Novel CAR Immunotherapies for Pancreatic Cancer with Dr. Ryan Alexander

Pancreatic cancer—especially pancreatic ductal adenocarcinoma (PDAC)—has consistently proven one of the hardest cancers to treat with traditional treatments as well as current checkpoint immunotherapies. One reason is that these tumors aren’t usually detected until they’re already at an advanced stage, when they’ve developed ways to protect themselves from both cancer-targeting drugs and the immune system.

To provide better treatment options for people with pancreatic cancer, Ryan Alexander, PhD, a CRI postdoctoral fellow at Boston Children’s Hospital, is exploring new ways to leverage the immune system against pancreatic cancer and make our treatments more effective against this deadly disease. Specifically, Dr. Alexander—one of the inaugural recipients of the CRI Irvington Postdoctoral Fellowship to Promote Racial Diversity that’s designed to support underrepresented scientists in immuno-oncology—seeks to utilize chimeric antigen receptor, or CAR, technologies, in order to tap into the power of two important types of immune cells: T cells and macrophages. 

We spoke with Dr. Alexander recently to learn more about his cutting-edge work, his path to becoming a tumor immunologist, and more!

VIDEO TRANSCRIPT

Arthur Brodsky, PhD  

Hello, I'm Dr. Arthur Brodsky, assistant director of scientific content at the Cancer Research Institute, and today I'm grateful to be joined by Dr. Ryan Alexander, a CRI postdoctoral fellow at Boston Children's Hospital. Welcome, Dr. Alexander!

Ryan Alexander, PhD

Hi, nice to be here.

Arthur Brodsky, PhD

As a CRI fellow, you're exploring a couple of unique immune cell engineering strategies in order to develop more effective treatments for pancreatic cancer, which is one of the hardest cancers to treat. First, you're developing a new type of CAR T cell therapy. For our listeners, in general, CAR T cells are made by taking a patient's own T cells, and then equipping them with specialized cancer targeting receptors. These have been really successful against blood cancers, but not so much against solid tumors, which includes pancreatic cancer. To address this, you're using nanobody-based CAR T cells, which you call nanoCARs, to target proteins that are found at uniquely high levels within pancreatic tumors.

What is the significance of these targets, and what potential advantages does your nanoCAR approach offer?

Ryan Alexander, PhD

First, the proteins we're targeting in pancreatic cancer, they're extracellular matrix proteins that are highly enriched in pancreatic tumors. There's a selectivity in that they're not expressed in normal, healthy adult tissues. Something that's unique about pancreatic ductal adenocarcinoma (PDAC), the type of cancer that I'm studying, is that it's surrounded by or encased by a very dense stroma. Stroma is connective tissue and vasculature that supports and protects the tumor. This physiology makes PDAC particularly hard to target–Pancreatic ductal adenocarcinoma, or PDAC–potentially hard to target by a chemotherapy or conventional immunotherapies because it protects the tumor. We've developed chimeric antigen receptors that target extracellular matrix matrix components of pancreatic cancer, so we can turn that protective casing into a targetable vulnerability in the cancer. As far as the antibodies go, these are antibody derivatives from camelids, such as alpacas, that are easier to express than the typical antibody components are using chimeric antigen receptors. These chimeric antigen receptors or CARs have antibody components extracellularly (on cell surface) that will bind to antigens and activate the CAR once the T cell interacts with the appropriate target. But one of the major drawbacks with these CARs is that they're difficult to express and require extensive optimization to be expressed properly at the surface of a T cell. So these antibody based CARs are easier to express and characterize in general.

Arthur Brodsky, PhD

Great. I want to go back to the extracellular matrix proteins, One of the reasons it's believed that the pancreatic cancer is so hard to treat is, like you mentioned, it has this encasing around it that–on one hand, one of the things it does is keep the T cells out. It sounds like your approach is trying to, to take it medieval, having like a battering ram knock down the outer fortress.

Ryan Alexander, PhD

Exactly. By targeting the stroma itself, it may further sensitize the tumors to other therapies. If we use these extracellular matrix targeted T cells, that may sensitize the pancreatic tumor to  chemotherapy or other approaches as well. Yeah, battering ram is a very good analogy.

Arthur Brodsky, PhD  

In addition to the nanoCAR T cells you're exploring, you're also exploring immune cells called macrophages, which literally translates to the "big eaters" of the immune system. These cells have really complex roles in cancer. On one hand, they can help eliminate tumors, including by swallowing tumor cells directly. But in many cases, including pancreatic cancer, the tumors actually actively recruit these macrophages to protect themselves from immune responses. I was hoping you can share a little bit about how you're planning to convert these pro-tumor macrophages into ones that instead support and carry out anti cancer activities.

Ryan Alexander, PhD  

Right. As you mentioned, it's a common strategy. Solid tumors actually actively recruit macrophages, because not only are macrophages involved in phagocytosis or cell eating, as you mentioned, but they also play roles in tissue remodeling and repair. There's signaling within tumors that will convert macrophages to play roles in supporting the tumor such as recruiting vasculature or playing immunosuppressive roles within the tumor microenvironment. PDAC is a prime example in that it has a rich infiltrate of macrophages, but a paucity of infiltrating T cells that are actively killing tumor cells. So, although macrophages are typically recruitedto play these tumor supporting roles, I thought if there's a way to affect the functional polarization of macrophages within the tumors that we can co-opt them for immunotherapy. I've designed chimeric receptors for macrophages that also have intracellular (inside the cell) portions that are based on other receptors called toll like receptors that will influence the signaling properties of the macrophages, such that every time they phagocytose (eat) a cancer cell, they also will secrete signals that are called type 1 interferons. In a sense, we're retooling the macrophages to not only actively eat cancer cells, but also to secrete the right signals that will be beneficial for immunotherapy.

