Cancer Immunotherapy: 2020 Research Update and a Look Ahead

Each year, advances in immunotherapy bring its lifesaving benefits to bear against more and more types of cancers. In addition to novel treatment strategies, a better understanding of immunotherapy’s mechanisms is allowing doctors to tailor their approaches to fit individual patients.

In this webinar for patients and caregivers, Padmanee Sharma, MD, PhD, of the University of Texas MD Anderson Cancer Center, discusses what breakthroughs and advances might lie ahead for the field of cancer immunotherapy in 2020 by highlighting the challenges and opportunities at the cutting-edge of immuno-oncology.

Learn about exciting developments in cancer immunotherapy research in the year ahead and how these aim to improve cancer patient treatment outcomes by:

• Testing promising new treatment combinations for hard-to-treat cancers like brain, breast, pancreatic, and prostate cancers
• Finding new, less invasive ways to screen patients for biomarkers that can guide personalized patient treatment plans
• Learning as much as possible from each patient in order to make existing immunotherapies more effective and speed discovery of new treatment approaches  

Dr. Padmanee Sharma is a Professor in the departments of Genitourinary Medical Oncology and Immunology, and the Scientific Director for the Immunotherapy Platform at the University of Texas MD Anderson Cancer Center. She is also the Co-Director of Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center. She is a trained medical oncologist and immunologist whose research work is focused on investigating mechanisms and pathways within the immune system that are responsible for tumor rejection and clinical benefit. She is the Principal Investigator of multiple immunotherapy clinical trials and conducts translational laboratory studies related to these trials. Her studies enable development of novel immunotherapy strategies for the treatment of cancer patients.

Dr. Sharma received the Emil Frei III Award for Excellence in Translational Research in 2016 and was inducted into the American Society for Clinical Investigation (ASCI) in 2018. She is the recipient of the 2018 William B. Coley Award for Distinguished Research in Tumor Immunology. In addition to the CRI Scientific Advisory Council, she is a member of the CRI Clinical Accelerator Clinical and Scientific Advisory Committee.

The "Cancer Immunotherapy and You" webinar series is produced by the Cancer Research Institute and is hosted by our science writer, Arthur Brodsky, PhD The 2020 series is made possible with generous support from Bristol-Myers Squibb and Foundation Medicine.
 
Browse our Cancer Immunotherapy and You Webinar Series playlist on YouTube or visit the Webinars page on our website to see other webinars in this series.

TRANSCRIPT

Arthur N. Brodsky, PhD: Hello, and welcome to the Cancer Research Institute Cancer Immunotherapy and New Patient Webinar Series. Today is Wednesday, January 8, 2020. And the title of today's webinar is Cancer Immunotherapy: 2020 Research Update and A Look Ahead. Before we begin, I'd like to thank our generous sponsors who have made this webinar series possible: Bristol-Myers Squibb, with additional support from Foundation Medicine. My name is Arthur Brodsky and I'm the senior science writer at the Cancer Research Institute, a nonprofit organization established 67 years ago, with a mission to save more lives by funding research that aims to harness the immune system's power to conquer all cancers.

This work has contributed to the development of lifesaving immunotherapies for a variety of cancer types. We present this webinar series to patients and caregivers to help them understand what immunotherapy is and how it differs from other treatments, to provide information on the latest developments in research and treatment, and to connect patients to immunotherapy clinical trials. Now it is my pleasure to introduce today's expert speaker.

Dr. Padmanee Sharma is a professor in the departments of Genitourinary Medical Oncology and Immunology, as well as the scientific director for the immunotherapy platform at the University of Texas MD Anderson Cancer Center, and also the co-director of the Parker Institute for Cancer immunotherapy at MD Anderson Cancer Center.

Dr. Sharma is a trained medical oncologist and immunologist whose research work is focused on investigating mechanisms and pathways within the immune system that are responsible for tumor rejection and clinical responses. She is the principal investigator of multiple immunotherapy clinical trials and conducts translational laboratory studies related to these trials which enable her to develop novel immunotherapy strategies for the treatment of cancer patients.

