In this video, IMF Chairman Brian G.M. Durie moderates a lively discussion about CAR T-cell therapy with Dr. Joseph Mikhael (IMF Chief Medical Officer) and Dr. Sagar Lonial (Emory University, Atlanta).
This video is the third in a six-part series that focuses on making sense of multiple myeloma treatment based upon the newly obtained input from three leading research conferences: the American Society of Clinical Oncology (ASCO) 2018 annual meeting, the International Myeloma Working Group (IMWG) 2018 Summit, and the European Hematology Association annual meeting, which all took place during the first two weeks of June 2018.
Dr. Durie provides an overview of chimeric antigen receptor T-cells, or CAR T-cells. He points out that CAR T-cells are not all the same. Trials use these cells may have
- different generations of creation of these CAR T-cells
- different molecular surface antigens
- different internal co-stimulation (signal 1 and signal 2).
Logistics of CAR T-cell therapy are discussed — a preparation process which takes 2-3 weeks itself.
Dr. Durie presents a chart on the B-cell maturation antigen (BCMA) T-cell Myeloma Trials data, including the following trials: Memorial Sloan Kettering, University of Pennyslvania, the bb2121 Bluebird Trial, and the LCAR-B38M trial.
Dr. Durie focuses on the bb2121 trial, which was presented at ASCO 2018. It had a very high response rate with only a small number of patients experiencing the adverse side effect of cytokine release syndrome. He comments on the enthusiasm about the trial’s efficacy and manageable toxicity.
Dr. Durie discusses the depth of response on this therapy: With higher levels of dosing, the response is better and perhaps deeper. He points to a footnote that MRD-negativity occurs very quickly with this therapy, but clinicians are unsure how to interpret such sudden onset of MRD-.
Dr. Durie says that the patients treated in the bb2121 trial were heavily pretreated myeloma patients.
He asks his colleagues to consider:
1. What do we think about these patients average remission is 11.8 months, and perhaps a bit longer for patients with deep responses?
2. Why are the patients who undergo CAR T-cell therapy progressing or relapsing?
3. Is this a therapy that will need to be repeated or combined?
4. How will the CAR T-cells be administered?
5. How well do CAR T-cells work?
6. What is the goal of CAR T-cell therapy relative to other therapies?
Dr. Lonial feels that bb2121 data presented at ASCO 2018 is exciting, with its 11.8 month results of PFS, which is much better in myeloma than lymphoma. He also states that it is too soon to know the true efficacy of this trial.
Dr. Mikhael explains that in one way, the bb2121 validated CAR T-cell therapy because it gave heavily pretreated patients up to almost another year of survival. However, he feels that CAR T-cell is not a cure-all and that there are a number of patients who have relapsed on CAR T-cell.
Dr. Lonial adds that the cytokine release syndrome (CRS) as an adverse side effect of CAR T-cell therapy may be able to be managed better in the future. He also feels that CAR T-cell is still in its early stages. Variables that must be considered include before implementing this therapy include:
- Things to manipulate patients’ T-cells prior to collection
- Things to do in-vitro with the T-cells to make them more effective
- Things to do the host after re-infusion to sustain the T-cells
The last point Dr. Durie identifies is the logistics and costs of the therapy and how it will impact how CAR T-cell therapy rolls out.
Dr. Mikhael feels that there has been too much hype around the cost of CAR T-cell therapy, especially since the logistics of implementing it are still in early stages.
Next, Dr. Durie explores the GSK 7916, which is another study that looks at another way to target the B-cell maturation antigen (BCMA).
Dr. Mikhael sees this antibody therapy as an exciting additional option, and feels that it may be easily administered. He doesn’t feel it will replace CAR T-cell therapy, but may work for some patients.
Dr. Durie was encouraged that soon, GSK 7916 uses a therapy that may be able to combined with other therapies.
Dr. Lonial suggests of thinking of BCMA-therapy as a test dose. For example, if a patient responds to a BCMA-directed non-CAR, it is predictor of a response to a BCMA-directed CAR T-cell therapy.