s short but we continue to follow these patients along and we can continue to accrue in this study. So hopefully towards the end of this year, We will have completed the other 2 dose levels in this cohort and we are hoping to improve with these results as well.

“The ALLO-316 it’s like the other commercially available CAR T-cell therapies in hematologic malignancies. It’s usually one infusion. It’s given after you get the lymphodepletion. Lymphodepletion, you get it over 3 days, it’s cyclophosphamide with or without the ALLO-647. So we have two different cohorts, one without the ALLO-647, an Anti-CD5062, another cord with the ALLO-647 patient and after they get 3 days of the lymphodepletion on day zero, 2 days after they get the lymphodepletion, they get the ALLO-316 infusion, usually over 10-15 minutes. And after that, the patient will be just monitored for any safety signals and for their anti-tumor activity at 1 month, 2 month, and then every 2 months after that. Patients are permitted to get a second infusion if they benefit from the first one, and they don’t have any, serious adverse effects. And indeed we were able to infuse two patients on this study so far. And reinfusion, it seems also the patients still have some expansion in their CAR T-cell and some potential benefit from, without, unexpected toxicities.” Professor Samer Srour from MD Anderson Cancer Center

Can you describe any notable adverse events that have been observed thus far in the TRAVERSE trial, and how are they being managed?

So the overall if you take all this study patients, we did not see any unexpected side effects outside what we see in the, autologous CAR T-cell products. But specifically if you wanna talk about the common things with deal with CAR T-cell therapy, we have seen some of these and the TRAVERSE study. The, cytokine release syndrome we have seen 58% of the patients had CRS, all of them except one patient had low grade CRS. And I would say in all cases, the CRS was manageable with conservative therapies and in few patients we were able to counteractive fact by giving. If you look at other important, uniqueside effects for the CAR T-cell products, for instance, the ICANS neurotoxicity, we didn’t see any of the patients had ICANS, which is very encouraging. That’s even better than what we see in those malignancies and this is another unique product.

There’s always a potential that those engineered T-cells. From the donated healthy donors, they can cause what we call graft versus host disease (GvHD). They can attack the recipient or the patient. So we didn’t see any incidences of graft versus host disease (GvHD) infections and cytopenias. We have seen what normal see with other CAR products.

So all in all, we are very encouraged with this safty profile. There was one patient who had, dose limiting toxicity. Andand that patient had liver toxicity, which eventually also was reversible with the immunosuppressive therapies. That’s kind a summary of the site safety profile.

How is the TRAVERSE trial structured in terms of study design and length of follow-up, and what implications might this have for the reliability of the study results?

So the TRAVERSE is designed similar to most otherphase 1 clinical trials. It adopts three plus three study design. Where we treat patients on different dose levels. We’re trying to find the optimum dose to expand on and perhaps move to the phase 2 study after that.

So to that point, we have 4 dose levels on this study from 40 million up to two 40 million so far, most of the patients we reported on received 40 and 80 million. There was just two patients received the dose level 3120. But most of the other 19 patients received 40 and 80 million dose levels.

And as I mentioned earlier, patients received the ALLO-316 two days depletion, and then they followed. For the safety for the first 24 days very closely, 28 days, very closely. And after 28 days, we continue to follow them on less frequent intervals for safety and for efficacy. And the other than that, like normal study design that, that we follow in the phase one study this again the other unique portion of this study  we are trying to explore not just the ALLO-316 alone, we’re trying to explore what is the best conditioning for that we can use and improve the activity of the ALLO-316.

And that’s why we have ALLO-647, which is CD52 monoclonal antibodies. So we have two different cohorts at the same time moving on parallel with this study.

What are some potential limitations or challenges that may arise in interpreting the data collected from the TRAVERSE trial, and how are these being addressed by the study team?

We should always be very careful to over-interpret the findings from a phase 1 safety design study. To that point I think we have not encountered any major issues that caused us to, to make any significant changes outside the normal of a phase one study design.

I think the these is to keep accruing on this study and the two different cohorts the ALLO-316 alone and the ALLO-647. And by accruing more patients, we probably get to know, you know, which arm is going to work better. What are the ALLO-647 anti-targeting? The CD52, or which, let me call it, enhanced lymphodepletion or just with ALLO-316 alone?