Dr. Sharma received the Emil Frei III award for excellence in translational research in 2016 and was inducted into the American Society for Clinical Investigation in 2018. She is the recipient of the 2018 William B. Coley award for distinguished research in tumor immunology, CRI's highest scientific honor, and a member of both the CRI Scientific Advisory Council and the CRI Clinical Accelerator clinical and scientific advisory committees. Thank you for joining us today, Dr. Sharma.

Padmanee Sharma, MD, PhD: My pleasure. Thank you for having me.

Arthur N. Brodsky, PhD: So 2019 capped an incredible decade for immunotherapy. And before we look at the upcoming year, I was hoping you could kind of quickly recap some of the most important advances and approvals from this past year.

Padmanee Sharma, MD, PhD: I think in 2019, we made a lot of advances with immunotherapy and focusing specifically on immune checkpoint therapy. I want to point out that we've had previous approvals, for example, in tumors like melanoma and lung cancer. And I think in the past year, we saw an approval in breast cancer for the first time. And that's exciting because for many people that we're treating breast cancer, the prior clinical trials in immunotherapy did not work as well. And for the most part, breast cancer is what we consider a cold tumor. And so to see that we could get treatment for breast cancer with clinical efficacy and clinical responses that led to FDA approval for a combination with an anti-PD-L1 agent plus chemotherapy for this tumor type was very reassuring. We still have a lot of work to do to get even more patients to respond in terms of breast cancer treatment, but I think we're starting to see now that it is possible. And 2019 was the year for that.

I think 2019 was also the year for another difficult tumor type which is pancreatic cancer, where we were able to see results with another combination trial, where we included an anti-PD-1 antibody with an anti-CD40 antibody and chemotherapy again in this novel triplet combination. And we’re able to see clinical responses for the first time in patients with pancreatic cancer as a result of these kinds of immunotherapies. So I think we have new approvals and new advances that we can build upon for 2020.

Arthur N. Brodsky, PhD: That's great to hear. And I'm really glad you mentioned– you brought up breast cancer and pancreatic cancer specifically, which as you mentioned, have been really hard to treat in the past. And hopefully, especially with respect to that pancreatic cancer one, while there haven't been that many patients treated so far, hopefully, it will continue to be effective as more patients are treated. So in that same vein, what might we be able to expect in terms of potential progress against some other hard-to-treat types of cancer in the coming year?

Padmanee Sharma, MD, PhD: Yes, I think outside of the breast cancer and pancreatic cancer space, we're also dealing with prostate cancer and glioblastoma multiforme, for example, as other tumor types that have not had approval with immune checkpoint therapy agents. And so these are still difficult to treat tumors that we're working with. In prostate cancer, we're beginning to see again that it will take combination strategies. And there were data presented with an anti-PD-1 and anti-CTLA-4 that looked promising in prostate cancer. And hopefully, as we see more data from larger numbers of patients, we'll be able to figure out whether or not that's a combination that can be moved forward for approval, hopefully, if we can see the data again in these larger trials, as well as the new PORTER trial, which is this clinical study where we're looking at an adaptive model as we take multiple agents in the combination for treatment of prostate cancer.

So in this PORTER study, we'll look at multiple different combination arms to see which combination can potentially be beneficial for patients with prostate cancer. So again, I think in the hard-to-treat cancers, such as breast, pancreatic, prostate, and glioblastoma, I'm hoping that 2020 will show new data that we can now look forward to possible approval of immunotherapy agents in these tumor types as well.

In the setting of glioblastoma, there have been new data to indicate that myeloid cells are an important component. And although we've been targeting a lot of T cells with the immune checkpoint therapy agents, such as anti-CTLA-4 and anti-PD-1, I think in 2020, we'll start to see targeting of myeloid cells as well as a combination strategy with the previous anti-CTLA-4 and anti-PD-1 agents to hopefully get clinical responses in tumor types like glioblastoma.

Arthur N. Brodsky, PhD: We share that hope as well. And just real quick, I was wondering if maybe you could elaborate a little bit on what the myeloid cells are. Obviously, I think T cells kind of get most of the attention. And sometimes, it might be easy to forget that there are other cells in the tumors such as the myeloid cells that can really dramatically influence outcomes.

