Although CAR T cells have proven to be an extraordinary tool for treating patients with relapsed and refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma, there have been a number of limiting challenges associated with delivering these therapeutics. Currently, each CAR T-cell product must be created ad hoc for each patient. This creates a built-in logistical time delay for candidate patients who have relapsed, progressive and refractory ALL and DLCBL. During this time, patients may develop progressive disease that makes them ineligible to receive CAR T cells.

Additionally, because CAR T cells to date have to be manufactured on a per-patient basis, these products are costly to deliver because each is individually manufactured; thus, they cannot be efficiently delivered on a basis that can benefit from the economies of scale that can be achieved for other pharmaceutics that are manufactured in large lots and that can be administered to multiple patients.

Finally, logistically, these cells can’t be successfully produced for every patient; there is a failure rate in cell production. All of these factors are challenges under our current CAR T model that may limit the utility and effectiveness of these cells. This study points toward a different direction — this idea of a universal CAR T cell therapy that may, in fact, help to overcome each of the three limitations that I described.

The results of the TruUCAR GC027 study are encouraging because they demonstrate the potential effectiveness of a “universal” CAR T-cell product. Creating an off-the-shelf product that can be repurposed for many patients allows us to expand the potential utility of CAR T cells. The fact that they can be delivered with a speed that is impossible with our existing portfolio of commercially available products really points to this technology as being one that is extraordinarily promising and vastly intriguing from a clinical perspective. I would, however, caution in overinterpreting the outcomes for a patient experience based upon a relatively small population. Although this study provides encouraging results for the antitumor effectiveness of these cells in both animal models and in the human subjects of this trial, these results should be validated in a larger population of patients with T-cell ALL so that we can weigh the full importance and the clinical relevance of this set of discoveries.

Moreover, we need longer-term results to see whether these cellular products can produce long-term, disease-free remissions for patients. The other issue here is when you look at the expansion kinetics of the peripheral blood of patients, you see an initial peak followed by a drop-off. One of the things that seems to be correlated with more successful CAR T-cell treatments is expansion and persistence of these cells in the blood of patients. So, I would like to see more data related to the persistence of the engineered cell population — that is, the therapeutic cells — in the blood of those patients who continue to survive. That will be a very important data point in understanding how this performs biologically over time.

The trial conducted by Wang and colleagues specifically targets CD7 with its allogeneic CAR construct. This introduces additional challenges because CD7 is expressed on the surface of T cells. So, to prevent fratricide — or CAR T cells killing each other — the strategy is to knock out CD7 with gene editing.

Despite this concern, Wang and colleagues were able to achieve complete responses with a single dose of CAR T cells and they did so without observable GVHD or neurotoxicity.

However, it is important to note the high rate of grade 3 or higher toxicities in this small study group, with all five patients experiencing at least grade 3 CRS. This may have something to do with the fairly high dosing levels used in this trial.

Perhaps the most interesting findings for those of us in the field are yet to come and will apply to the durability of responses that will follow this relatively short 7-month monitoring period.

We will start to see more genetic features, such as knock-ins and knock-outs, as well as manufacturing protocol optimizations geared toward promoting T-cell persistence and function.

The debate will continue over whether its inherently better to do things off the shelf or to use autologous cell therapies. In the end, the correct answer may depend on the type of disease and the number of previous therapies the patient has received and, therefore, the impact on T-cell quality that can be obtained from the patient.

As we develop more sophisticated ways of engineering T cells, we need to be cognizant of the potential trade-off in T-cell function. The more genetic features we put in, the more difficult it will be to ensure uniformity and genetic stability of the T-cell product. There is a balancing act we must consider as we continue to further engineer and manipulate these T cells.