Shaping the Future of Cancer Care: Dr Saurabh Saha of Bristol-Myers Squibb Impossible is Temporary: Dr Laurie Glimcher on the Future of Cancer Treatments
by Leah Kinthaert
On Wednesday, September 11 Leaders In had the pleasure of hearing Dr Saurabh Saha’s presentation “Precision Medicine: Shaping the Future of Cancer Care” at Xconomy’s Xcelerate event, part of Biotech Week Boston.
Dr Saha is the Senior Vice President of R&D and Global Head of Translational Medicine for all disease areas at Bristol-Myers Squibb. He is also the Site Head for Bristol-Myers Squibb R&D headquarters in Cambridge MA. Dr Saha was a Venture Partner at Atlas, a venture capital firm in Cambridge MA, and most recently served as President and Chief Executive Officer at Delinia. In 2017, he led the acquisition of Delinia by Celgene for $775 million.
The Bristol-Myers website describes Saha’s work: “Saurabh leads the hundreds of world-class researchers that make up Bristol-Myers Squibb’s translational medicine team. This innovative group aims to integrate scientific understanding into portfolio decision-making and enable and expedite the discovery and development of new medicines for patients. Saurabh’s integrated team uses emerging technologies to analyze vast amounts of data and gather essential insights, with the goal of uncovering life-changing treatments for some of the most challenging diseases facing patients.”
Dr Saha shared several slides on Bristol-Myers Squibb’s work with checkpoint inhibitors, so it’s important to first understand what those are. Cancer Research UK has a great explanation: “Checkpoint inhibitors are a type of immunotherapy. They block proteins that stop the immune system from attacking the cancer cells.” Basically the body has systems in place to stop pathogens, but proteins exist that interfere with this process. Checkpoint inhibitors help the body make sure T cells can do their job.
Key in Dr Saha and his team’s work is understanding the resistance to “checkpoint blockade”. Dr Saha apprised us of what they have figured out so far: “We know now that the tumor cell could be invisible to immune cells. The immune cells could be invisible to the tumor. Checkpoint inhibitor therapies boost T cell response. Not one therapy will be the panacea for all cancer. Our job is to help define those patient populations to better identify patients who will respond.”
Dr Saha’s talk echoed many of the ideas on “thinking outside the tumor” that Dana-Farber CEO Dr Laurie Glimcher conveyed earlier in the day with her Keynote at Biotech Week Boston: “Tumors change, immune biomarkers may be dynamic. We have to take into the account a myriad of factors, not just the tumor, but the genetics behind tumor itself, also the environment in which that tumor lives which is very complex. Host environment exacerbating the cancer, microbiome, and the genetics behind the immune system.”
The work being done right now in cancer immunotherapy is progressing fast, however, roadblocks exist where much more data is needed. Dr Saha elucidated:
“Two attributes have emerged in cancer: Inflammation and antigenicity – counting the number of mutations cancer has. Both are interesting markers which could predict response to immunotherapy. The technology we have is 80 years old, we need more precise technology. One has to collect huge amounts of data and then be able to generate the data to tell a physician ‘you should use this therapy’.”
Throughout his talk, Dr Saha made it clear that data was of primary importance if any progress is to be made in treating incurable cancers. He envisioned what the future would look like, once that data is acquired: “Ten years into the future, one can imagine that when a patient goes in to get diagnosis, their cancer has been profiled and will fall into a bucket, where there already has been a clinical trials with response rate and hazard rate for survival. (A doctor can say, for example) You need chemo, two checkpoint inhibitors, followed by a targeted therapy - based on the phenotype of your cancer. We’re doing this in a rudimentary way now, but this will explode.”
Dr Saha proceeded to give us a birds-eye view of some of the interesting, and in some cases, first-of-their-kind technologies that Bristol-Myers Squibb is working on: “One of the technologies we’re developing is gene expression. (It’s) been around for decades (but now we’re beginning) to really profile the tumor microenvironment. (If you) match therapies the with gene signature of a tumor, you can to make sure the T cells have a fighting chance.”
