Hi everyone and welcome to episode 129 of Cell & Gene, the podcast. I'm Erin Harris. I had the great fortune to reconnect with Dr. Zachary Roberts, EVP of Research and Development and Chief Medical Officer at Allogene Therapeutics. Nearly two years after his last appearance on the podcast, we explore how the field of allogeneic CAR T therapy has evolved and why the conversation around off-the-shelf cell therapy is more relevant than ever. Zach and I dive into the momentum behind the company's Alpha 3 study. We talk about the growing role of MRD-driven intervention strategies and what it could mean to move CAR T therapy earlier in disease treatment with safer, more accessible outpatient approaches. Also along the way during our conversation, we tackle some of the bigger questions facing cell therapy today. So we talk about scalability, physician adoption, reimbursement, and whether allogeneic platforms can finally bring curative therapies to more patients beyond major academic centers. Zach brings both clinical and strategic insight to our conversation, and he really offers a compelling look at where cell therapy may be headed next. And so without further ado, here is my conversation with Allogene Therapeutics' Dr. Zach Roberts. Enjoy.
Welcome back to Cell & Gene, the podcast. Zach Roberts. Zach, I'm thrilled to have you back. Listeners, I encourage you to go back to episode 84 to check out my conversation with Zach. In a nutshell, he and I talked about why allogeneic therapies are really truly scalable. That was almost two years ago, and we have a lot to catch up on. And so, Zach, I'm thrilled you're here back with us on Cell & Gene podcast. Thanks for your time.
It's great to be back, Erin. Thanks for the invitation.
Absolutely. So, let's go ahead and start with bringing our listeners up to speed. A lot has happened in the past two years. So, talk to us about Allogene Therapeutics and its mission and kind of where we are today.
Sure. So, the mission has not changed since we spoke in August 2024. We are continuing to develop off-the-shelf CAR T cells based on healthy donor manufacturing, otherwise known as allogeneic CAR T cells, for the treatment of patients with cancer as well as autoimmune disease. I think our conversation a couple years ago was primarily focused on the Cemacabtagene program, and that continues to be our lead program. It's a CD19 CAR T cell. And the study that we talked about in 2024, Alpha 3, is going very strong. We just released our first data a couple of weeks ago, a glimpse at how things are going there. So, we are continuing on our mission to treat patients with cancer and autoimmune disease.
Terrific. Well, I'm glad you brought up Alpha 3 because that's where we're going to concentrate next. So it's definitely being viewed as a potential turning point for allogeneic CAR T. Now, what do you think the study says about where we are more broadly in cell therapy in terms of proving earlier-line and potentially curative intervention, excuse me.
Yes. So the Alpha 3 study, I think, is a great new frontier for CAR T cells. We have known for a long time that treating patients earlier on in their course of disease with CAR T cells tends to lead to better outcomes. We've seen that in the autologous world with the outcomes improving from third line to second line. There is reason to believe that treating these patients earlier biologically may lead to better outcomes. The patients tend to be in a little bit better shape, having seen less therapy, more willing or more able to tolerate some intensive therapy. What we're doing in Alpha 3 is a little bit different, though. To remind the listeners, this is a study in which we are treating patients really as early as they can be treated with CAR T cells, and that is before they've actually experienced a clinical relapse. So these are patients who have completed frontline therapy but remain very high risk for a future relapse event based on our detection of something called minimal residual disease in these patients. So they're in remission, but using an ultra-sensitive blood test, we can find traces of residual cancer. And so we're treating those patients with CAR T cells, which is a very novel application of the therapy. And the goal here, make no mistake, is to cure these patients, is to eradicate that residual disease and prevent that relapse from ever happening. So I think Alpha 3 is a great example of how we as a field continue to innovate and look for ways to bring this curative therapy earlier to patients and to try to avert some of the trauma associated with the disease recurrence.
Yes, of course. Okay. And you mentioned minimal residual disease. So the trial uses MRD to identify patients who may benefit before relapse. So talk to us a little bit, perhaps more broadly, how are you seeing biomarkers, diagnostics, patient stratification reshape how cell therapy is designed and deployed?
That is a great question. I think it is one that will define the next several years of oncology drug development. In my opinion, the gains being made on the diagnostic side are every bit as exciting as what we're seeing on the therapeutic side. And it's not simply because these tests are able to offer more accurate prognostic information to patients, but it provides us with an opportunity to actually intervene. And that is a fundamental shift in how we think about delivering care, particularly as it applies to diseases like non-Hodgkin lymphoma. We have been doing treatment of patients who are in remission for a long time in solid tumors. There we call it adjuvant therapy, where patients who undergo a definitive frontline treatment like a surgical resection, but who are known to be high risk based on clinical factors, they're offered adjuvant therapy after they're in remission, and that is to hopefully mop up any residual disease. What these new diagnostic tools are doing are offering a far more accurate read on whether there is residual tumor or not than the standard and historical clinical factors that people use to determine the need for adjuvant, or in blood cancers we call it consolidation therapy. So as these diagnostic tools begin to proliferate across oncology, it is going to create opportunities for us to run studies like Alpha 3. And I'll give you a very specific example. Just a few months ago, there was a very exciting study that read out in muscle-invasive bladder cancer, which is a very high-risk solid tumor. And these patients underwent a complete resection, had all of the visible tumor removed from their body by surgery, and then they underwent an MRD test very similar to what we're doing in Alpha 3. And the patients who were found to be MRD positive were randomized to treatment with more therapy, in this case an immunotherapy called Tesetaxel, which is a checkpoint blocker, or placebo. And that study read out in October and showed a very significant improvement to disease-free survival and even overall survival when you take these MRD-positive patients and treat them with more therapy. So that's a great example of how we are going to use these new diagnostic tests to intervene earlier and hopefully improve patient outcomes, just as we're seeking to do in Alpha 3.
Good. Okay. Thank you for that detailed explanation. Now, if and when the approach succeeds, we were talking about the fact that it could really reshape sequencing in large B-cell lymphoma and potentially beyond. So again, kind of more generally, how is the field thinking about moving therapies earlier in disease, improving value in settings where patients are still more clinically stable?
