Improving the Odds in Cancer With First-Time Immunotherapies

Innovation That Matters

By Rich Soll, Senior Vice President, Research Service Division, WuXi AppTec (@richsollwx)

With a strong belief that precision medicine is the future backbone of medicine, combined with advancements in the cancer immunotherapy field, and a unique platform, four-year-old Cambridge, Mass. biotech player Jounce Therapeutics is paving its own path toward creating first-time treatments for patients. Jounce became the first local biotech firm to go public this year by selling $117 million (gross) worth of shares. The young biotech also scored a partnership with Celgene last year, which included acquired options on Jounce’s lead drug candidate, JTX-2011.

At the helm of this hot company is industry veteran Richard Murray, who has a penchant for providing immediate impact to patients. Murray and his team at Jounce are on a mission to develop a biomarker-informed approach in the creation of a range of novel immunotherapies, which target different immune cell types both including and beyond T-cells. 

The company has created an integrated patient selection and stratification strategy, coupled to each novel immunotherapeutic, to attempt to enrich subsets of patients that may be more likely to respond. While immunotherapies are increasingly recognized as a critical component of cancer therapy and are beginning to fundamentally change the paradigm for treating patients, only a minority of all solid tumor cancer patients respond to the current immunotherapies as single agents, in part due to the lack of predictive biomarkers to identify responsive patient populations. 

I recently spoke with Murray, who explained the strategy behind Jounce’s early investment in translational science, the company’s quest to advance the next generation of novel cancer immunotherapy targets and drugs via novel biomarkers, and how the biotech plans to mitigate risky science, all in the name of providing more effective treatments to patients.

Rich Soll: You’re dealing in a hot area right now – immunotherapy, the tumor microenvironment, and targets beyond PD-1. You have a strong platform, great founders, and science. What was the genesis of building Jounce?

Richard Murray: The years leading to the founding and launch of the company were during the emergence of immunotherapy, particularly in the checkpoint field, mediated by monoclonal antibodies, but with a clear view that there are certain patients who seem to be able to respond to any one of these therapies, initially anti CTLA-4, and increasingly PD-1. Certain patients are, in fact, having a response, opening the door for longer-lasting, more durable benefits.  In oncology research and development that durability has been long sought after, but had been elusive. As the evidence of this benefit started emerge, there was a strong desire at Jounce to understand why some patients respond well to these therapies, but candidly, most patients did not. A patient’s immune system, the immune status, and the types of immune cells that might be resident within the tumor microenvironment are patient and situation-dependent. It has led us to the establishment of one of the key features of Jounce’s approach, which is to initiate a coordinated effort on identifying the biomarkers that may indicate a given patient is more likely to be responsive to a certain immunotherapy.

Rich Soll: How does Jounce’s approach fit into precision medicine?

Richard Murray: The ultimate deliverable of our whole concept points toward a future of precision medicine. We’re firm believers in that across all medical categories, and particularly so in oncology. From the earliest onset of the company, we took on a comprehensive analysis of the immune system characteristics within large numbers of human tumors. We then hope to coordinate biomarkers with the particular immune cell type and target we are looking to modulate with the new immunotherapy within the tumor. If we can effectively establish the relationship between predictive biomarker expression and clinical response in a subset of patients, this may allow continued development of the immunotherapy in the patients who may best respond.  In that manner the new immunotherapy product candidate is more “precise” in its use.

Rich Soll: What is your strategy in identifying those patients who will respond?