Padmanee Sharma, MD, PhD: Absolutely. I mean, T cells, of course, are the soldiers. So T cells go out to do the job of attacking and killing the tumor cells. But the T cell response is dependent on other cells within the immune system, such as dendritic cells and myeloid cells. And if myeloid cells give out signals to the T cells that make the T cells stop working, or make the T cells not capable of becoming activated, then those T cells will never be able to do their job against the tumor cells.

So we have to study the myeloid cells, for example, to understand what signals they are propagating to the T cells within the tumor microenvironment, and how can we manipulate those signals from the myeloid cells so that they are giving the T cells the right signals for the T cells to go out and be soldiers against those tumor cells?

Arthur N. Brodsky, PhD: Yeah, I think it's definitely a very exciting space. And hopefully, as your studies and other people's studies start to improve our understanding of the relationship and how all these different cells interact, hopefully, it'll lead to the development of better strategies for patients in more cancer types. And so while it's kind of become clear that immunotherapy by itself, it did help against some tumor types, specifically, the melanoma, bladder cancer, lung cancer, and a few other types, immunotherapy has worked when it's used alone. But we're now really starting to appreciate that the immune system's power against cancer can be enhanced by combining different types of treatments, as you mentioned, in the pancreatic and prostate cancer trials.

And nowadays, we also have novel approaches like CAR T cells and vaccines that can provide clinicians with new tools to treat patients. So what are your hopes for these cutting-edge strategies in the coming year?

Padmanee Sharma, MD, PhD: I think these strategies are going to be, again, moving forward. Especially in the CAR T cell space where we've seen dramatic clinical responses and FDA approvals of some CAR T cell therapies, we're going to now be able to hopefully take that into other tumor types beyond liquid tumors that we've been treating, or the hematologic malignancies that we've been treating, and hopefully even start thinking about treating solid tumors maybe with the potential for improving survival of these CAR T cells by genetic manipulation. And I know, for example, there are studies using CAR T cells where the PD-1 has been deleted from the T cells. And maybe this will lead to data that maybe we can combine immune checkpoint therapy and CAR T cells, even.

So those are some of the exciting studies with CAR T cells. I think in terms of vaccines, they've gotten a bad rap in the past because vaccines, by themselves with monotherapy, have not worked well in clinical trials with very few exceptions. And sipuleucel-T, for example, is one of those. But they've still not really lived up to the promise of what immunotherapy can do. And that's because I think vaccines are also going to require combination strategies with immune checkpoint therapy agents. And that will then lead to more effective anti-tumor responses. So I have a lot of hope for seeing vaccines combined with immune checkpoint therapy in the future.

Arthur N. Brodsky, PhD: Great. And like you mentioned, I think by themselves, they haven't. The vaccines haven't provided maybe the strong responses that we'd hoped, although on a cellular level, I think from my understanding, a lot of the sites have shown that the vaccines are succeeding and at least starting these immune responses. But there's other things, such as checkpoints, that maybe hold them back from accomplishing the goal of eliminating the tumor. Is that correct, that maybe the vaccines are maybe just the first step in a combination strategy that then they need to be combined with something else to kind of unleash them?

Padmanee Sharma, MD, PhD: Yes, certainly. I think vaccines are one component. But they allow for initiating that immune response, but they may not allow for maintaining the immune response, since the immune response is well-controlled, as you mentioned, by multiple check points. And so that's why combination strategy will be important.

I think it will also be important for us to redefine what we think of as vaccines, because many times, we thought of vaccines as tumor antigens that were shared among many different patients. And more and more people are beginning to recognize the importance of these neoantigens which seem to be specific for each patient's tumor. And are those going to be the best vaccines to use as compared to the shared tumor antigen vaccines? And these are things– these are questions that we'll have to address in the future in terms of research and clinical trial development.

Arthur N. Brodsky, PhD: And so I want to focus real quick, you mentioned the neoantigens, which are– every patient's tumor is somewhat different, because aside from genetic twins, everyone starts out with their own unique genome. But as tumors evolve, the mutations that occur are, in some ways, random in every patient. No patient, no two patients have the same exact types of mutations in their tumors.