Arthur Brodsky, PhD 

That's really interesting. With a follow up on the T cells you mentioned earlier, there's a lot going on in the environment, and the macrophages are kind of one of those, I guess, manager general stuff there. And they kind of help dictate what behaviors kind of allowed there. So in that regard, do you think that you know, do you think that your strategies with T cells and your strategies democra, macrophages could complement one another when used together?

Ryan Alexander, PhD

Yes, entirely. Type 1 interferons are very broadly used in cancer therapy. The chief drawback is that if they're administered systemically, that they can have off-target toxicities. But one of the draws of interferons is that they promote T cell activity and proliferation. The ultimate goal of this is to have CAR macrophages that are infiltrating the tumor and persisting in the tumor microenvironment. But they're also producing these interferons that could augment the activities of CAR T cells. It could help the CAR T cells both infiltrate the tumor and persist more robustly than they normally would. Yeah, a potential synergism between the two is the ultimate goal.

Arthur Brodsky, PhD  

That's great to hear. So, as you know, CRI launched this new component of our fellowship program, in order to improve access for promising young scientists such as yourself who are from communities that are traditionally underrepresented in the STEM fields (Science, Technology, Engineering, Medicine). You mentioned before that your older brother who went to medical school was a big influence as far as getting you into science. It reminded me of how I grew up idolizing my father, who was also a cardiologist, like I understand your brother now is. And it just makes me realize how important it is for us, especially as children, to have role models who are similar to ourselves and remind us of ourselves, and who can inspire us and stimulate our imaginations, as far as what opportunities are out there for us in life. Obviously, this is especially critical when it comes to groups of people for whom there aren't many examples highlighted in popular culture, and certainly when it comes to more specialized fields like science and medicine. First, now that you're in a position to be an example and a role model who can inspire others, what words of encouragement or advice would you offer to young people of color today, as far as potentially pursuing a career in a STEM field? And second, how might science and medicine ultimately benefit from becoming more inclusive and equitable?

Ryan Alexander, PhD  

To the first point, I would say from my own experience the best advice I can give is that even if you feel like an outsider in your field or you feel different, even if there's pressure or any level of toxicity that comes your way from anyone, the most important thing to focus on are the people who are supporting you in the situations that are working. Speaking from my own experience, I've had great mentors, I've had great colleagues at every stage of my career. On the other hand, I have experienced bias during my career at different points, if I'm going to be honest. But I always had the most traction in what I was doing when I focused on the relationships and the parts of my career that were working. Even if you feel discouraged by something, you have to look at the big picture. You have to look at your career in a holistic sense. There are people who are invested in you, there are things that are going to work, so if you encounter any kind of toxicity, just look forward and keep going and have your own plan in mind. I would say that research isn't simply benefited by diversity, but research, at its core, requires diversity. Because science is at the frontier of new knowledge, and it requires innovation. At its best, science should be a collaboration between people with very different backgrounds and very different perspectives, because that's the crux of innovation. I'm fortunate now, at this point in my career in the Ploegh lab, to be working with an international team. There's a multidisciplinary team and I feel enriched by that, I feel invigorated by that. Because for any thing I think about, there's so many diverse perspectives on how to address them. Something that's completely not intuitive to me is intuitive to someone else and vice versa. I think science is at its best when there is an environment where diverse people can communicate transparently and safely and collaborate to make new discoveries.

Arthur Brodsky, PhD  

I thought that was very well put. It's not just an added bonus, that it might make it a little better you. I think you hit the nail on the head, that [diversity] really is a core component of [science]. And it's limited and not as good, frankly, without it. Especially again, with research and science pushing out into new territories, it literally is the unknown. And the old, I think there's an Einstein quote about the old ways of thinking aren't going to solve our new problems. The more perspectives and infusion of new ideas and concepts, I think is absolutely a great thing to advance the entire field. Overall, what does the CRI fellowship mean to you? And what do you hope that it will enable you to accomplish, both over the next few years and as a springboard for your future career progression?

Ryan Alexander, PhD  

What I appreciate most about this fellowship is that I feel established and I feel secure in saying that I am a tumor immunologist. That is my dream. That is my direction. When early in grad school, my sister was diagnosed with breast cancer and was treated for that, but she's been in remission since then. But my research focus changed for tumor immunology in part because of that. It's part of who I am at my core, to be able to study cancer and assist in making these innovations. This fellowship is a symbol of my career progress, my trajectory into being a tumor immunologist. I'd say my ultimate goal is to pursue an academic position. And I'd like to manage research group with a focus on these chimeric receptors, as well as the adoptive immunotherapy modalities. That's my ultimate direction and goal.

Arthur Brodsky, PhD 

That's awesome! It's been great to hear about your work and your journey, and I can't wait to follow you in the future.

Ryan Alexander, PhD  

Yeah, thank you so much. This has been great. I really appreciate the opportunity to do this.