Richard Murray: Let’s use the anti PD-1s as an example – there are a percentage of patients across a variety of different solid tumor indications that respond to treatment. When all patients are treated there is a different percentage of responsive patients depending on the indication.  Importantly, there are certain pre-treatment characteristics (potential biomarkers) that are in common in the responsive patients across those indications. As we have learned from PD-1 studies, it is possible to find predictive value in testing for those biomarkers for therapeutic response. If we extrapolate this idea further it is possible to envision a different percentage of patients from those same indications, who do not respond well to PD-1, but do respond to a different immunotherapy mechanism, or perhaps respond to a combination of immunotherapies.  Thus the biomarker and companion diagnostic approach could conceivably start to redefine tumors by immunotherapy response criteria rather than the typical definition of indication. In the context of immunotherapy and solid tumors, we now tend to look at any given tumor as “hot,” meaning immunologically inflamed, to “cold,” meaning no involvement with the immune system. While PD-1 inhibitors lead to benefit in at least some of the hot tumors, little beneficial impact has been seen in the cold tumors. Our goal is to expand upon that concept of the immune characteristics to try to identify the patients across indications who may be more likely to respond to particular immunotherapies We believe this is where the science and eventual regulatory paths may take us.

Rich Soll: Let’s talk about the translational platform that you have put in place. You have a very interesting molecule, JTX-2011. Can you share the background on that?

Richard Murray: JTX-2011 is a monoclonal antibody that binds to and activates the Inducible T cell CO-Stimulator (ICOS) expressed on certain T cells within certain tumors from many indications. ICOS was both part of the translational information that we are generating, but also from the beginning of the first days of the company, aided by some early work that was done by our two of our founders, Drs. Jim Allison and Pam Sharma. They wanted to understand immune system molecules and mechanisms in cancer patients. Those studies examined patients treated with Ipilimumab (anti CTLA-4), using an unbiased analysis to characterize which immune mechanisms changed during therapy. The results were that ICOS changed substantially in those patients, but most importantly, the increased ICOS expression was associated with better response and survival. It is that relationship to outcome that revealed a context of human cancer biology, and we found that compelling. These findings were brought back to the lab to show that activating ICOS reduced tumors in mice. It is this type of approach and result that is now representative of how we are operating in our full-scale translational platform.

Rich Soll: I hear a lot about PD-1, PDL-1 and CTLA4, but I don’t hear much about ICOS as a leading target. Are you the first in this area?

Richard Murray: Yes, it is a first-in-class target. We, as well as GSK, both have declared programs. We could, perhaps, expect to see more programs in the future. Based on our belief of getting the right immunotherapies to the right patients, we coupled the creation, characterization, and manufacture of JTX-2011 for clinical development with a coordinated effort to define biomarkers to be used to screen for the types of patients that may be more likely to respond.

Rich Soll: Can you give us an update on where you are in the clinical trial process?

Richard Murray: It’s a four-part adaptive clinical trial design, with Phase 1 and Phase 2 portions, with both JTX-2011 single agent evaluation as well as in combination with a PD-1 inhibitor. The study is expected to enroll over 200 patients if all cohorts are advanced. We recently announced the start of the Phase 2 single agent portion. In that portion, as well as in the Phase 2 combination portion, which will start in Q2 2017, we will use the biomarkers to ensure that we are enrolling the patients that may be more likely to respond. We’re doing everything we can to maximize the possibility to characterize a JTX-2011 signal in a certain patient population.  Overall, the study is designed to move the program forward as quickly as possible, if we are able to establish the right type of response from certain patients.

Rich Soll: Celgene has a very strong history of recognizing great science. Can you tell me more about the Celgene deal?

Richard Murray: We are happy with the scope of the Celgene deal, but did not view it solely as a capital raising exercise. Really for us, it was like-minded thinking about the future of immune-oncology – the patient selection component – and the alternative mechanisms that we think will start to reach toward the patient populations that have yet to benefit from immunotherapy as we understand it today. Also, we believe Celgene is a great partner as we build Jounce. They have a strong history of creating “win-win” partnerships.

Rich Soll: So let’s shift a little bit from the company to you. What did you take away from your experience at Merck?

