Krishna V. Komanduri, MD: Hello, and thank you for joining this OncLive^® Peer Exchange^® titled “CAR T-Cell Therapy Used in B-Cell Malignancies.” FDA approvals of the first chimeric antigen receptor CAR T-cell therapies mark the beginning of a new era in oncology, with exciting new therapeutic approaches on the way for several clinically challenging hematologic malignancies. In this OncLive^® Peer Exchange^® panel discussion, I’m joined by a panel of renowned experts who have been working toward bring these exciting new cellular therapies to the clinic. Together today, we will navigate the complexities of using CAR T-cell therapies in clinical practice, the data surround their use, and patient selection for the products that will become available soon.

I’m Dr. Krishna Komanduri, Kaler’s Family Chair and professor of medicine and microbiology and immunology and director of the Adult Stem Cell Transplant Program at the Sylvester Comprehensive Cancer Center at the University of Miami. Participating today on our distinguished panel are Dr. David Maloney, professor of medicine at the University of Washington, the medical director of Immunotherapy at the Seattle Cancer Care Alliance, and Leonard and Norma Klorfine Endowed Chair for Clinical Research at the Fred Hutchinson Cancer Research Center in Seattle, Washington. We have Dr. Michael Pulsipher, professor of pediatrics at the Keck School of Medicine at USC, who is a section head of Blood and Marrow Transplantation at the Children’s Hospital in Los Angeles, in Los Angeles, California. And finally, Dr. Stephen Schuster, professor of medicine, director of the Lymphoma Program and director of Lymphoma Translational Research at the Abramson Cancer Center University of Pennsylvania in Philadelphia. Thank you so much for our panelists for joining us today, and I’d like to begin.

The first segment that we’re going to talk about today is really going to set the stage for the rest of the discussions that we’ll have, and that’s about the status of chimeric antigen receptor-modified T-cell therapy in hematologic malignancies. And I’d first like to start with really a background about the design of these constructs, and I’m wondering, David, if you can try and talk to us about the mechanism of action for CAR T cells and about how the generations of CAR T constructs are designed.

David Maloney, MD, PhD: Yes, thanks very much. The field of immunotherapy has just exploded and, obviously, 20 to 30 years ago we developed monoclonal antibodies to target cancer and that represented a major advance. T cells are incredibly potent and they can kill virally infected cells and cancer cells, but they’re also very hard to find. Tumor-specific T cells are hard to find, expand, and use for therapy. So, the real breakthrough came through with the realization that you could use an antibody molecule to actually redirect the T cell to a cancer through a common antigen, and the first-generation CAR T cells didn’t work very well. They didn’t really expand, they didn’t go after the cancer, but a breakthrough that really enabled the field was the recognition that if you put a CAR T-cell costimulatory domain attached to the receptor—so, CD28 or 41BB—the T cells would then greatly expand when they encountered the antigen. And this led to these dramatic remissions we’re seeing in lymphoma and leukemia. And so, now the key is, what are the targets you can use? If you can find an antibody that’s directed against a tumor-restricted or relatively-restricted target, then that would enable this therapy to potentially treat that cancer. This is why it’s such an exciting field.

Krishna V. Komanduri, MD: David, thanks for that overview of how CAR T cells are designed. So, why don’t we talk about some of those targets? Steve, do you want to talk to us about the targets that have been recognized?

Stephen J. Schuster, MD: Yes. So, basically, as David said, anything you can make an antibody to, you could make a CAR T cell for, or direct a T cell towards that antigen. The very first CAR products that were put into clinical trials targeted CD19 because it’s a B-cell antigen. It’s not expressed on other tissues, and it’s present throughout a number of B-cell malignancies. So, CD19 has been used to treat acute lymphoblastic leukemia, non-Hodgkin’s Lymphomas. We’ll talk more about that later. People now are also developing CARs against BCMA because that’s expressed almost entirely by plasma cells and some mature B cells. And there’s other antigens that tend to be lineage, specifically CD22 at this meeting has been used in combination with CD19 CAR.

So, the idea is to identify an antigen which is present on tumors, not normal tissues. We’ve been lucky in the B-cell arena in that we have several unique antigens on precursor B cells and plasma cells. And they’ve been the target to the initial CAR products.

Krishna V. Komanduri, MD: We’re going to hear a lot, I think, about the exciting developments clinically in targeting those products today.

David Maloney, MD, PhD: Could I just add to that? I think the key to remember here is the antibody specificity is absolutely critical. And when we give an antibody to patients, off-target toxicity has not been really a big issue. But when you put a CAR, a killing T cell behind an antibody, and it reacts with other normal tissue, then you can get off-target effects that are off tumor but are on-target effects that can be critical. So, it’s stressing the system of specificity and we’re having to look at all the antibodies again.

Krishna V. Komanduri, MD: That’s a great point, David. I think one of the recurring themes in our discussion today is that each individual product that’s a cellular therapy product is going to have unique on-target and off-target effects, and that we can’t really lump all these together with respect to thinking about how they can be applied.

Transcript Edited for Clarity