Parker Institute for Cancer Immunotherapy -Tumor Neoantigen Selection Alliance (TESLA)

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Mana Chandhok:

Hi everyone. Welcome to this podcast from Cambridge Healthtech Institute, for the Impact Conference, which runs December 5th to 7th, 2017 in San Diego, California. I'm Mana Chandhok, an associate producer. We have with us today one of our speakers from the Neoantigen Based Personalized Immunotherapy Track, Dr. Danny Wells, who is an informatic scientist at the Parker Institute for Cancer Immunotherapy. Dr. Wells, thank you for joining us.

Danny Wells:

Thank you, Mana. I'm excited to be talking to you today.

Mana Chandhok

Please explain a little about what the Parker Institute is and what the Tumor Neoantigen Selection Alliance, or Tesla, Collaboration is.

Danny Wells:

The Parker Institute is a collaborative network that brings together the best researchers in the nation and the world to collaborate on science to ultimately help empower our bodies, or the body's, immune system to destroy cancer. We were founded in mid April 2016, although we'd been in the works for about a year before that with a $250 million grant from the Parker Foundation, founded by Sean Parker.

The structure of our institute is a little unique. Along with our central office in San Francisco, where I sit, we have six institutes that we work really, really closely with and kind of serves our scientific arms to what some people call the central brain here. Of course, all the best scientists are at all these institutes. Those institutes are UCSF, Stanford, UCLA, MD Anderson, The University of Pennsylvania and Memorial Sloan Kettering Cancer Center. The goal of the institute, kind of like our belief, is that by bringing the best scientists together and then giving them the tools and resources they need, like one stop shop clinical trials and legal help and informatics and data science, which is what I do, that we can kind of vastly accelerate the translation of breakthroughs and ultimately kind of drive the creation of new treatments.

The Tesla Consortium that you mentioned is actually part of this, so I'll talk about Tesla kind of briefly. Tesla is a global research consortium that was founded at the Parker Institute along with our collaborators at the Cancer Research Institute, focused on figuring out how to better identify neoantigens, which, for those maybe unfamiliar, are small pieces of degraded protein inside of a cell that contain a mutation, where these protein peptides would not be found natively in a healthy cell, and they are presented by the tumor, and then allow the immune system to recognize that tumor cell as foreign, and thus serve as a path to recognition of the tumor by the immune system.

The goal with Tesla is really to figure out, for any particular neoantigen, and some tumors like melanomas could have thousands of different, unique neoantigens derived from different mutated genes. What makes a good one? What are the properties of that neoantigen? If it's high expression or high [inaudible 00:02:51] penetrance throughout the tumor, or strong binding to HLA or what have you. What are those features of a particular eight to 12 mer peptide, that really elicit a very strong anti tumor immune response.

Taking that knowledge, we hope to be able to translate that to be able to develop, or to improve the development, of computational algorithms to detect neoantigens from tumor exome data, which is sequencing the tumor, along with taking the [ar-nay-seek 00:03:22] of that tumor, and then being able to predict, which neoantigens found there will elicit a strong immune response. Those are kind of the short term goals. We ultimately hope to take all of those goals together, or take the results of this whole project, and be able to, hopefully, build better methods for developing personalized vaccines that can be tailored to an individual patient's tumor, and thus, hopefully have fewer side effects compared to the side effects we see with say, [inaudible 00:03:50] therapy.

The consortium is, frankly, quite amazing. It's 30 of the most prominent research groups in neoantigen discovery, from groups in academia, non profit, industry, including Genentech, Bristol-Myers Squibb, Neon Therapeutics, as well as places like Washington University in St. Louis, The [Brit 00:04:07] Institute. TalTech is involved, and many more. There's 30 plus groups at this point, so it's too many to list.

Mana Chandhok:

What are some of the biggest challenges that scientists working on neoantigen based therapeutics are faced with today, and how can we overcome them?

Danny Wells:

By their nature, neoantigen therapies are personalized. They're tailored to the individual, and that comes with kind of incredible benefits, but it also means that every patient has to be evaluated on a case by case basis, and this is kind of very, very different than the way some immunotherapies are right now, where we can use a single molecule, say like anti-PD-1, developed by Merck for thousands of patients. In neoantigen therapies, every patient has to be evaluated individually. This creates some bottlenecks in terms of: How can we do this at a rate that's going to be clinically relevant? We can't take three months to take out a patient's tumor, process their DNA, sequence it, identify punitive neoantigens, and then validate those in the lab. That period of time is much, much too long for the patient, so accelerating that pipeline where we can do this in two weeks is a tremendous challenge. I think it's going to require both new computational methods as well as new outside technologies that are really sensitive and high [inaudible 00:05:19] compared to what we have now.

Along with that, the biggest issue, or one of the big issues with personalized vaccine therapies has been, and remains, making them affordable and making them something that every patient can benefit from. It's one thing to say we can treat one patient in a clinical trial, but it's another one to say, "How can we make this a therapy that everyone is going to ultimately be able to have access to?" For personalized therapies, where you're engineering new antibodies to be put into a human, that's always going to be expensive when done with good manufacturing practice, and so really figuring out where are the ways we can make that more efficient are really important.

On the other side, on how the scientific or biological side, I would say what's more of the operational side, I think one of the biggest challenges in all of immunotherapy and certainly with neoantigens is figuring out how to expands the application of these therapies to tumors with what's called a low mutation burden, or tumors, which don't have a lot of neoantigens. These, right now, are where a lot of neotherapies are having trouble, so we're having just totally tremendous success in melanoma and now in non small cell lung cancer and some other cancers. But, how do we get this to, say, like a pancreatic cancer, which traditionally may only have five or 10 possible neoantigens that are expressed? If we could develop vaccines that could target those handful of neoantigens and strengthen an immune response, those could potentially be synergistic with things like PD-1 and kind of give the immune system a helpful nudge in the right direction for where it should be looking, and so that's a totally tremendous challenge, but one that I'm excited to see the scientific community take on.

