“We’ve all been touched by cancer,” said Andrew K. Tsai, co-chairman of the Cancer Research Institute (CRI) Board of Trustees and co-founder and chief investment officer at Chalkstream Capital Group, as he kicked off CRI’s inaugural “Immuno-Oncology: A Future Look” event for healthcare investment analysts and media on Friday, June 21, 2019, at the New York Academy of Sciences in New York City.
“I lost my mom to cancer when I was a kid, I’ve had a couple battles with cancer myself,” Tsai continued. “It’s what brought me to CRI.”
“CRI was started 65 years ago, on a view that harnessing the immune system could be the ultimate cure for cancer. Now, for the first 55 years or so, there wasn’t much proof of this.” Nonetheless, Tsai said, “What’s amazing about [CRI] is that they persisted.”
Andrew Tsai, Co-Chairman of CRI's Board of Trustees
“CRI stayed the course, and we’re now reaping the benefits of that persistent vision,” said Jill O’Donnell-Tormey, Ph.D., the chief executive officer and director of scientific affairs at CRI. “But as we know, the majority of cancer patients are still not yet benefiting from immunotherapy and there’s a great deal of work to be done before we realize its true potential.”
Today, as immunotherapy is poised to revolutionize treatment for all types of cancer, O’Donnell-Tormey added, “CRI remains committed to the mission we’ve always had: We believe that the support of basic and translational research is critical.”
Spurred by recent successes, CRI has also amped up its efforts to speed discovery in the clinic via its Anna-Maria Kellen Clinical Accelerator. Through this program powered by collaboration with nonprofit, academic, and industry partners and fueled by CRI’s venture philanthropy fund, CRI supports immunotherapy clinical trials and, to help guide its investment decisions, also “developed the first in-depth quantification of the immuno-oncology landscape.”
“Our unique clinical strategy is a collaborative model that’s helping to inform and de-risk immune-based combination therapies and accelerate their development… and [CRI’s Immuno-Oncology Landscape] is also a resource that is available, and I think valuable, to the entire field.”
Additionally, with an international scientific brain trust that has been cultivated over the last six-plus decades, CRI is able to convene the world’s leaders in the immunotherapy space.” As O’Donnell-Tormey put it, this “really helps position us as a global thought leader.”
This event showcased that ability and the strength of the CRI network in both the academic and biotech or pharmaceutical industry spheres. It was, in many ways, a logical extension of CRI’s time-tested formula for fostering collaborations that help advance the field.
O’Donnell-Tormey led a panel with three immunotherapy luminaries from the CRI Scientific Advisory Council, including director and 2018 Nobel Laureate James P. Allison, Ph.D. Allison, who serves as the chair of immunology and the executive director of the immunotherapy platform at the University of Texas MD Anderson Cancer Center, was joined by Philip D. Greenberg, M.D., the head of immunology at the Fred Hutchinson Cancer Research Center, and Robert H. Vonderheide, M.D., D.Phil., the director of the Abramson Cancer Center at the University of Pennsylvania.
Following the academic panel, CNBC Biotechnology and Pharmaceuticals Reporter Meg Tirrell hosted an Industry Fireside Chat with Awny Farajallah, M.D., vice president, head U.S. Medical Oncology at Bristol-Myers Squibb, and George D. Yancopoulos, M.D., Ph.D., founder, president, and chief scientific officer at Regeneron.
Overall, the discussions shed light on both the scientific hurdles and the organizational challenges that the field is confronting.
Allison, whose recent Nobel Prize cited his pioneering work in checkpoint immunotherapy, began with the idea of using these treatments as a “core” to build around in order to help more patients. Checkpoint immunotherapies work fairly well on cancer types such melanoma and lung cancer, which usually have high levels of mutations and are “hot”—meaning that they’ve already been recognized and infiltrated by killer T cells. However, most tumors are cold, so Allison said the goal now is “getting pancreatic cancer, glioblastoma, and some of the other [cancer types] that have not responded well yet, to respond.”
And to do that, a better understanding of why patients don’t respond will be needed.
There are biomarkers—such as PD-L1 expression, tumor mutational burden, and T cell infiltration—that can tell doctors whether certain patients are more likely to respond. “But there’s no biomarker that excludes a patient from responding yet,” noted Greenberg. “And that’s what we need to get because these therapies are, unfortunately, expensive and have some risk of toxicity.”
Dr. Jill O'Donnell-Tormey moderates an academic panel with Drs. Jim Allison, Phil Greenberg, and Bob Vonderheide.
Checkpoints, though, are just one factor in the tumor microenvironment that dictates the success of immune responses against cancer. In pancreatic cancer, for example, which is usually driven by a mutated KRAS oncogene, immune cells known as macrophages appeared to be one of the main causes of these tumors to be cold. As a result, targeting these macrophages could potentially make immunotherapy more effective.
Vonderheide discussed such an approach that he’s exploring through a CRI-funded pancreatic cancer clinical trial, which is using the combination of a checkpoint immunotherapy with chemotherapy as well as a treatment that targets and activates macrophages and dendritic cells in patients with metastatic disease. Thus far, the preliminary results from the Phase 1 study have been extremely promising, and patients have already been fully accrued for the Phase 2 portion.
“It’s really an amazing time. I’m pleased to be at the epicenter of what’s going on,” Vonderheide stated.