I would say the only major change we have made so far in this study is based on the preliminary results when we looked at the CD70 expressing tumors. So when we started this study, we did not recommend to screen for CD70. So every patient with kidney cancer can be a potential patient. But after collecting the data from the first 15 to 18 patients, and we looked at the responses for these patients and the CD70 expression, we found that, patients who have expression to CD70 compared to those, ones who don’t have expression they did benefit more from the other ALLO-316. So to that point, we have amended the protocol, right now, we only include patients who have CD70 positive tumors. I think that’s the measure change that we learned over this study. This study continues to accrue without any other restrictions.

Can you discuss any preliminary findings or interim analyses that have been conducted on the TRAVERSE trial, and how these may inform future clinical development of ALLO-316?

I think what we learned from the these prelimnary results, a few things, number one, the ALLO-316 on its own without even addition of ALLO-647 is to expand very nicely early on after infusion. And we have proof that because we have fludarabine without the ALLO-647.

We have seen very nice expansion of the ALLO-316. And the other thing is what we have, it’s kind of a unique mechanism for the ALLO-316 to help on its own, to improve and persist over time. There is something called the DAGGER effect, what we have seen is the ALLO-316 will start to expand after day 4 it can actually by itself deplete or kill the host T-cells that express CD70, and that by itself will allow like more lymphodepletion if you want, and more persistence of the ALLO-316 over time. So this is something unique we’ll learn of, but above all the most, the most important finding from this study are number one, the safety profile. We were able to infuse this product to 19 patients. We did not see any serious side effects that triggered us to stop the study, which is very important. This is a safety, again, remember numerous study. So there’s a proof of concept here that there’s no on-target of tumor toxicity. We just saw toxicity that we see with other autologous commercial available CAR T-cell products, and this is very important because many studies actually, they were halted or stopped early just because of this toxicity on target of tumor toxicity will stop automatically because patients life can dangerous, so this is a huge achievement for this cancer study. The other achievement, which is very encouraging, as I said earlier, is the early anti-tumor activity. So if you look at the disease control rate for the CD70+ patients, we get 100%. These were 10 patients, so we get like 100% disease control rate and objective response of 30%, again, we’re talking about low dose levels. So these are very encouraging. The safety profile combined with those prelim anti-tumor activities make us think that this will have hopefully, a bright future for our patients who have unmet need for such noble therapies.

How does ALLO-316 fit into the current treatment landscape for advanced or metastatic clear cell renal cell carcinoma, and what role do you see it potentially playing in the future?

Again, I wish I could leave you the right, you know, the different answer. Because again, in the context of the phase 1 clinical trial, we cannot right now predict how things be in the. But we are very encouraged with this, the first 19 patients were treated on in this study. Our work right now is to finish accrual of this dose escalation phase hopefully by end of 2023. As I said, we still have two dose levels to explore dose level 3 and 4, up to two 40 millions. And my personal hope is if not only to replicate, maybe to improve on these results. These are good results, but why not? We can maybe improve, get deeper responses and more durable responses to dose level 3 and 4 and then we expand from there on the best optimum dose to our expansion phase or even phase 2 study and include some other tumor subtypes if we replicate and improve these results. I will definitely see this will be one of the treatments on the algorithm of treating those patients. One of the beautiful advantages or big advantages of the CAR T-cell therapy compared to other standard therapies available, it’s all undone by one infusion, patients will get one infusion, they can have responses, we hope for many month and years, but even if you get response for 6 months with one infusion, when you get it again, that’s something very attractive for our patients and for the quality of life. So I’m hopeful that this will fit in, into the algorithm for treating kidney cancer and other cancers.  But we’ll get to know more towards end of this year and moving forward.

Is there anything you would like to add in closing?

I just wanna highlight again, the fact that these results are very encouraging and provide a proof of concept and reassurance for all the researchers who work in this field that we are able to treat solid tumors with CAR T-cell therapy. What been successful in this study and then 30% objective response rate and 100% disease control rate in heavily patients makes us think that there’s a way to go  in treating kidney cancer, other solid tumors with CAR T-cell therapy, way to go with success. So let’s keep going and let’s beat the solid tumors with CAR T-cell therapy soon hopefully.

10 Key Takeaways from the TRAVERSE Clinical Trial in Advanced/Metastatic Clear Cell Renal Cell Carcinoma

Professor Samer Srour – About The Author, Credentials, and Affiliations

Samer Srour, MB, ChB, MS, an Associate Professor in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas.