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CAR-T Meeting 2021 | Second CD19-targeted CAR T-cell infusion for R/R B-cell malignancies

CD19 CAR T-cells are transforming the treatment of relapsed or refractory (R/R) B-cell malignancies. However, complete responses are not seen in all patients, and in a significant proportion, these responses are not durable. Jordan Gauthier, MD, MSc, Fred Hutchinson Cancer Research Center, Seattle, WA, discusses second infusions of CD19 CAR T-cells (CART2) as a possible approach to improve outcomes in patients with R/R B-cell malignancies. An analysis of the outcomes after CART2 in patients with R/R acute lymphoblastic leukemia, non-Hodgkin lymphoma, and chronic lymphocytic leukemia treated on a Phase I/II clinical trial of CD19 CAR T-cells of defined composition showed that CART2 was feasible and safe in most patients. Additionally, two modifiable pre-treatment factors independently associated with better outcomes after CART2 were identified. This interview took place during the 3rd European CAR T-cell Meeting.

Transcript (edited for clarity)

CD19 CAR T-cells are revolutionizing the field to treat patients with relapsed or refractory B-cell malignancies, yet the outcome are clearly still perfectible and complete responses are not seen in all patients and in a significant proportion of patients, these responses will not be durable. And if we look at our data using a defined composition CD-19 targeted CAR T-cells, there are about 25 to 30% of patients only that will remain progression or leukemia-free in the long-term...

CD19 CAR T-cells are revolutionizing the field to treat patients with relapsed or refractory B-cell malignancies, yet the outcome are clearly still perfectible and complete responses are not seen in all patients and in a significant proportion of patients, these responses will not be durable. And if we look at our data using a defined composition CD-19 targeted CAR T-cells, there are about 25 to 30% of patients only that will remain progression or leukemia-free in the long-term. So still definitely room for improvement.

One possible approach would be to infuse these patients with a second infusion of CAR T-cells, but there’s very limited data to date. Is the approach feasible? Can we make a second CAR T-cell product? Is this safe? Where is the toxicity profile? And is this just efficacious? We did this approach and we analyzed retrospectively 44 patients treated on their phase one, two clinical trial.

And what we saw is that it was indeed feasible using our in-house manufacturing to make a second CAR T-cell product. In most patients, we had to use simply cryo-preserved cells that were used for the first CAR T-cell infusion. So there was feasible in a vast majority of patients. In addition to that, we did not see a significant increase in the toxicities and cytokine release syndrome, or in biologic toxicity. And so this approach was safe in these patients, although overall, the response rates and progression-free survival was lower than it is seen in the CAR T-cell naive setting.

We did observe durable responses in a subset of CLL and NHL patients after the second infusion of CAR T-cells. And importantly, we identified that two pre-treatment and potentially actionable factors were strongly and independently associated with outcomes. The first factor was the type of lymphodepletion prior to the first infusion and Cy-Flu lymphodepletion. Cyclophosphamide and fludarabine was associated with better outcomes.

And the second factor was that giving a higher dose of CAR T-cells the second time was also associated with more robust in vivo CAR T-cell kinetics and superior antitumor efficacy. Having said that, we don’t fully understand why we see lower efficacy after second infusion of CAR T-cells. And we have preliminary data suggesting that anti-CAR immune responses, in other words, immunogenicity could be an important factor contributing to the impairment of the efficacy of CAR T-cells, but there’s also other factors. Obviously, T-cell fitness or poor T-cell function in vivo and other factors related to the tumor microenvironment itself. So there’s a vast number of strategies to try to improve. Repeat infusion of CAR T-cells. One of them is to use a fully human CAR and we have a clinical trial at the institution at the Hutch currently enrolling using CD19 CAR T-cells with a fully human scFc. And we are looking forward to look at the data and treat more patients.

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Disclosures

Consulting: JMP, Eusapharma, Multerra Bio