Richard Murray: I spent five years at Merck as senior vice president of biologics and vaccines. My role at Merck was to set up the monoclonal antibodies and the more biotech-type of products. As I stepped into that role, it was right at the beginning of the fuse being lit for checkpoint therapies, as we have now come to appreciate them. So the role became very much centered on Keytruda. Many of the principles we look at today – our understanding of checkpoints – were still all greenfield space at the time. I think Merck did a great job as an organization to clear the path for such an important program. For me personally, it was a fantastic experience of going from the discovery stages of that molecule through approval. Probably one of the most exciting aspects of immunotherapy for cancer researchers in this field is the immediacy of the impact of the results and the durable benefit that immunotherapies bring to cancer patients.

Rich Soll: So is that a driver for you – the fact that Jounce was taking on these new classes of interventional opportunities?

Richard Murray: Absolutely. Historically, I’ve always been involved with large molecules and monoclonal antibodies, and back in the day, there was immunology as a separate discipline and oncology as a separate discipline. Then with immunotherapy, and for me personally with Keytruda, that all came together in a hurry. Immunotherapy creates such opportunity to impact cancer patients’ lives that it was clear I wanted to continue in the field. I like the small company dynamic, and I like the ability to move quickly, to make decisions quickly – all that is very appealing. While biotech has its ups and downs, it is also where innovation can really thrive. The Boston/Cambridge community is a great example of that.

Rich Soll: What are your top priorities for Jounce?

Richard Murray: Clearly the progression of JTX-2011 and the additional novel molecules, coupled with patient selection strategies, occupies our top priorities. But importantly, I think the culture of the company is extremely important, and our senior team spends a lot of time on this – significant value that can be created in these small, tightly-knit companies. A culture where patients come first, everyone in our employee base matters, and everyone has some equity skin in the game, can create a terrific environment. That is important to me and to the senior leadership here, and I’m thrilled with the way that is working out. I’m a strong believer that making that impact to patients with safe and efficacious immunotherapies, and ensuring the right immunotherapies are getting to the right patients – all of that drives the business opportunity that we have. Through our Celgene deal and through programs that aren’t necessarily part of the Celgene deal, we want the ability to commercialize our own products, if approved. It is all driven by that goal to make an impact in cancer patients’ lives.

Rich Soll: What do you see as your near-term milestones?

Richard Murray: We’ve embarked on our Phase 1 / 2 study for JTX2011. As a public company now, we’ve been clear about our upcoming key milestones. We were invited to a symposium at AACR on the science. In the first half of the year, we will be disclosing our Phase 1 safety, PK and PD data at the ASCO meeting in June. In the second half of the year, we’ll have a first look at data from some of the Phase 2 portion of the study, which was designed to evaluate preliminary efficacy.

Rich Soll: I think we’re all on the edge of ours seats for that one. We know about the great promise of this science, but what do you see as the risk, and how are you mitigating it?

Richard Murray: I think we have a view here at Jounce – among the management team and within the culture – that we want to go after programs that will bring new innovation. We’re committed to that, and of course, within doing that is inherently a step toward more risk of testing things that to date have been untested. However, I think there is a way to optimize likelihoods of success. For example, we have chosen a path forward in immunotherapy that’s largely predicated on monoclonal antibodies as therapeutic modalities. We know each antibody is nuanced differently in terms of development and manufacturing, but it’s an established path forward as opposed to an immunotherapy approach that also requires a novel manufacturing path. That puts a bit of balance into that risk profile.

Rich Soll: Do you see Jounce as the leading company for these novel mechanisms?

Richard Murray: Certainly. As mentioned earlier, as you get away from the hot or warm tumors to the more refractory tumors, we think those will require novel mechanisms to make an impact. Our internal novel discovery programs evolve toward the colder tumors – that’s the right thing to do; those are the patients who have the highest unmet need. Staying on the cusp of the innovative new mechanisms and new biology is squarely in our mission.

Rich Soll: Do you have any closing comments?

Richard Murray: As we look at healthcare in the future, clearly the opportunity to provide real benefit is just fantastic news. But I do think we need to, as a community, look at the benefit being provided to the right patient and to the right patient groups. We are firm believers in this kind of precision medicine concept for the future – it’s one that we need to embrace, and it is a noble aspiration for all of us no matter where we sit in the field of human health.

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