CTA:  What are some new design approaches for CAR-T? I have been hearing about CAR-T products that have multiple targets, or are BCMA-directed, allogeneic, NK [natural killer]-directed, and then ones that have suicide switches or other mechanisms to circumvent resistance. What are the most promising approaches or constructs, in your opinion?

Dr Levine:  Well, all of them, or most of them, at least. We could have a conversation for several hours about that! The consensus has grown — and we’ve always thought — that [by] targeting 1 antigen, you’re hoping that that will prove effective, and that certainly is effective in a durable way for many patients.

But there are relapses through antigen escape, so there have been several approaches, as you’ve seen, with targeting a second antigen, either through 2 CARs — and we are taking that approach in a couple of trials — or by engineering a CAR that can recognize 2 antigens.

It’s yet to be shown whether one approach is better than the other, but again, I think the consensus is that targeting 2 or possibly more antigens is going to be, in the end, a more effective strategy for durable remissions.

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CTA:  What about the resistance mechanisms that have developed?  And, what are the biggest concerns for resistance in terms of the development of new constructs?

Dr Levine: Resistance can take place in several ways. One is antigen escape, and then the strategy there is to have another CAR in the garage, or to come out with 2 CARs or 3 CARs or targeting 2 or 3 antigens.

The second mechanism is early disappearance of the CARs, and perhaps the T cells are nonfunctional, which means it would be a T-cell–intrinsic defect, and we obtain the raw material from the patient, so we’re beholden to that for autologous therapies.

[Another] mechanism may be tumor-induced immunosuppression; either expression of high checkpoint ligands or a secretion of immunosuppressive molecules.  So, that can be addressed by delivering [a] checkpoint antibody or engineering checkpoint resistance into the CAR-T cells, perhaps with a switch receptor, to convert a positive signal into a negative one.

For a secreted immunosuppressive agent, such as TGF-beta — we actually have a clinical trial with a TGF-beta–dominant negative receptor. So, that makes those T cells immune to the immunosuppressive effects of TGF-beta.

Going back to the early disappearance of the CARs or T-cell–intrinsic defects, one could address this by encouraging the growth or selection of more potent CAR-T cells, and one can do that by adding distinct cytokines or chemical modifiers to the culture. So, for example, we and others are culturing T cells with IL-7 and IL-15 now instead of IL-2. [Doing this] encourages the growth of central memory T cells.

Bluebird has a new product, bb21217, in development with an agent that they add to the culture that they say (or that they think, at this stage) may result in more potent T cells. 

Those [examples represent a number of] ways that the field is addressing mechanisms of resistance.

CTA:  What about T-cell infiltration?

Dr Levine: That one [we] might label as T-cell trafficking, the ability to get into the tumor — in particular, a solid tumor — and solid tumors may have poor [vasculature]. They may have a dense stromal matrix that prevents T-cell infiltration, and a way to address that is to engineer into the T cell, or perhaps into the CAR, a cytokine or chemokine that will aid in the trafficking to [the] tumor.