Applied Clinical Trials sat down recently with Jennifer Buell, PhD, chief operating officer at Agenus, a biotech focused on immuno-oncology, with a pipeline of checkpoint-modulating antibodies, cancer vaccines, adjuvants, and allogeneic adoptive cell therapies. Buell, who helped transform Agenus from a single-product, vaccine company to a platform organization with capabilities from target discovery to GMP manufacturing, discussed the unmet need for additional immunotherapies and combination strategies in cancer. Critical to this effort, Buell stressed the importance of building on learnings from the first wave of approved immune checkpoint inhibitors that target protein receptors PD-1, PD-L1, and CTLA-4 (e.g., Keytruda, Opdivo, Libtayo, Yervoy).

Agenus is headquartered in Lexington, Mass., where its vaccine manufacturing is also housed; the company’s discovery function is based in Cambridge, UK, and GMP manufacturing for its antibody candidates is conducted in Berkeley, Calif.

Q: What’s your view on the direction of the immunotherapy field at the moment?

Jennifer Buell: One of the big questions in this area is how to bring real benefit to patients in a more effective way. How we’re looking at this-a 300-person company-is to build on the learnings from these huge trials that Merck and others do, and we’ll say, this subset of patients, they’re being cured, right? Why is that? And how do we increase the benefit or increase the number of patients that fall into that category?

One example that we came under great scrutiny for was CTLA-4. In 2014, it was widely thought that anti-CTLA-4 was going to go away. The field concluded that it was too toxic, and would be replaced by anti-PD-1 [instead], for example. But we knew that CTLA-4 and PD-1 are very different mechanistically. They play different roles in the immune interaction with cancer. We have seen that with PD-1, patients will see some incremental benefits, but they are not seeing curative responses-and you don’t have the tail of the curve phenomenon with PD-1 that you have with CTLA-4.

So, we not only pursued a first-generation CTLA-4, but in studying that tail of the curve, we identified cases where patients-the non-responders-have a genetic polymorphism. This population represents about 40% of patients; that’s a big population with a very precise reason for not benefitting. So we went after engineering our CTLA-4 antibody and designed it to amplify the beneficial features of the first generation and add features to expand the benefit to those patients who are not responding to the first-generation CTLA-4s.

Q: How is that candidate progressing?

JB: Our next-generation CTLA-4 is advancing in the clinic. We will start combinations with our PD-1 imminently. We believe this could be transformative for the field. Our first-generation CTLA-4 and PD-1 are in the clinic in trials designed to support our BLA [biologics license application] filing. When you take a PD-1 and you know that it works for lung cancer or melanoma, you add CTLA-4 and you increase the response rates and the durability. The most recent case was in renal cell carcinoma.

Right now, we have two approaches to get to a BLA. One is a PD-1 monotherapy for patients with second-line cervical cancer. And then we have a combination, where we believe adding CTLA-4 on to that PD-1 will provide real benefit for patients.

Q: Harnessing these combination immunotherapies, which can be more potent and less toxic than single agents-is essentially the key mission today, correct?

JB: What we know right now is that monotherapy has brought some good benefit to some patients; when you add the combination, you see these remarkable responses and you see durability-and they’re mechanistically-driven. The shortsightedness that the field had when it thought PD-1 was going to be the answer, was addressing only a single component of a complicated system. In cancer, putting all of your eggs in a basket, focusing on just one target location-the tumor, isn’t going to work. Think about systems biology, CTLA-4 is operating in a very different place; regulating in areas of immune modulation. With PD-1, you’re regulating locally. If you put the two together, that’s when you start to see the real antitumor benefit.

It’s the first time we’ve been able to put “cure” and “cancer” in the same sentence. A good proportion of patients [in clinical trials with these combinations] have not relapsed beyond five years. That’s the benchmark today. Sometimes there’s a combo that isn’t as commercially rewarding. This is an important consideration. These effective products need to be accessible to patients. But you can take a CTLA-4 and a PD-1, and Bristol has shown this [in prostate cancer]; and then Merck came out last year at AACR and demonstrated that Keytruda plus a chemotherapy can not only bring benefit, but it’s also feasible-it’s cheaper, chemotherapy is accessible, centers are comfortable using it. At Agenus, our approach is to have the most effective agents, like antibodies, allogeneic cell therapies, and neoantigen vaccines, in-house. And we do. We plan to deliver high impact results for patients that can be easy to deliver for providers.

What’s the real bar, then, [to combined checkpoint inhibition]? it’s access, right? We want patients to have access.

Q: So is access more so the issue than actual response?

JB: Both are imporant. Right now, with MSI-high (H) colorectal cancer, you put PD-1 and CTLA-4 together, you see the real change in huge response rates and durability. You see the same with renal cell carcinoma. You have a PD-1 approved, you add CTLA-4 on to it, and you see real durability. That was a subject of the most recent approval for Bristol, and that the FDA looked at the durability response. Comparable response rates and durability of response was much more dramatic with the combination with CTLA-4. That’s the holy grail-the durable responses.

But market access is an important one, too. Merck has used a smart approach, in which they’ve taken their PD-1 and put it on top of standard-of-care approaches. We can do the same, Bristol can do the same. But our focus is on much more disruptive changes. We’re looking at those polymorphic patients that aren’t going to respond to [anti-]CTLA-4, creating a product that can address the problem, and giving them the combination.

Given that we own all of the products and the efficient process to develop them, we are in a strong position to enable access.

Q: What technologies is your company using to help advance discoveries in I-O?

JB: We’re leveraging computational approaches to I-O. We’ll be publishing very shortly on a big data platform, in which we interrogate a series of omics-genomics, transcriptomics, proteomics. We’ve fully characterized the life cycle of a T-cell-we know when it’s tumor-fighting, we can watch it, and then we know when it gets really tired. And we know what it’s showing or expressing when it’s fatigued. And we also know when you can start to intervene. With certain therapies, you can reinvigorate that T-cell.

We’ve fully cut through big data and adaptive learning approaches, and now we’re intervening with different therapies in our pipeline to see when you can actually make that T-cell start fighting again. What’s the best way to do it? Sometimes it might be a monotherapy approach, sometimes it’s a combination of two approaches, sometimes it’s a bispecific antibody approach. We have two molecules in the clinic that were born out of this concept. The design of the molecules came from findings in our platform. One of the molecules is partnered with Gilead-that was the largest preclinical I-O deal in 2018.