Immunotherapy: A Look at the Year Ahead for 2019

2018 was a big year for cancer immunotherapy. In addition to several approvals of checkpoint immunotherapies for new cancer types, combinations strategies involving these treatments were approved as first-line options in two cancer types and showed promise in clinical trials for several hard-to-treat cancers. Important advances were also made with respect to immune-related biomarkers, cellular immunotherapies, and personalized vaccines.
 
In this webinar for patients and caregivers, Elizabeth M. Jaffee, MD, covers these remarkable immunotherapy breakthroughs from the past year and discusses the field’s ongoing efforts to overcome the challenges ahead and enable immunotherapy to benefit even more people with cancer.
 
Elizabeth M. Jaffee, MD, currently works at Johns Hopkins University in Baltimore, where she holds many prestigious positions, including serving as the deputy director of the Sidney Kimmel Comprehensive Cancer Center, the associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the Dana and Albert “Cubby” Broccoli professor of oncology, co-director of gastrointestinal cancer and diseases program, and co-director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care.
 
Outside of Johns Hopkins, Dr. Jaffee also currently serves as the chair of the National Cancer Advisory Board for the National Cancer Institute, the co-chair of the National Cancer Institute Blue Ribbon Panel for the National Cancer Moonshot Initiative, the leader of the Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Dream Team, and the president of the American Association for Cancer Research, among other roles. Dr. Jaffee has received numerous awards in recognition of her contributions, including the AACR Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Cancer Research in 2015 and the Johns Hopkins University Office of Women in Science and Medicine Vice Dean’s Award in 2012. She is a member of the Cancer Research Institute Scientific Advisory Council.
 
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 2019 series is made possible with generous support from Bristol-Myers Squibb and Cellectis.
 
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.

Webinar Transcription

Arthur Brodksy, PhD:

Hello and welcome to the Cancer Research Institute Cancer Immunotherapy and You patient webinar series. Today is Wednesday, December 19th and the title of today's webinar is Immunotherapy: The Year in Review and a Look at the Year 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 Cellectis.

My name is Arthur Brodsky and I'm the science writer at the Cancer Research Institute, a nonprofit organization established 65 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. And we present this webinar series to patients and caregivers to help them better 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 guest, Elizabeth M. Jaffee MD currently works at Johns Hopkins University in Baltimore, where she holds many prestigious positions, including serving as the deputy director of the Sydney Kimmel Comprehensive Cancer Center, the associate director of the Bloomberg Kimmel Institute for Cancer Immunotherapy, the Dana and Albert "Cubby" Broccoli Professor of Oncology, the co-director of the Gastrointestinal Cancer and Diseases Program, and co-director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care.

Outside of Johns Hopkins, Dr. Jaffee also currently serves as the chair of the National Cancer Advisory Board for the National Cancer Institute, the co-chair of the National Cancer Institute Blue Ribbon Panel for the National Cancer Moonshot Initiative, the leader of the Stand Up 2 Cancer Lustgarten Foundation Pancreatic Cancer Dream Team, and the president of the American Association for Cancer Research, among other roles. Dr. Jaffee has also received numerous awards in recognition of her contributions to the field, including the AACR Joseph H. Birkenau Memorial Award for outstanding achievement in clinical cancer research in 2015, and the Johns Hopkins University Office of Women in Science and Medicine Vice Dean's Award in 2012.

Dr. Jaffee, it is an honor to have you with us here today.

Elizabeth M. Jaffee, MD:

Thank you very much. I'm honored to be here.

Arthur Brodksy, PhD:

So we'll hop into some questions. So first I wanted to start off with the checkpoint immunotherapies, especially those targeting the PD1, PDL1 pathway. In 2017, these were approved for the first time for certain patients with liver, stomach, gastroesophageal, and colorectal cancer, in addition to having already been approved for subsets of patients with advanced cancers such as lung, kidney, head and neck and bladder, as well as melanoma and lymphoma.

So, regarding these PD-1, PD-L1 immunotherapies, what new cancer types were these approved for in 2018?

Elizabeth M. Jaffee, MD:

Yeah, you know it's really an exciting time. The approvals just keep coming. Most recently in the past year, we've seen approvals for cutaneous squamous cell carcinoma. We've seen it for cervical cancer, small cell lung cancer, and then non-small cell lung cancer, stage three. So prior to this it was stage four. Now we're moving closer to earlier lung cancer. And as everyone knows, we're even moving to surgical patients. Hopefully we'll see approvals for that in another year or two.