Dr Saha continued: “Use of AI can increase the accuracy and precision of an existing PD-L1 IHC approach. We’re really excited about combining machine learning and clinical trial datasets we’ve generated in house. We have a partnership with Path AI. (It’s about) understanding the limitations of what a pathologist can read Vs. AI to pick out what tumor cells are immune, where they are located and what markers are on the immune cells and tumor cells. And that’s just the beginning. In a clinical setting often cases where tumors are biopsied (by humans), come back negative for PDL1 and they are positive. It’s not fair for the patient.” Bristol-Myers Squibb has developed an in house technology that uses a single PET (positon emission tomography) scan to personalize cancer treatment. It gives real-time visualization of PD-L1 positive tumors. Dr Saha explained its importance: “You’d have to biopsy every single lesion, but this tech helps us ‘see’ (without doing that).” Dr Saha closed his talk with a request to the audience:
On Tuesday, September 11, Dr Laurie Glimcher, President and CEO of the Dana Farber Cancer Institute did a Keynote presentation entitled “Dana Farber: Cancer in the 21st Century” for Biotech Week Boston. Dr Glimcher is considered a pioneer in immunotherapy, a treatment that uses parts of a person’s immune system to treat cancer. Her inspiring talk offered an incredible history of immunotherapy, explained where we are now, and expressed what she hopes will happen in the next ten to twenty years.
Dr Glimcher opened her keynote by explaining Dana-Farber’s mission: “We need to remember why we’re here…it is because of the patients.” When someone is told “You have cancer” Dana-Farber wants their first reaction not to be “fear and dread, but some hope and some promise.”
Discoveries around immunotherapy have grown exponentially in the past ten years. Dr Glimcher used her own very personal experiences to show have far we’ve come: “We are in a revolutionary phase of developing new drugs for cancer. My mother died, ten years ago, there was nothing to treat her with. We didn’t have immunotherapy, targeted medicines.”
“Ten years later, an 11-year old girl named Emma had a very rare renal sarcoma. Her doctor in NYC told her to go to Dana-Farber, the #1 pediatric cancer center in the world. We genetically profiled her tumor to see if there were any mutations that we had drugs against. We have over 1,000 existing clinical trials… (and) had a clinical trial that had just launched, we were able to match her mutation with a new drug. Her tumor started to shrink.”
Dr Glimcher continued: “Today Emma is 13 and living life to the fullest. Her outcome would not have been possible 5 or 10 years ago. Her treatment was based on the latest research in cancer care. It illustrates how quickly we can move that science forward when we marshal the combined efforts of so many of us here today.”
Cancer has overtaken heart disease in wealthy countries to be the leading cause of death. Cancer is going to be the #1 killer around the world in the next decades if current trends continue. It is 40% of all deaths; one out of every two men, and one out of every three women will die of cancer and unfortunately, it is growing.
Dr Glimcher theorized why cancer is growing, and she believes it’s namely due to our ageing population and the increasingly unhealthy lifestyles of younger people. Obesity is a major reason that Dr Glimcher believes cancer is growing in young people. In the US, 1 out of 3 adults are obese, and 1 out of 3 children are obese.
By 2030, 1 out of every 2 children will be obese. “I believe obesity will replace tobacco as major cause of cancer”, said Dr. Glimcher.” But exactly why obesity causes cancer is not known. Dr. Glimcher threw out ideas such as the microbiome, or perhaps because obesity causes inflammation, inflammation causes cancer. Dr Glimcher expressed her immense concern as well as hope that the epidemic will create a sense of urgency.
As we’ve mentioned, immunotherapy helps our immune system to kill the pathogens in our bodies. Tumor cells contain something called neoantigens; naturally, our T cells, a type of white blood cell, should recognize them and kill them off. Cancer happens when T cells don’t do that. Immunotherapy attempts to remedy that and was initially discovered over a century ago by someone named William Coley. Dr. Glimcher gave us a history lesson: “(Coley) made the observation, when he removed a sarcoma if the wound became infected some of those patients went into remission. He postulated there is some system in the body that became activated against bacteria and viruses and in the process killed off tumor cells. He made medicine out of the bacteria, called it Coley’s toxin. People thought he was a quack. This was supplanted by radiation therapy and chemotherapy.”
