CAR-T Cell Therapy in Hematologic Malignancies

Transcript:Ian W. Flinn, MD: Fred, let’s talk about CAR-T (chimeric antigen receptor) cells. This is a novel cellular therapy. It seems like there’s been almost instantaneous development, but in reality, these therapies have been worked on for decades now. There have been some major changes in how these therapies are designed, and they resulted in increased efficacy. Can you talk to us about that?

Frederick L. Locke, MD: CAR-T cells refer to T cells that have the insertion of a gene that expresses a protein within otherwise polyclonal T cells. And the expression of that gene or that protein has an extracellular domain that is derived from an antibody. So, it can bind to whatever it’s designed to bind against. It has a hinge, or transcellular domain, and then it has an intracellular domain that provides the signaling mechanism to activate that T cell. The first generation CARs were described all the way back in the 1980s by Zelig Eshhar, so it’s been a long time coming, as you mentioned. The second generation CARs don’t just include the CD3 zeta signaling domain, which activates T cells. They also include the costimulatory domain, the second signal to activate T cells. There are several different costimulatory domains that are in use today. There’s a CD28 costimulatory domain and a 4-1BB costimulatory domain.

And what’s happened is that individual investigators and groups at different labs around the country and the world have come to find that CD19, which is on the surface of B-cells and B-cell malignancies, serves as a model and a perfect target for these chimeric antigen receptor T cells. So, anti-CD19 CAR-T cells were developed at these individual institutions and were shown to have great success against B-cell malignancies like B-cell ALL and diffuse large B-cell lymphoma.

What’s happened since that time is that drug companies have come and licensed those constructs, those genes that express those CARs. And so now we have several drug companies developing these; 3 are quite advanced towards getting approval or at least are in trials seeking to get FDA approval of these chimeric antigen receptor T cells targeting CD19. So, not unlike what we do for an autologous hematopoietic stem cell transplant, the patient goes on an apheresis machine, they have their T cells collected, and then that gene is inserted into those otherwise polyclonal T cells to redirect them against, in this case, CD19. And then, the cells are infused after lymphodepleting chemotherapy.

The lymphodepleting chemotherapy drives down the existing lymphocytes that are within the body, creates space for those transferred T cells, and then once they’re infused back in, they proliferate. Generally, there’s a spike in the number of those CAR-T cells within the patient, and they act as T cells do with these CAR constructs to attack the CD19-bearing tumor. It’s pretty exciting times! There have been amazing responses with CAR-T therapies.

Andre Goy, MD, MS: It’s very impressive, clinically very powerful! We have worked with Kite Pharma and Jim Kochenderfer, and also with Steve Rosenberg’s team at the NCI, for 7, 8 years now. We had some patients at the beginning that had really extensive disease, refractory large-cell lymphoma. These were basically patients that would be a candidate to go to hospice, unfortunately, but who had one injection of CAR-T therapy and have remained in remission for several years. There’s one patient, in particular, that was treated at the NCI who had a primary mediastinal large-cell lymphoma relapse with extra-thoracic disease, liver metastasis, 10 prior therapies, and was a young woman, around 35 years old. CAR-T cells resulted in 4 years of remission. So, this is really something that is very critical.

Transcript Edited for Clarity

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