Arthur Brodksy, PhD:

Great. And especially with respect to you mentioning lung cancer, that claims more lives than any other cancer. So I want to stick with lung cancer for a second. Because I also understand that there are approvals in 2018 that now enable more patients to receive immunotherapy as a first line therapy, or in other words, without having to receive another treatment such as chemotherapy first. Could you talk a little bit about those combinations of immunotherapy and chemotherapy?

Elizabeth M. Jaffee, MD:

Yes. In fact, we're really excited that we can give immunotherapy up front in two new indications this year. Because what this means is that we're giving the immune system more time to get educated to the cancer and kill the cancer. Sometimes immunotherapy takes a little longer than chemotherapy. So two in particular were approved, two combinations.

One is first line either PD-1 and PD-L1 blockade with chemotherapy for lung cancer, non-small cell lung cancer. Again, you know this is the cancer that used to be a deadly disease. We've now converted it into more of a chronic cancer.

And the other is in kidney cancer. So first line PD-1 blockade with anti-CTLA-4 combination in kidney cancer. So again, very important. It's a bad disease, that up until recently didn't have a lot of options. Now we have yet a new option for it.

Arthur Brodksy, PhD:

Great. So I wanted to just pause right here and … lung cancer has come up in both of these answers. And I wanted to just let the audience know that the reason that so much of the immunotherapy breakthroughs have dealt with lung cancer is that because it kills more people, both men and women, than any other cancer. So naturally the advances there would figure to have the biggest impact.

But I'm also sure that a lot of people are also wondering about how effective immunotherapy is for other cancer types, especially those that are considered hard to treat with traditional approaches. Did we learn anything new in 2018 about immunotherapy's potential in these hard to treat cancers?

Elizabeth M. Jaffee, MD:

Yeah, that's a great question. So there was recently an important positive study for triple negative breast cancer. And again, this is for blocking PD-L1 with chemotherapy. We're very excited about that. We're now moving into yet another common cancer that, and as many know, triple negative breast cancer is the most aggressive of all the breast cancers. So to have immunotherapy as an option really provides patients with something very important that they didn't have before.

And then ovarian cancer, so in patients with ovarian cancer who have the BRCA mutation, PARP inhibitors have had some activity. Well now we're seeing in ovarian cancer that blocking PD-1 together with a PARP inhibitor actually has significant activity. So both of these are big advances in two cancer types where we really hadn't seen as much activity of immunotherapy prior to this year.

Arthur Brodksy, PhD:

So I just want to highlight one thing that you just mentioned. You mentioned that the immunotherapy combinations were effective for the ovarian cancer patients with the BRCA mutation. I thought this would be a great time to bring the biomarkers into the discussion. Of course BRCA would be one example of a biomarker. And for our audience, a biomarker is basically any biological factor that can be measured and that helps doctors better understand their patient’s individual disease characteristics.

So then the doctors can use this information to help predict which people are most likely to benefit from which immunotherapies. And thus they can help guide their treatment decisions. Can you talk a little bit about where we are now with respect to biomarkers and immunotherapy?

Elizabeth M. Jaffee, MD:

Yes. So right now, the only FDA approved biomarker has been the PD-L1 expression biomarker, as well as high mutational, a change in mutational burden, the microsatellite instability for certain types of genetically associated cancers. But there's also a number of biomarkers that are under development. And we're finding a lot of correlation with clinical outcomes.

So for instance, looking at the tumor infiltrating lymphocytes, which are what these agents work on, well, we can now determine using PD-L1 and tumor infiltrating lymphocytes, an immunoscore we call it. And this is something pathologists looking at the tissue to come up with who may respond better to immunotherapy. And as I mentioned, tumor mutational burden has also gotten a lot of evaluation in the setting of these treatments.

And we're finding that a certain level of mutational burden, in fact, 10 mutations per– we call it 10 mutations per mega base within a cancer cell or higher, would predict that patients will respond well to anti PD-1 or anti PD-L1 therapy. And so many of our clinical trials now are using these biomarkers to confirm that they predict who will respond. This is important because we don't want to give agents that could also have toxicity to patients who won't respond. So to be able to identify those patients who will respond is very important.

There are other areas that we're working on too. The tumor microenvironment is very important to understanding not only the tumor infiltrating lymphocytes and whether they express PD-L1 or not, the tumors express PD-L1 or not, but there are other signals within the tumor microenvironment that also inhibit the immune system from killing the cancer. And so, our hope is to better understand these other signals and turn them into biomarkers to help predict who will respond to some of the new agents that we're developing in the field.

And finally, the gut microbiome is a very important area that we're doing research in now as well. And it's turning out that we all have natural bacteria in our colons. But what we didn't realize before is that these natural bacteria can also determine how well we respond to immunotherapy. And antibiotics can alter the types of bacteria you have as can other types of therapy, including chemotherapy.

