Love that cover, if you like the band they live here: http://thecars.org/)
I don’t think we’ll see the very best of the CARs at AACR16; that may have to wait until ASCO, but an abstract jumped out at me today as it addresses one of the issues I discussed in the last post (http://www.sugarconebiotech.com/?page_id=37). As a brief refresh the last post was concerned primarily with 2 issues:
1) The cell population used to make the CAR T cell prep, with emphasis on a mixture of naive CD4+ T cells plus central memory CD8+ T cells, based on work coming out of labs with close ties to Juno.
2) The ability of CARs once injected to expand appropriately if antigen were not abundant (or as abundant as CD19 is on leukemia and lymphoma cells). This is a common observation not tied to any particular lab or company.
An interesting paper to be presented at AACR is by Timothy Langer et al. from the lab of Adrian Bot at Kite Pharma, in collaboration with the NCI (Steven Rosenberg, Steven Feldman, James N. Kochenderfer). The abstract is #2305: link.
What Langer et al. describe is the phenotype of Non-Hodgkin Lymphoma patient T cells prior to their transduction/expansion and the relationship of this phenotype to outcome.
In summary they took peripheral blood containing circulating T cells from the patients, then isolated the T cell fraction. Using textbook CAR T techniques they activated the T cells then transduced them with a retroviral vector that encodes their CAR19 construct. Then they expanded the T cells further in culture with IL-2 until they reached the target “dose” of the T cells (which serve as the “drug”).
Importantly they froze down the starting peripheral blood prep and the CAR T cells then went back, thawed them both out (patient by patient matched samples) and analyzed by flow cytometry. Basically they set out to compare the starting point, the “drug” and then the result (i.e. the outcome for the patient). Now some caveats: sample size is small (n = 14), and it’s not clear to me which trial this is (so what the outcome data are). Regardless, it’s a starting point for a dataset that will surely grow over time.
OK, what did they find?
- all 14 samples yielded useful CAR T cells (i.e. were transduced and expanded successfully)
- all patients samples were different, in particular the ratio of CD4+ T cells to CD8+ T cells varied from patient to patient.
- since the abstract doesn’t show the data we don’t know those ratios, we might guess that there were more CD8s than CD4s in most patients, but we don’t know at this point
- however, the CD4/CD8 ratio in the starting prep for each patient was positively correlated with the CD4/CD8 ratio in the “drug”
- the starting T cell population generally had similar percentage of effector T cells (by definition these include activated T cells, effector memory T cells, and central memory T cells of both the CD4 and CD8 lineage) and naive T cells (not activated at all).
- the CAR T cell preps showed a shift to a greater percentage of naive T cells, that is, either they preferentially expanded (likely) or the effector T cells died out (less likely).
Now it gets interesting:
All of the CAR T cell preps were active in vitro and were delivered to their respective patients. Clinical responses occurred regardless of the CAR T cell prep phenotype including CD4/CD8 ratio or effector T cell/naive T cell ratio. So whatever was determining successful responses in the patients or unsuccessful responses – this wasn’t it. They are now further characterizing the cell phenotypes to look at other parameters, e.g. PD-1 expression. They reference these trials as using essentially this exact protocol: NCT02348216, NCT02601313.
This is a markedly different story than told by the Riddell lab recently, as we discussed last time (http://www.sugarconebiotech.com/?page_id=37). So, as Jules Winnfield (the immortal SLJ) said in Pulp Fiction, “well then allow me to retort…”
I’ll be fascinated to watch how this plays out among different groups, each of which is doing its’ very best to get the manufacturing process highly optimized to produce the best possible CAR Ts for patients.