Mechanism of CAR T Cells in R/R Diffuse Large B-Cell Lymphoma

Matthew J. Frigault, MD: What makes CAR [chimeric antigen receptor] T cells so fundamentally different from prior therapies is that they are immunotherapy designed from the patient’s own immune system. Patients have an apheresis or leukopoiesis process that collects peripheral blood mononuclear cells, or PBMC. This is done through an apheresis machine. It can be done over 4 to 6 hours using peripheral access. Those cells are then sent off a manufacturing facility where T cells are isolated or bulk PBMC is manufactured. The goal is to generate a population of CAR T cells that are now genetically modified and are instructed to target lymphoma.

What we’ve always tried to do with graft-vs-leukemia, graft-vs-lymphoma, or graft-vs-tumor in the allogeneic stem cell transplant setting is elicit an immune response against specific aspects of tumors, leukemias, and lymphomas. Unfortunately, that does come at some cost, and that cost is graft-vs-host disease. The thought behind CAR T cells is that rather than leaving it up to random HLA [human leukocyte antigen] mismatch or minor antigen presentation to elicit that immune response, we’re engineering exactly what we want the T cells to go after. In the case of the FDA-approved and currently pending products for lymphoma and leukemia, they’re going after an antigen called CD19. CD19 is fundamentally expressed on most, if not all, B cells and is thought to be expressed in low levels in multiple myeloma.

The thinking is that, by wiping out all CD19-positive cells, you knock out not only the lymphoma but normal, healthy B cells. As we’ve seen in follow-up data from patients after B-cell aplasia and hypergammaglobulinemia, which can result from B-cell aplasia, this does not seem to be detrimental overall with appropriate maintenance. Rather than using chemotherapy or targeted radiation therapy, it’s an immunotherapy using a gene therapy that retargets a patient’s own immune system to eradicate lymphoma or leukemia.

Based on all the outcomes we’ve looked at, this is a fundamentally game-changing therapy. These are novel mechanisms. Therefore, mechanisms that the tumors develop to be resistant to typical therapies—whether those tumors are high-risk TP53-mutated CLL [chronic lymphocytic leukemia], another type, or double-hit lymphomas—don’t play out in cellular therapy as much as they do in historical chemotherapy. It’s very promising.

Transcript Edited for Clarity