But one of the other kind of concerns that's out there, especially on a lot of patients' minds, is the cost of immunotherapies, especially with the kind of, I guess, more towards with the cell treatments but some others as well. And some people might be thinking, you know, if we have to make a vaccine for each patient because each patient's tumor is different, that might get really expensive. Is that necessarily the case with the vaccines that are being used today?

Padmanee Sharma, MD, PhD: No. Actually, it turns out, the vaccines are quite easy to make. Synthetic peptides or proteins are quite easy to make and should be considered very cheap. And I think in a lot of ways, you know, even as we make monoclonal antibodies, it's pretty cheap to make them. It's just, how will they be priced by companies is a different question and something that I think we need to bring a lot of different people to the table, including scientists and physicians and pharma companies and regulatory groups, to try and make those decisions together. But from our standpoint, we see that making the vaccines is actually not an expensive process.

Arthur N. Brodsky, PhD: That's good to hear. And by that same token as far as bringing all the different stakeholders to the table, you've had some experience working with our CRI Clinical Accelerator, of trying to not necessarily focusing on the prices of these things, but at least getting all these people in the same room and trying to, you know what? We're all going after the same goal of trying to eliminate cancer. And doing it in these different silos might not be the most productive way. So could you talk a little about kind of these efforts on the collaboration front, about how these might help lead to better strategies?

Padmanee Sharma, MD, PhD: Yeah, I mean, it's been clear that the more people you put in the room that are focusing on a problem, the better the chances are that you can come up with strategies that work. You know, we each have our strengths that we bring to the table. And not one person is going to solve all the problems. So that's why it's important to have teams that work together.

And I think that was a problem, and maybe still is a problem to a certain extent. Because the language that we all use and the ways in which we think of the problem, we need to be able to communicate our science in a way that somebody else can understand. So sometimes, the regulatory teams may use a different set of jargon and the scientists may use a different set of jargon. And when they communicate, they're not understanding each other because it sounds like two different foreign languages, right?

So we're trying now to be better at breaking down our jargon and our scientific concepts into lay terms that anyone can understand. And that, I think that level of communication will help the process as we each start to see the strengths that we can bring together to really formulate effective plans for how to make things work better, a combination of strategies, how to have multiple different pharma companies be able to combine their different agents in clinical trials, and how to hopefully bring drug prices down.

Arthur N. Brodsky, PhD: I definitely agree that that is an important component that will hopefully help move the entire field alone. So at this point, I want to move to another promising area of research that's kind of a buzzword these days, and that's biomarkers. These can take many different forms. But in general, these are kind of pieces of information about a patient or their general health or their tumors or their immune system's health that can kind of help doctors better understand the individual patient's disease and potentially even help guide the doctors with respect to which treatments might work best for individual patients. So could you talk a little bit about biomarkers and what you're excited about with respect to 2020, and what more we might learn about them?

Padmanee Sharma, MD, PhD: Yeah, I think biomarkers are so important because they really help us to select patients according to their tumors and what treatments may work best for them. And I think this all came about in the era of genomic medicine when we were really basing our treatment strategies on the specific mutations within the patient's tumor.

So for example, if a patient had a BRAF mutation, then the patient got the drug that targeted the BRAF mutation. And the drug was developed specifically for targeting the BRAF mutation. So it made a lot of sense to use the BRAF mutation as the biomarker to select the patients and that type of tumor for the BRAF inhibitor, for example.

So I think that worked out well in that era of genomic medicine. And it's been something that we've been struggling a bit with in the immunotherapy world because the immune response is so dynamic. It changes day to day. As we're sitting here and talking, our immune response is changing. So to say that we can have a single biomarker at a single time point for patients to select a treatment may not be possible. And we've had to start thinking a little bit broader than that.

And what we need to do, maybe, is think about how to use an immune-type related biomarker as well as the genomic biomarkers so that we're looking at multiple different components to then select patients for treatment. And so I'm really hoping that we bring together multiple fields. So genomic medicine fields will look at mutation status and the immunotherapy field and the immune experts within the fields will look at what the immune biomarkers would be that can combine with genomic biomarkers.

