The rapidly shifting field of cancer research is moving toward tailored, individualized treatment strategies that offer the greatest possible benefit for patients. Partnering Insight sat down with Saurabh Saha, M.D., Ph.D., SVP, Global Head of Translational Medicine, Cambridge, Mass. Site Head at Bristol-Myers Squibb (BMS), to hear his perspective on the current landscape, what’s on the horizon for immuno-oncology (I-O) and how BMS is advancing research in precision medicine.
Q: What can you tell us about the current state of oncology drug development?
A: It was only about two decades ago that the emergence of drugs directed at specific oncogenes ushered in the first breakthroughs in targeted therapeutics to treat cancer. This genetic-directed approach laid the foundation for the current era of precision medicine in cancer. Over the past ten years or so, the development of immunotherapies, which work with the immune system to fight cancer, has heralded a new focus on I-O drug development that has really transformed how we treat certain cancers.
While we are starting to see long-term remissions in some patients receiving I-O therapies targeting well-established immune pathways like PD-1/PD-L1 or CTLA-4, the problem is that not all patients respond, and if they do, maybe they only respond for a limited time. Researchers are now utilizing several innovative technologies like image analysis, artificial intelligence and bioinformatics to explore tumor biology on an individual patient level. The idea is that if we use all of these cutting-edge tools we can better understand the nuances of the immune system, and of cancer, and how the two intersect and change over time, and all this information can help us better predict a patient’s response to therapy.
Q: What are some challenges that we’re seeing with Immuno-Oncology?
A: Overcoming I-O resistance is one of the toughest challenges we are facing right now. There are two different types of resistance: primary and acquired resistance. In patients with primary resistance, their tumors do not respond to treatment from the outset. In acquired resistance, tumors may initially respond to therapy, but eventually stop responding. We’ve seen a small subset of patients that have durable responses of more than two years. That leaves a significant proportion of patients—around 80 percent depending on the type of cancer—whose tumors are treatment resistant or become non-responsive after a few months. We need to find new pathways and new ways to target the immune system to increase responses for these patients.
The second half of this challenge is validating these novel pathways and therapeutic targets in patients. It can be challenging for researchers to obtain tumor samples from patients before and during treatment, as well as after resistance occurs, making it difficult to understand how tumor biology changes over time.
Q: How can researchers begin to overcome these challenges?
A: Through translational medicine, we are pioneering research to better understand cancer biology and its intersection with the immune system to address these challenges. For example, an emerging area of research is examining both inflammation and antigenicity, which may enable us to more accurately map tumors for therapy. Antigenicity is a measure of a tumor’s ability to generate antigens that T cells can recognize. Low antigenicity can make a tumor less likely to respond to I-O therapies. We’re also focusing on the role of inflammation in resistance, as hot, or inflamed, and cold, or not inflamed, tumors respond differently to I-O therapies.
Our integrated translational medicine team is tackling these complex scientific questions at our dedicated research sites. For example, we recently established a research and development facility in Cambridge, Mass. Here, our scientists are solely focused on identifying the underlying biologic and genetic factors that may explain why a tumor becomes resistant to immunotherapy, and to overcoming this challenge.
Q: Why did BMS decide to establish a research presence in Cambridge?
A: Cambridge is a nexus of healthcare innovation. In our research facility there, we’ve invested in next-generation science, including single-cell RNA sequencing, genomics, proteomics, experimental research, bioinformatics, imaging and digital pathology, to help enhance our understanding of resistance mechanisms and uncover why some patients do not initially respond or stop responding to treatment. With some of the nation’s top cancer research centers in our backyard, our presence in Cambridge allows for rapid knowledge sharing with leaders who are also working to tackle these challenges. We recognize that cancer is a heterogeneous disease and will require a strong collaborative effort to advance the development of new and hopefully more effective therapeutics.
Q: How can biomarker research help achieve the goals of precision medicine?
A: Optimal biomarker research starts with the tumor tissue sample. With fresh tissue, its gene expression captures what’s going on with the patient. But when you bank and preserve the sample, you often lose the architecture of the tumor sample, which can mean the original gene expression profile is altered. Fresh tissue samples are also better suited for innovative technologies such as single cell sequencing, which helps researchers understand the various immune and tumor cell populations. This technique is more challenging with preserved tissue samples, highlighting the importance of fresh tissue in helping researchers identify the set of biomarkers that make tumors unique.
But we haven’t always used this approach. For the past ten years, administering I-O therapies has largely been based off a patient’s PD-L1 levels, as expression of this protein can be a good predictor of response for certain cancers. While we’ve made great progress, we’ve learned that no one biomarker can tell the entire story. It takes detailed mapping of multiple biomarkers to help predict how a patient may respond. This focus on composite biomarkers can help us understand—and then treat—individual tumor biology in greater detail. The ultimate goal is to identify the right combination of therapies—likely based on a combination of biomarkers—for each individual patient as early as possible after diagnosis, and have the ability to better predict how that therapy will need to change over time.
Q: How close are we to achieving precision medicine for all cancer patients?
A: It takes time to collect enough tissue to test our hypotheses in clinical trials, more time to understand a large amount of patient data and yet more time to do that prospectively—to identify specific biomarkers, administer specific therapies and then watch and analyze the results. By using technologies like artificial intelligence, we are processing massive amounts of data significantly faster and with more accuracy than ever before. In fact, we’ve already seen early success with this approach by testing new hypotheses with biomarkers beyond PD-L1, and by evaluating both inflammation and tumor antigenicity at once. There is a lot to look forward to in what technology can achieve for medicine, but we need to be patient too. I believe we will look back to this point of time in hindsight and see this as an inflection point—where the technology is catching up with the science. For now, know we are constantly working to discover and leverage new technologies and methods of analyses that will bring us another step closer to precision medicine for all patients with cancer.
Join Dr. Saha on September 11, 2019, for his keynote address at Xcelerate, during Biotech Week Boston, to learn more about how precision medicine is shaping the future of cancer care.