EBMT 2023 | CARBON: results of Phase I study of CTX110 allogeneic CRISPR-CAS9-engineered CAR-Ts in R/R LBCL

This is a very exciting clinical trial and it addresses some of the concerns that we have with autologous CAR T constructs, that there’s a long manufacturing time, the cells are collected from a patient who may have dysfunctional T cells. Some patients are at risk of progression of their disease prior to the manufacture of CAR T-cells, it may take a month, a month and a half at times. So third party allogeneic CAR T-cells from a normal healthy donor can be secured and made for many patients, 100 patients for example, and be ready immediately. So, the CARBON trial, a CTX110 construct is designed for ready accessibility for patients and it’s a Phase I dose escalation trial looking at the safety, the incidence of adverse events, and the overall response rate, and the expansion cohort as a primary endpoint. Now, if you take a third party donor’s T-cells and infuse them into a patient, a patient will either promptly reject them or if they don’t reject them, the T-cells can attack the patient’s tissues and cause a problem called graft-versus-host disease. So to address this issue in the CARBON trial, the constructs actually are gene edited with a process called CRISPR-Cas9 with incredible precision whereby the T-cell receptor that which is responsible for causing this graft-versus host-disease problem is edited out so it’s not there. Indeed in the trial we didn’t see any graft-versus -host disease. Class I molecule which allows recognition of cells, as self or non-self and to be rejected, that too is edited out with this technology. So the cells will persist for a longer period of time. The study results very encouragingly showed an excellent safety profile and effectiveness so that once the first couple of dose levels had been achieved when a dose level in what’s called the cohort three started showing responses and therefore in the trial when we started seeing those responses and the cells were dosed at 30 to 600 million in these various cohorts, once we got up to 300 million mark and above, we started seeing responses, some of which have been quite durable. For example, there are three patients now who exceed two years from receiving these CAR T-cells who continue to be in complete remission. For the preparative regimen that’s used for this, we give chemotherapy that depletes the patient’s own T-cells so that they don’t compete for molecules that stimulated the CARs called cytokines and deplete cells called T regulatory cells that would inhibit these CAR T-cells. We saw good expansion in patients and these quite remarkable responses. The lympho-depleting chemotherapy used to bring that about is basically identical to what we use in our commercial CAR T-cells approved by the Food and Drug Administration, so no extra toxicity there. This is the first allogeneic CAR T trial to use that type of a preparative regimen and achieved these types of responses. The overall response rate once we reached that cohort three, is 67% and the complete response rate was 40%. Now we have treated some patients with more than a single dose and a two-dosing group of patients, in patients who had an initial response, complete response or partial response, but then lost that response, they received second doses and that very encouragingly showed remarkable deep, complete remissions in some of the patients. So very encouraged by that. An expansion cohort will include patients from the upfront who will receive two doses of the CAR-T, four to eight weeks apart and so this allows for repeat dosing, which is a particularly important advantage. So the advantages here are from the time of enrollment in the clinical trial to the time CAR T-cells were ready at the center was two days to start of lympho-depleting chemotherapy. Very encouraging results. As mentioned, it takes us a month to month and a half to get autologous CAR T-cells. The T-cells expanded and we saw a very good safety profile and excellent, excellent remissions.