So better understanding how the gut's bacteria contribute to those patients who will respond versus those who won't is very important too, because we can alter the gut microbiome in many ways. And we'll learn how to do that even more precisely in the future.

Arthur Brodksy, PhD:

Excellent. So I'd like to pivot now from checkpoint immunotherapies. It's amazing to hear about all the progress that's been made thus far and hopefully with smarter use of biomarkers and combinations, hopefully that those can help even more people. So one of the other types of immunotherapies is cellular immunotherapies, which include the CAR T cells, in which doctors take a patient's own immune cells and equip them with that CAR receptor that then enables them to better target and eliminate cancer cells.

Then after they are equipped with that CAR, the immune cells will be put back into the patient. So while the first two CAR T cell immunotherapies were approved at the end of 2017 for leukemia and lymphoma and were very important to highlight their potential, there's still a lot of work to be done to improve both their effectiveness and their safety. So to that end, first, could you discuss some of the advances that have been made in the cellular immunotherapies in blood cancer in 2018?

And second, I know there are also many efforts to apply this revolutionary approach to solid non-blood cancers. So could you give us an update on that front as well?

Elizabeth M. Jaffee, MD:

Absolutely. So it as you've pointed out, these types of therapies work best currently in blood cancers and in some leukemias where young people get it. So it's a very exciting area where we can actually turn deadly diseases into long term survival and maybe even cures. But they do come with a lot of toxicity.            

And so what's been going on over the past year is the ability to really modify both the CAR T cells so that they're less toxic, and in doing so, you know it becomes more appropriate for more patients. So for instance humanized CD8, the CD8 8 receptor on a T cell in lymphoma has decreased neurotoxicity, and it's allowed for enhanced responses in again, another blood cancer called lymphoma, which is a very common type of cancer among the blood cancers in even older people but also in younger people.

The other area is besides toxicity, improving toxicity, and that's going to– the next advances will come from improved engineering, we also want to be able to regulate these CAR T cells, expand them when we need to because the more T cells you have the better they can attack large burdens of cancer. And so there's been engineering advances as well as using drugs to enhance these T cells.

So there are some drugs that can enhance the CAR T cells that they expand better by hitting one of their receptors. So we have drugs that can hit the CD20 or the CD22 receptors. So that can expand these CAR T cells. And this has worked well for chronic lymphocytic leukemia.

And then ideally, we'd like to be able to engineer these CAR T cells so that basically these lymphocytes and be able to have more of a generic engineering of these T cells so that we can kind of take off the shelf CAR T cells for any type of blood cancer. And so there are people working on trying to better engineer these CAR T cells so that they're not going to fight against the patient's own tissue, but only fight against the cancer itself.

So there's been some preclinical improvements in that, particularly using pluripotent stem cells. And this has been done by a colleague, Dr. Sadelain who's making a lot of headway in this area. And then there's also been new targets. So in solid tumors, you know, one of the problems we've had for solid tumors is that we don't know what to target.

So for leukemias, there are something called differentiation antigens. So as a blood cell differentiates and becomes more mature, they have certain molecules. And so you can get rid of all of the blood cells with a CAR T cell. And we can support patients with the normal blood cells until their normal cells are able to repopulate.

But unfortunately there aren't good targets on solid tumors right now. We don't know the best targets because there's no differentiation antigens, nothing that differentiates them from the normal cell, that would allow us to kill off the cancer cell without hurting the normal cell. And unfortunately, unlike blood cells, we can't support a liver or pancreas or a colon. It's just a different kind of situation.

However, people like Steve Rosenberg have been targeting oncogene proteins, so mutations in certain genes that cause cancer. And he was able to show in one case that he can actually cure a patient or get a patient to remission with a cholangiocarcinoma that had a mutated KRAS using T cells engineered to target that particular mutation.

So there's a lot of work going on trying to better understand what antigens to target. Also getting the T cell into a solid tumor is not that easy either because there are barriers, a lot of different signals. There's stroma. There are big barriers to getting T cells in. So we need to be able to modify those barriers, take down those barriers as well.

So if we are going to be successful with CAR T cells and solid tumors, it's going to be through combinations of agents, the CAR T cells or similar type of cellular therapy with agents that take down the barriers in an organ.

Arthur Brodksy, PhD:

That last, but not the very last part, but the part you mentioned about the mutation specific targeting T cells, I think that's really important. I think it really helps highlight immunotherapy's amazing potential. Because every person's tumor is unique and has different mutations, as treatments can be better tailored to individuals, they could presumably become more effective. So the biomarkers from earlier are part of that improving the treatment. But so is also identifying those patient specific mutations, like the cellular immunotherapy you just mentioned.