A big focus of this and other CRI trials is that the exploratory scientific component is built into the plans. Not only are doctors looking at whether the patients are responding in terms of tumor shrinkage, but they’ll also be looking at a number of other factors, including how the identity and activity of immune cells change during treatment, to try to discern the mechanisms behind outcomes. These clues could then eventually be used to help more patients benefit from immunotherapy.
Greenberg referenced those results in pancreatic cancer in stating that sometimes it might be better to recruit these cancer-supporting cells rather than deplete them. He also discussed advances in his personal area of expertise—cellular immunotherapy. Some of these approaches—like T cell receptor (TCR) engineered and chimeric antigen receptor (CAR) T cells—essentially enable immune responses to be generated from scratch. Through synthetic biology, these cells can also be modified in other innovative ways. For instance, while some signals cause normal T cells to shut down, synthetic T cells could be engineered to react to these negative signals as if they were positive ones—then they could become more strongly activated and be able to overcome an immunosuppressive microenvironment as a result.
Improved models will also help the field better understand the underlying mechanisms that dictate either the success or failure of immune responses against tumors. “Genetically engineered mouse models now really do replicate a lot of the issues of the disease,” said Greenberg. “They’re not perfect but, increasingly, we’re understanding what their imperfections are and you can build that in.”
Another topic of interest that came up during both sessions was the impact of the microbiome, specifically the trillions of bacteria that inhabit our gastrointestinal tracts. Allison pointed to the interesting finding that probiotics were linked to worse outcomes in patients treated with immunotherapy, and work from several groups that showed certain bacteria were associated with responses to immunotherapy.
However, “we don’t know enough yet about how to predict it,” Allison acknowledged. “The data is very clear…the role of the microbiome in responding to cancer treatments is unequivocal. The problem is that we are in the infancy of trying to understand that.”
During the fireside chat, Farajallah and Yancopoulos also discussed the merits of the microbiome.
“Obviously the microbiome is important for a lot of different settings in patients,” said Yancopoulos. “We’re going to certainly find areas and applications” where it can help, but Yancoupoulos cast doubt on the idea and that he thinks “too much value is being given to it… right now.”
“We take a different approach,” said Farajallah. “It is important for us to understand it. We know that there is a role there… we just have to systematically and scientifically approach it.”
Meg Tirrell (CNBC) moderates an industry fireside chat with Drs. Awny Farajallah and George Yancopoulos
When asked how he could be so confident about the promises of the microbiome’s benefits being oversold, Yancopoulos acknowledged that there will be diseases where it’s useful and plays a direct role, but also stressed that “cause and effect is really important… and science tells you that when you have little data and great enthusiasm, most of the time that enthusiasm is unwarranted.”
“That’s exactly why we need to study it,” responded Farajallah.
Moving on, Farajallah stressed the need to refine how we care for patients as well as monitor them throughout their journey—in order to understand how tumors evolve over time and in response to various treatments. As Yancopoulos put it, “You try to understand why patients are responding and why they’re not, and to understand the biology and the mechanism.”
Regarding the cost of treatments, Yancopoulos had a frank answer: “I do personally think that unfortunately, compared to drugs outside of cancer, I think that most of these cancer drugs are a little too highly priced. And I think certainly when we’re talking about combinations… we’re going to have to figure out and come up with a much more responsible way to control pricing there because we can’t be layering a $150,000 drug on top of another drug that costs that much as well. We’re going to have to deal with that, and if we don’t figure out how to deal with it, somebody will figure out how to deal with it for us.”
Farajallah also discussed the importance of efforts to recruit patients from different backgrounds, especially underserved communities, in order to learn more about how different factors can influence outcomes—so that doctors can maximize immunotherapy’s benefits for more patients.
Turning to machine learning, Yancopoulos called it “a useful tool” that can “recognize patterns in data sets that are going to provide you with hypotheses.” However, he cautioned, this pattern recognition is only as good as the structure of the data.
Looking toward the future, both were optimistic, and emphasized the possibilities presented by ongoing technological advances.
“Now that we made—thanks to Jim [Allison]—this big insight that we can harness the immune system, we’ve got to do, collectively, a better job. And it’s going to involve all these different new ideas that people are talking about,” said Yancopoulos. “I think there will be incremental advances and hopefully we’ll crack [individual cancer types] and maybe there will be a big breakthrough…this is why we all need to be investing in research at all levels.”
At the end of the event, CRI announced its newest research investment, by introducing three scientists from the inaugural class of its prestigious Lloyd J. Old STAR Program (Scientists Taking Risks).
Along with Allison, O’Donnell-Tormey greeted Yvonne Y. Chen, Ph.D., of the University of California, Los Angeles and member of the UCLA Jonsson Comprehensive Cancer Center, Amanda W. Lund, Ph.D., of Oregon Health & Science University, and Gregory F. Sonnenberg, Ph.D., of Weill Cornell Medicine.
Drs. Jim Allison, Amanda Lund, Yvonne Chen, Gregory Sonnenberg, Jill O'Donnell-Tormey
Through this program, these scientists—along with Alexander Marson, M.D., Ph.D., of the University of California, San Francisco, and Andrea Schietinger, Ph.D., of Memorial Sloan Kettering Cancer Center, who did not attend the event—will receive $1.25 million over five years to provide a degree of flexibility and freedom for the investigators to explore out-of-the-box and disruptive avenues of research in cancer immunotherapy.
The kind of research, we hope, with the potential to revolutionize the whole field of immuno-oncology once again.