Mana Chandhok:

What do you see in the future for clinical applications of neoantigens?

Danny Wells:

Like PD-1 therapy or anti PD-1 therapy, I think that in neoantigen based monotherapies, have a potential to be successful on their own, but when I think about the area that I am really the most excited about is kind of similar to the PD-1 space right now, is combining neoantigen vaccines, but other modalities of immune therapy, to hopefully improve treatment. There's a really beautiful example of this that just coincidentally came out, I guess yesterday or today, in nature, from Cathy Wu and her collaborators at the Dana-Farber Cancer Institute. They actually developed a neoantigen based vaccine and did a phase one trial in six patients, and what they saw was really, really encouraging. In 2/3 of those patients, the vaccine by itself was able to elicit a durable clinical response, so you just give them the vaccine and they were treated.

However, in 1/3 of the patients, so two of the patients, the vaccine monotherapy didn't elicit a durable response by itself. However, if you gave PD-1 after you gave the vaccine, the PD-1 response was tremendous, so you had patients having a complete response and having a durable clinical benefit from PD-1 after treatment with the vaccine, which is actually quite rare, so for PD-1 to elicit a complete response, essentially, to allow the immune system to totally wipe the tumor out, they mentioned in the paper, happens in about 6% to 7% of cases, and so here it happened two out of two for these people who had these vaccines. The idea of using a vaccine to kind of stimulate the immune system and then get it boosted, and then to use PD-1 to release the break, to release the tumor induced immune suppression and allow the immune system to use the clues and the breadcrumbs that the neoantigen vaccine laid to target the tumor is tremendously exciting and I think that's where we're really going to potentially see some real breakthroughs.

Mana Chandhok:

What new frontiers in cancer immunotherapy are you particularly excited about?

Danny Wells:

I'd be remiss to say, I'm extremely [inaudible 00:08:48] and excited about neoantigen based therapies, but there's a few other things that we're working on here, and I'm a part of, that I'm really, really excited about. One of those things is that a lot of the new discoveries that we're seeing in cancer immunotherapy are really forcing us to begin to treat cancer more systemically, and something that's wrong with our entire bodies, and that can be addressed by targeting different areas of our bodies.

One example, we work with Dr. Jennifer Wargo at MD Anderson Cancer Center. In the past couple months, she's been presenting some extremely compelling evidence that the composition of a patient's microbiome can shape how they respond to PD-1 therapy, and so this is the presence or absence of certain microbes is very, very predictive, essentially night and day for if you're going to respond. The question then is: Why is this? What is it about these particular bugs that predict that you're going to respond to PD-1? And two, if we somehow therapeutically drive a particular patient's microbiome to look more like that of one of these super responders, one of these people who has these microbiomes that predict response, will that change how they respond? Can we shape response to a cancer drug by changing the bacteria that's in your gut?

That's kind of amazing that we can now think about treating cancer non locally and kind of far away, so to speak, from the site of the tumor, because our immune system is always learning things all throughout our body and bringing that information and kind of sharing it, or it's getting distributed throughout our bodies. That's one area that I'm really excited about.

We also work with a scientist at UCSF, Matt Spitzer, who's done a lot of really amazing work to show how a systemic immune response is required for an effective response to PD-1 therapy, and I think you'll see a lot more, or a much deeper understanding, of why that is the case coming out soon.

The other area that I'm really excited about is some of the new technologies that we're seeing get developed, and one that will kind of allow us to take more measurements, faster measurements, deeper measurements, et cetera. The one that I'm ... Of the many, and there's so many things happening here right now, but one of the technologies that I'm really excited about is called Multiplex Ion Beam Imaging. This can measure upwards of 40 different markers or cell [inaudible 00:11:12] markers in solid tissue, so it can be thought of as being kind of like a mass cytometer, or like a very, very high dimensional flow cytometer, but something that can work in [inaudible 00:11:23] embedded tissue and it's also able to preserve spatial information, so you're able to say, not only. What are the markers on this cell? Is this a CD8 positive cell? Is this a CD25 positive, 553 positive cell, or what have you? But, really say, "Okay, and who are that cell's neighbors and what do they look like?"

What we're learning, and it's really, really early days for this, but what's starting to be understood is that cell state and what a particular cell looks like is contextual and depends on its neighbors. What an activated CD8 t cell looks like depends on the CD4 cells and the dendretic cells around it and what they look like. I think that's ... It's almost a profound reshaping, or it has the potential to kind of profoundly reshape how we think about the immune system, as this very flexible, truly adaptive community of cells, who are always kind of informing each other or changing each other's behaviors through secreted molecules. That deeper understanding, I think, is going to allow us to figure out how to more deeply penetrate or break up the tumor micro environment, when we really understand. What are these cells looking like who are inducing immune suppression and why are they doing that and who are they affecting?

We can really get that kind of knowledge about this whole network and this 3D embedded mesh of cells. I think that's going to really allow us to identify therapeutic targets that allow the immune system to more directly target a tumor and ultimately lead to a cure, or at least a durable response.

Mana Chandhok:

Dr. Wells, thank you for your time and insights today.

Danny Wells:

Thank you so much, Mana.

Mana Chandhok:

That was Danny Wells, and informatic scientist at the Parker Institute for Cancer Immunotherapy. He'll be speaking at the Neoantigen Based Personalized Immunotherapies Track at the upcoming Impact Conference, which takes place December 5th to 7th, 2017 in San Diego, California. If you'd like to hear from him in person, please visit for registration information and enter the key code, podcast. I'm Mana Chandhok. Thank you for listening.