And so now I'd like to turn to vaccines, which kind of take this a step further and can help educate a patient's immune system about what their cancer looks like so it can be eliminated. To me, these are one of the most exciting ideas in immunotherapy and are part of what makes it so special. Now I know these truly personalized vaccines are still only in clinical trials at this point, but what did we learn about the promise of these approaches in 2018?

Elizabeth M. Jaffee, MD:

Right so we've seen publications of a number of early personalized vaccines in patients with melanoma and glioblastoma as well as human papilloma virus associated cancers. And what we're learning, one of them is an RNA based vaccine that targets these mutations I was talking about. So high mutation burdened tumors that have lots of new mutations, we can actually make vaccines either using RNA that expresses these mutations or actual peptides, small pieces of protein that express these mutations.

And two studies were reported showing that when you vaccinate patients with melanoma or glioblastoma with these peptide specific or RNA specific vaccines, you can get T cells that we can measure against these new antigens, these neoantigens or new mutations. So we don't know for sure yet that this work will result in, you know, curing patients of their tumors.

And I suspect that we’ll still need to give agents that inhibit PD-1 or PD-L1 or some of the other inhibitors that sit in the tumors, particularly solid tumors, in combination. But it's definitely a start. And there was recently a publication just this month in glioblastoma where those T cells did infiltrate the tumors. That's the first example of T cells infiltrating the tumor after being induced with the vaccine.

So I think it's an exciting time. I think everyone should be looking toward seeing more about this. And you know, I'm certainly excited about the opportunity to be able to more precisely for each patient develop immunotherapy strategies.

Arthur Brodksy, PhD:

Great. Well, Dr. Jaffee, we're almost out of time. But I think you did an excellent job of highlighting the many promising advances that occurred in immunotherapy in the last year. And throughout your responses, you also alluded to some of the ongoing efforts to make immunotherapy even better and what will be needed to take advantage of immunotherapy's full potential. So before we wrap up, I was hoping you could leave us with your thoughts on, in general, what will be needed to address the challenges ahead and how the field is improving its ability to address those challenges.

Elizabeth M. Jaffee, MD:

Yes. Thank you for giving me that opportunity. I first want to mention that the Cancer Research Institute has a very large and diverse portfolio that has for many, many years been helping our field to get to where we are today. And will continue to help our field move from where we are now to the next level, all with the goal of helping patients with cancer.

The areas that I think are really exciting that are really helping to fuel really this revolution in immunotherapy are the better tools and technologies that are available to us now. We now have very specific tools and technologies that allow us to study a patient's cancer, even a small little biopsy of a patient's cancer, and understand the different types of immune cells coming in, the signals.

And what that does for us is tell us what immunotherapies may work for patients and how to improve our immunotherapies to better work for individual patients.

The other area that's very important is we now have more innovative clinical trial designs. We're no longer saying everyone with colon cancer or breast cancer or lung cancer gets this type of therapy. We can now determine, as we were talking about with biomarkers, which patients will benefit from what therapies. And this is very important because now, it's no longer a colon cancer or a lung cancer or a breast cancer. It's a genetically determined cancer.

So it could be all of those cancers. It could be a subpopulation of all of those cancers in our clinical trials. And what we do with those trials is we'll test our agents in a number of different types of cancers as long as they have a particular genetic predisposition that we think caused that cancer. So again, we're moving to more precision based immunotherapy studies.

And finally, I can't say this enough. Collaborations between academia, the pharmaceutical and biotech industries, and nonprofit partners are critical for discovering new drugs and getting those drugs to patients and getting approvals. Not one group can do this on their own. It's a continuum, a collaboration, and there are major interactions that have really helped this field go from discovery to all of these new agents that are working for patients with cancer.

Arthur Brodksy, PhD:

It is very promising. And I think that, like you mentioned, I think the field is heading in the right direction and hopefully that it will be able to help patients even more soon. So that is all the time that we have for today. Thank you so much, Dr. Jaffee, for your extremely informative and inspirational webinar.

For more of our webinars and 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 www.cancerresearch.org. Here you can read and watch stories shared by others who have received immunotherapy treatment across a wide variety of cancer types. You can register for one of our immunotherapy patients summits, browse our entire library of past webinars featuring the world's leading immunotherapy experts such as Dr. Jaffee, 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 Cellectis. And again, you can watch this and all of our other webinars at www.cancerresearch.org/webinars. To learn more about the immunotherapy options and a number of cancer types Dr. Jaffee. 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 help patients. We wish you the best of luck.

Thank you very much.