So those are some ways to think about it and I think that those the kinds of advances we'll see in 2020. Because the immune response is so dynamic, It's not going to be a single biomarker in a single time point, the way we were lucky to have that happen in the genomic field.

I also think that the new methods, such as liquid biopsies and novel imaging strategies, will be helpful in looking at multiple biomarkers and combinatorial biomarkers for patient selection. So again, this idea of combination comes into play, as we're discussing combination therapies, and now we're talking about combination biomarkers that will help with the patient selection. And breaking down silos between genomic medicine and immunology will also be another piece that we see happening in 2020 to then move the field forward and help us with the patient selection for treatment.

Arthur N. Brodsky, PhD: Definitely. And so I do want to hone in, you mentioned the liquid biopsies. Just to pull back for a minute, traditionally, the best way doctors have had to learn about a patient's cancer is to get a biopsy and get a physical piece of their tumor and then study that in the lab. But this has some drawbacks, obviously. First and foremost, it's uncomfortable for the patient to have them keep coming in, like you mentioned, to get these sequential samples. And secondly, it's not always possible for various reasons.

So going back to the liquid biopsies, which I just want to clarify for our audience, would be– or at least, one of the major forms of it would be taking a sample blood draw and then using that to analyze. How could these be beneficial both for patients and for physicians?

Padmanee Sharma, MD, PhD: Yeah, I think the liquid biopsies are promising. I think they still have to be proven, of course. And that's why we're doing research on them. But I think it will be very helpful for patients because it is a simple blood draw. It's not as invasive as having to go under a CAT scan with a needle to take a biopsy of a tumor, for example, that may be embedded in their abdomen or deeper tissues. So I think the liquid biopsies can be very helpful from that standpoint.

And then the liquid biopsies, as you mentioned, will be easier for physicians and researchers too. Because if you need to get multiple time points because a single time point is not going to be able to give you the answers and you need to see the dynamic changes in an immune response for example, then the liquid biopsies are much simpler because you can do that multiple times to get those samples to do the research work.

So I think from that standpoint, liquid biopsies hold a lot of promise. But we have to do the work to really show that the liquid biopsies can give the same amount or as meaningful and relevant the information that we get from the actual biopsies of the tumors. And that's the research we'll see happening in 2020.

Arthur N. Brodsky, PhD: That's great to hear. So now I want to move from biomarkers to another buzzword that's been in the news a lot, especially this past year, and that's the microbiome, which is the collection of the trillions of bacteria and other microscopic organisms that reside within us—a lot of them in our gut tract, but also on our skin and the lungs and some other areas. So what do you think 2020 might have in store for us when it comes to better understanding and taking advantage of that complex relationship between the microbiome, our immune system, and cancers and how we might be able to use that to improve care for patients?

Padmanee Sharma, MD, PhD: Yeah, I think the data is definitive. And the evidence is great to indicate that the microbiome is playing a role in how the immune response develops and how the immune response that's generated by things such as immunotherapy with immune checkpoint agents evolve for leading to anti-tumor responses and clinical benefit. So the microbiome is definitely playing an important role, it's just now understanding which microbiome that is.

So we need a really deeper understanding of the types of microorganisms that we're talking about and then whether or not we can manipulate the microbiome. And how do we do that? Do we give that– do we do that in terms of giving patients microbiome? Do we take microbiome from patients who have the good ones and transfer them to patients who don't have the good ones? Are there ways to give other therapies to manipulate the microbiome? Do we avoid things like antibiotics in certain settings so that we don't eliminate the good microbiome?

And then there are nutritional factors. Do we give patients certain high fiber diets, for example, that can help drive certain microbiomes? These questions are still unresolved. But I think they're all being addressed in different research formats, whether it's a clinical trial or more laboratory-based studies to look at the types of microorganisms that we're talking about.

And with the data that's being generated from these studies, I think, we'll have a sharper focus of how we can really manipulate the microbiome and specific microorganisms within the microbiome to drive the clinical benefit that we're seeing with immunotherapy agents.

Arthur N. Brodsky, PhD: Yeah, I think you brought up a lot of great points there. You know, it's great that we've come to appreciate its potential impact. But at the same time, it's such a complex situation. There's so many different types of bacteria, so many different potential interactions. And it'll really be important, as you mentioned, to kind of tease apart what are the causes and effects in that situation.

