Liso-Cel Highly Active in Relapsed/Refractory DLBCL

David Maloney, MD, PhD

For patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), treatment with the CD19-targeted chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, formally known as JCAR017) demonstrated a complete response (CR) rate of 63% and an objective response rate (ORR) of 81%, according to findings from the phase I TRANSCEND trial.¹

Several data sets from TRANSCEND were presented during the 2017 ASH Annual Meeting. At the 3-month assessment for the dose being used in an ongoing pivotal trial for liso-cel, the ORR was 74% with a CR rate of 68%. By month 6, the ORR and CR rates were both 50% in this group. Regarding safety, only 30% of patients experienced cytokine release syndrome (CRS). Neurotoxicity at any grade developed in 14 patients, including 10 with grade 3/4.²

OncLive: Please provide an overview of the TRANSCEND trial.

In an interview with OncLive at ASH, David G. Maloney, MD, PhD, a member of the Clinical Research Division, Fred Hutchinson Cancer Research Center, discussed the promise of liso-cel in patients with DLBCL.Maloney: JCAR017 is a CAR T-cell product directed against CD19. This is in multicenter clinical trials in aggressive large B-cell lymphoma. The product is different from other CAR T cells since it is a subset population where patients have their cells collected and CD4 and CD8 cells are independently transduced in 2 CAR T-cell populations. They are then given back to the patient in an equally defined ratio. By being able to give the T cells in a defined mixture of CD4 and CD8 cells, we get a better relationship between the dose response and the dose toxicity.

That was based on technology developed at the Fred Hutchinson Cancer Research Center, and animal models suggest that this was important. Because of this, Genome Therapeutics Corporation has instituted a multicenter trial using this technology, termed JCAR017. This has been used in 91 patients in a phase I dose-escalation study. We have been able to find remarkable activity but also much lower toxicity than what was seen in some of the earlier CAR T-cell therapy trials.

As far as the safety data goes, the bottom line is that this is associated with CRS of any grade in around 30% of patients, which is much lower than what we have seen with some of the other CAR T-cell trials. This includes a lower risk of neurotoxicity and, because of that, we have been able to use this product and explore the ability to utilize outpatient administration.

In several of the centers that have robust outpatient clinics where the patients can be seen daily, including the weekends, and then triaged 24/7, we have been able to deliver this treatment to patients in the outpatient setting and then admitting them to the hospital if they develop fevers. This product seems to be effective. We do not have long-term data yet, but it appears to have a much lower incidence of severe CRS.

Of 91 patients, only 1 patient developed grade 3/4 CRS and there was a much lower use of tocilizumab (Actemra) and dexamethasone in the entire population. That is what is fueling the excitement of CAR T cells. In the field, we are fortunate to have the first drug approval with axicabtagene ciloleucel (Yescarta), which is a CD19-directed CAR T cell based on the CD28 factor. That is now FDA approved for relapsed/refractory large cell lymphoma, and there are exciting results being presented [at ASH] updating the long-term complete remission rate and duration of remission.

What else is on the horizon in the CAR-T space?

There were 2 major presentations that updated both the axicabtagene ciloleucel [data], as well as the JULIET and TRANSCEND trials. There are 3 different trials with large cell lymphoma all showing very impressive overall response rates. We will need to see what the duration of remission is. It is a very exciting time for new treatments for patients with lymphoma who have no other options. One of the issues with CAR T cells is we are currently directing it against a single target. We already know that in some cases, tumors can escape that have lost the antigens. CD19-negative escape has been seen with acute lymphoblastic leukemia but has also been seen with patients with a lower frequency and large cell lymphoma. We are currently questioning how to deal with that.

What are the next steps with liso-cel?

An option would be to use a second target. There are clinical trials ongoing of CD22-directed CAR T cells and CD20-directed CAR T cells. Both could be combined in the same molecule or you could use 2 different CAR T cells. Much like you would treat a very serious bacterial infection with more than one antibiotic to prevent resistance, there may be a time where we will need to consider treating patients with 2 different CAR T-cell therapies to limit the emergence of negative-antigen escape. The next step for the JCAR017 trial is to enroll the pivotal cohort. That will then be used to submit to the FDA for a planned registration trial. That group is now actively enrolling.

References

1. Abramson JS, Palomba ML, Gordon LI, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 581.
2. Maloney DG, Abramson JS, Palomba ML, et al. Preliminary safety profile of the CD19-directed defined composition CAR T cell product JCAR017 in relapsed/refractory aggressive B-NHL patients: potential for outpatient administration. In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 1552.