Fast forward to the late twentieth century when James Allison and Tasuku Honjo: “Made discoveries that led to the development of ‘checkpoint inhibitors,’ drugs infused into patients to block molecules that put the brakes on T cells. By releasing these brakes, the body’s own immune system is able to fight cancer.” Now due to these therapies, we have a disease such as metastatic melanoma where Dr Glimcher points out: “ 20% are still alive today, that’s only 20% but it’s a heck of a lot better (than where we used to be).” She continues: “PD-1/PD-L1 is now the mainstay of immunotherapy… (we know there are) ten tumors that are responsive to checkpoint blockers. …. We can treat 20% (of cancer patients) successfully with immunotherapy.”
PD1 and PD-L1 are proteins that are on the surface of cells. Abcam.com explains their importance: “PD-1 and PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors that can halt or limit the development of the T cell response. The PD-1/PD-L1 interaction ensures that the immune system is activated only at the appropriate time in order to minimize the possibility of chronic autoimmune inflammation.” Immunotherapy blocks this so the T cells can do their job.
Dr Glimcher expounded on how new technology is helping fight tumors: “A normal cell becomes malignant because it has a genetic mutation in the DNA. Over the last decade, scientists have sequenced tumors of patients. Dana-Farber is the only cancer center that offers that to every patient. (This is) not covered by insurance, they raise philanthropic dollars to offer this. We’ve identified most of the genetic mutations that exist. This enables us to develop drugs that block and disable mutation. We’ve turned some cancers into a chronic and manageable disease.”
One of the newest branches of research is taking a look at the microenvironment that lives around a tumor, Dr Glimcher elucidates: “The hostile immune microenvironment that lives around a tumor…. It’s like a moat around a castle. So even if you have activated your T cell, if it can’t get across the moat it cannot do anything. We’ve begun immune profiling, we not only sequence the tumor but every single immune cell that surrounds the tumor. Why does one patient respond (to immunotherapy) when another does not, what’s different about their immune system?”
Big data is key in getting to the bottom of why this is the case. Dr Glimcher continues:
“If you gather all the right data when the patient walks in the door and analyze that data, eventually we should be able…to predict what drugs that patients going to respond to. We don’t put them on a drug or a clinical trial that is not going to help them.”
To effectively use data, a scientist at Dana-Farber has developed a tool called PRISM, explained by Dr Glimcher as an “algorithm that picks out twenty most important data points in every medical record.” It is “ a powerful statistical tool that combines scientific graphing, nonlinear regression, understandable statistics, and data organization” and is being shared with the scientific community, in order to help find cures faster.
Dr Glimcher closed her talk with a moving call to arms to the biotech and pharma community. “So many cancer treatments were discovered in the 20th century. I believe we are at an inflexion point... We are focusing on the science that underlies the deadliest cancers. Hodgkin’s lymphoma, leukaemia, prostate, breast, and bladder cancers. There are some cancers we have failed to affect such as pancreatic, the third leading cause of cancer death, brain cancer, and ovarian cancer. They are silent cancers, not obvious like a melanoma. By the time they present they are widely metastatic. The top cancer centers have the responsibility to attack those cancers.”
Dr Glimcher discussed the cutting edge of innovation going on right now at Dana-Farber - “Target Teams” which are based on the concept of Skunk Works® that were developed at Lockheed Martin. Dr Glimcher elaborated: “(You have an) unsolvable problem, put together a multidisciplinary team. Give them all the resources. (Make it ok that) we know you’re likely to fail… be bold, innovative, take high risks. (We have a) Pancreatic target team (with a) biologist, geneticist, clinicians, bioinformaticians… all different people coming together. We are seeing some hopeful signs. We discovered that with pancreatic cancer 50% comes from inherited mutations.”
Dr Glimcher continued: “I’m tired of seeing friends and colleagues die of pancreatic cancer and glioblastoma… How many of the twenty-thousand proteins (in existence) have been targeted by FDA approved drugs? Just one thousand. We have many proteins who have been claimed to be undruggable, we don’t believe that. The mission is: ‘What we can do to make cancer a chronic disease that is manageable like diabetes.’” There are hopes that the future of cancer treatment will be proactive instead of reactive.