And so now, a little bit before we wrap-up, obviously, it's going to take us longer than just 2020 to achieve our ultimate goal, which is to ultimately cure all cancers. To that end, in your opinion, what are the biggest questions and challenges in the field that you hope we'll start to make progress on in 2020 in order to create a even better future for patients?

Padmanee Sharma, MD, PhD: I think 2020 is going to be seeing even more work in how we study the immune response. You know, I've been an oncologist for a really long time, 20 plus years. And in oncology, we've always looked to laboratory data to help drive what we're going to do in the clinic. And so the laboratory data, though, came from mouse models that didn't have an immune system. Can you believe that?

We studied a lot of tumor responses in these sort of xenograph models, or mice that lacked an immune response because we wanted to look at how the drugs targeted the actual tumors. And without taking the immune response into consideration, we were missing a piece of the picture, clearly.

So I think in 2020, we're going to start to look at how do we develop better laboratory models to study the immune response and the tumor microenvironment, and drugs within the tumor microenvironment a little bit better? That's one. But two, I think importantly, we're going to recognize that actually, the immune response in patients, that needs to be studied even better. And we need to do a better job of what I term reverse translation.

So for many years, translation consisted of looking at what happened in mice and then taking it to the clinic. Now I'm hoping, because we have over 2,000 plus immunotherapy trials ongoing—so we have a lot of patients receiving immunotherapy—that we can then take the samples from the patient, the tumor biopsies and the liquid biopsies and the blood samples, to take those samples and take them back to the lab to study the patient's immune response and the patient's tumors, so that we can design, then, proper scientific laboratory studies based on patient data. And generate the models and generate the mouse models specifically from the patient's data to test specific hypotheses that we can then figure out, what are the appropriate combinations to overcome some of the resistance? And to help more patients and bring that back into the clinic.

So these types of reverse translational studies I'm hoping will be a bigger part of 2020. We've already seen some of the data coming out from that. So addressing this challenge of how do we blend and integrate the laboratory with the clinic, I think we'll see progress on that front. But we're not missing the vital components like we did before when we were just studying mouse models with tumors but without an immune system.

Arthur N. Brodsky, PhD: Yeah, I think that's so crucial, like you mentioned, that we're at the very least starting to, as you mentioned, the mice without immune systems. And being able incorporate that, whether it's the microbiome, all these different things. And as you mentioned, it's not just a one way route from the mouse and then try it in humans. And if it doesn't work, go back to the drawing board. It's this continuous cycle where what we do in the lab informs what you do in the clinic, and then what we observe in the clinic then informs the next round of experiments, and so on.

I think it's become a very good model. And hopefully, it'll pay dividends. So that is all the time that we have for today. Thank you so much, Dr. Sharma, for your extremely informative and inspirational responses. For more of our webinars and the additional resources that we have for patients and caregivers as part of CRI's answer to cancer educational programs, we encourage you to check out our website at cancerresearch.org/patients.

Here, you can read and watch stories shared by others who have received immunotherapy treatments across a wide variety of cancer types. You can register for one of our immunotherapy patient summits, browse our entire library of past webinars featuring the world's leading immunotherapy experts, such as Dr. Sharma, access information on other resources, including treatment, emotional support, and financial assistance, and find help locating an immunotherapy clinical trial.

Finally, I'd like to thank our sponsors one last time for making this webinar series possible, Bristol-Myers Squibb with additional support from Foundation Medicine. I'd also like to recognize and thank BioRender, whose platform was used to create the majority of the graphics that you saw today.

And again, you can watch this and all of our other webinars on our website at cancerresearch.org/webinars to learn more about the immunotherapy options and a number of cancer types. Dr. Sharma, I just want to thank you so much again for taking the time with us today and for the amazing work that you are doing to advance immunotherapy for patients. We wish you the best of luck.

Padmanee Sharma, MD, PhD: Thank you so much. Happy 2020 to everyone.

Arthur N. Brodsky, PhD: Thank you, Dr. Sharma.