Next-Generation Focus in Immuno-Oncology

October 24, 2019

Pharmaceutical Executive

Jennifer Buell, chief operating officer at Agenus, discusses the need for additional immunotherapies and combination strategies in cancer-building on learnings from the first wave of immune checkpoint inhibitors.

Pharm Exec sat down recently with Dr. Jennifer Buell, 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. In the past three years, Agenus, which has partnerships with Gilead, Merck & Co., GSK, Incyte, and AgenTus Therapeutics, has filed applications for 13 investigational new drugs (INDs), all of which are now in the clinic in monotherapy or multiple combinations. The company has several other projects in the preclinical stage.  

 

PE: 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.

PE: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.1

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.

PE: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 cancer2]; and then Merck came out last year at AACR and demonstrated that Keytruda plus a chemotherapy can not only bring benefit,3 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.

PE: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.

PE:Is there also almost a process-of-elimination approach in some of these really challenging-to-treat cancers, such as brain cancer5, for example?

JB: It’s an incredibly tough area. We’ve been working with brain cancer for a long time, and we started by using a vaccine approach. We published at ASCO a couple of years ago, presenting data showing that when you administer a vaccine to patients with brain cancer, first you see that it actually educates the immune system to go to the tumor, which is biologically important, yet rare with current approaches for that to happen. And only when the T-cells are there, can you start modulating with CTLA-4 or PD-1 inhibitors or in combination.

We presented data showing that if a patient [with brain cancer] had high peripheral PDL-1 expression, which means they’re immune suppressed, the vaccine wouldn’t work. But in the cases where they’re not immune suppressed, they don’t have active immune suppression, we vaccinated, induced immune education so that the immune system can find the tumor and you actually see dramatic benefit. We’re doing a trial right now with Merck’s Keytruda and our vaccine, and the trial is being run through the National Cancer Institute and funded by them.

But I’m not surprised that PD-1 failed [in brain cancer]. Essentially, what we identified is there is a sophisticated mechanism in which PD-1 regulation is just not going to work alone. You need to incite CD8 T-cells, you need to traffic them to the tumor.

PE: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 2018.6

PE:What’s Agenus’s potential commercial strategy for its therapies?

JB: We’re a pre-commercial company, we needed a quick path to generate revenue. We took the path to say CTLA-4 and PD-1 inhibitors are known entities. Many people need them, they bring benefit in combination with other agents. We created these assets to have them in-house, to give us flexibility, but we also pursued paths to get a label so that we could start selling the product. So we’re pursuing accelerated approval for a fast-to-market approach.

Then we built on all of the learnings that we’re seeing in the field from our own data on tumor escape mechanisms. And we started generating molecules such as the next-generation CTLA-4-a molecule now in the clinic. We endeavor to obtain US commercial rights but to leverage rest-of-world commercial partnerships, because that’s where we can take the footprint of some of the giants and do what we do best, which is intelligent design of new molecules.

And then our multispecific and bispecific molecules. We did license a molecule to Gilead, we’ve optioned two others to Gilead that are moving forward. We have a formal collaboration with Incyte, with Merck, and with GSK-they have our QS-21 adjuvant; it’s in their shingles vaccine, it’s 97% effective. We have retained the rights to the adjuvant in our vaccine programs.

And then we have a number of molecules that we’ve not disclosed that we’re moving forward, some of which we will develop on our own, some of which we’ll strategically develop with partners. All of which generate value for the company in royalties, milestones, and commercial value.

PE: Being a chief operating officer, do you have any thoughts on the complexities around the costs/pricing of I-O and vaccine products?

JB: We grew up focusing on the individual patient. We have brought individualized neoantigen vaccine approaches to those patients. We believe that cancer is an individual disease, but we know we have to be reasonable about how we approach it at scale, so that we increase value for patients but also for shareholders. That’s a big focus for us. So how do we do that? One important mechanism that we’ve approached is bringing everything in-house, so that we don’t have to depend on external manufacturers and the multiple-costs scale that we see with using CMOs (contract manufacturing organizations) and others. What we’re going to do now is find disruptive ways of getting our products into the hands of patients, with the focus on individual patients, knowing that we have no value if we can’t get access for patients.

PD-1s are multibillion-dollar markets. The goal is to increase access to this market by increasing the number of indications we have on our label through generating data across a number of indications. Think about it, Keytruda has only tapped into a couple of tumors. As we learn about how to better use it, we can expand into more.

Operationally, we will try to stay contained; we will strategically leverage partners for commercial infrastructure so that we can be very sophisticated in how we get our products into the hands of providers for their patients.

 

Michael Christel is Pharm Exec's Managing Editor. He can be reached at mchristel@mmhgroup.com

 

References

1. www.healio.com/hematology-oncology/genitourinary-cancer/news/online/%7bfc336100-14f2-4bf5-9e04-fe41f48737f6%7d/fda-approves-opdivo-yervoy-combination-for-renal-cell-carcinoma

2. https://www.healio.com/hematology-oncology/prostate-cancer/news/online/%7B976c1006-7375-4bb8-851e-4e14136c7770%7D/nivolumab-plus-ipilimumab-shows-activity-in-metastatic-castration-resistant-prostate-cancer

3. www.medscape.com/viewarticle/896700

4. https://www.oncology-central.com/disease-area/renal/nivolumab-ipilimumab-combo-approved-first-line-treatment-advanced-renal-cell-carcinoma/

5. https://www.fiercepharma.com/pharma/bristol-myers-squibb-s-opdivo-fails-third-straight-test-tough-to-treat-brain-cancer

6. https://www.prnewswire.com/news-releases/gilead-and-agenus-enter-into-collaboration-to-develop-immuno-oncology-therapies-300769402.html