An Interview With The 2018 Young Scientist Keynote, Dr. Kipp Weiskopf
Kent Simmons:
Well, welcome everyone, to this Cambridge Healthtech Institute podcast, presented in conjunction with the planning for the 14th Annual PEGS Boston Event, which will be held April 30th through May 4th of 2018, at the Seaport World Trade Center in Boston. I'm Kent Simmons, I'm the Program Director with CHI, and our special guest today is Dr. Kipp Weiskopf, resident physician in the Internal Medicine group at Brigham and Women's Hospital, and the presenter of the 2018 Young Scientist Keynote at PEGS Boston. The PEGS Boston Young Scientist Keynote, was launched at the 2017 PEGS to recognize a rising star in the field of protein science who is currently in a postdoc program or who has completed a postdoc in the last five years. Dr. Weiskopf was selected by our advisory group from a field of over 30 candidates from leading industry and academic research groups in the fall of 2017.
Thanks for joining us today, Dr. Weiskopf.
Kipp Weiskopf:
Thank you so much, Kent. It's really an honor to be selected and I'm excited to speak at PEGS this year.
Kent Simmons:
So, I wanted to talk to you a little bit about your work, and maybe start at the foundation of your field of research. Your work focuses on some really exciting new developments rapidly growing field of cancer immunotherapy. I wondered if you could just give us a few thoughts on where you think this field is heading and what you see as being the next generation of cancer immunotherapy.
Kipp Weiskopf:
Well the majority of immunotherapies to date have focused so far on adaptive immune cells, particularly T-cells, and immune checkpoints are molecules that regulate immune cell activation against cancer cells. I see the next generation of immunotherapy as things that focus on other arms of the immune system, particularly the innate immune system. There are some studies currently looking at NK cells and we've been looking at myeloid cells, the cells of the myeloid immune lineage, including granulocytes such as neutrophils, as well as monocytes, dendritic cells and particularly, macrophages. I think that macrophages are cells with tremendous potential as effectors of cancer immunotherapy.
Kent Simmons:
Tell us a little bit more about macrophages and about their potential in this space.
Kipp Weiskopf:
I really think that macrophages are the most interesting cells in the body. They're found in all tissues and they participate in essentially all states of pathology. Macrophages are specialized to eliminate pathogens via the process of phagocytosis and in cancer, there tends to be a high number of macrophages that infiltrate tumors. When you look at histological sections of tumors, up to 25% or more of the cells in a mass can be entirely composed of macrophages. Macrophage infiltration often correlates with poor prognosis and the thinking is that macrophages secrete factors that promote tumor growth and tumor dissemination. I think that macrophages are poised to be tremendous effectors of cancer immunotherapy and attack tumors, but they just don't recognize the cancer cells as foreign. One interaction in particular that regulates macrophage activation in tumors is the CD47/SIRPα interaction, which we've found is a myeloid-specific immune checkpoint.
Kent Simmons:
So, how does targeting of the CD47/SIRPα axis produce antitumor responses?
Kipp Weiskopf:
CD47 is highly expressed on many different types of cancer, and SIRPα is an inhibitory receptor that's expressed on macrophages and other myeloid immune cells. When CD47 binds from cancer cells to the receptor SIRPα on macrophages, it sends inhibitory signals to the macrophage that prevents the phagocytosis of the cancer cells within the tumor microenvironment. A number of different preclinical studies have shown that disrupting the CD47/SIRPα interaction using antibodies or recombinant proteins or genetic ablation of the interaction lowers the threshold for macrophage phagocytosis of cancer cells. This seems to be effective in many different preclinical models of cancer representing both hematologic malignancies as well as solid tumors. It seems to play particular importance in the setting of combinations with tumor-opsonizing antibodies—so therapies like rituximab, which is an anti-CD20 antibody used for the treatment of B cell lymphoma, or trastuzumab, which opsonizes HER2-positive breast cancer cells—and in this setting, it seems like the tumor opsonizing antibody sends a pro-phagocytic stimulus to macrophages via the Fc receptors and blockade of CD47 and SIRPα augments the response to that therapeutic antibody.
There's also now some evidence that combining CD47 blocking therapies with other conventional immune checkpoint inhibitors, like therapies targeting PD1 and PD-L1, might lead to augmented, adaptive, and innate immune responses together. So, this is how the CD47/SIRPα interaction can be disrupted for the benefit of patients. This is why we think there's so much potential in targeting this interaction for the benefit of patients.
Kent Simmons:
So, what are some of the different strategies for targeting the CD47/SIRPα axis?
Kipp Weiskopf:
There are now a number of different strategies for targeting the CD47/SIRPα interaction and all of these strategies likely differ in their effectiveness, their adverse effects, and also their pharmacological properties. The best characterized therapies are anti-CD47 antibodies, which have been investigated in a number of preclinical models. But, there are also now recombinant proteins, recombinant variants of SIRPα as Fc fusion proteins, as well as some of the work that I did as part of my graduate work engineering “high-affinity SIRPα variants” that bind to CD47 and block the interaction with SIRPα on macrophages. We've now also developed anti-SIRPα antibodies as well as other groups have been working on those, too. Now there are bispecific agents targeting CD47 and a tumor antigen, as well as SIRPα and a tumor antigen. Currently there are nine clinical trials underway investigating some of these therapies, and we expect that there will be more clinical trials in the future going forward based on the tremendous promise of targeting this axis.
Kent Simmons:
Are there any other indications for which targeting this axis might be an effective therapeutic?
Kipp Weiskopf:
I've attended PEGS the past couple of years, and I've found it to be a really outstanding conference. I've been impressed with the quality of the speakers and the seamless blend between academia and industry. It's been a really great forum for the exchange of ideas, establishing new collaborations, and opportunities for networking as well and meeting new people. There's been a lot of excitement in the field of protein engineering and new target discovery. I'm looking forward to attending because the conference is really becoming one of the preeminent conferences in the field. For all these reasons that I'm excited for PEGS 2018. I'm looking forward to seeing everybody there and I'm looking forward to the opportunity to speak.
Kent Simmons:
We'd very much like to congratulate you on your recognition as the Young Scientist Keynote for next year. I've enjoyed working with you over the last month or so on this process and we're all greatly looking forward to your talk at the meeting.
Kipp Weiskopf:
Thank you so much, and again, it's a tremendous honor to be selected and I’m very excited for PEGS 2018.
Kent Simmons:
Well, thank you everyone for listening today. This has been an interview with Dr. Kipp Weiskopf, a resident physician in the Internal Medicine group at Brigham & Women's Hospital, and the presenter of the 2018 Young Scientist Keynote at PEGS Boston. PEGS will be held April 30 through May 4th, 2018, at the Seapoint World Trade Center in Boston. If you'd like to register for PEGS or learn more about the more than 350 scientific presentations at the event, please visit www.pegsummit.com. This has been another Cambridge Healthtech Institute podcast. I'm Kent Simmons, and thank you for listening.