Exploring DARIC CAR T-Cells for Autoimmune Indications

Peter Cook, PhD

Seattle Children’s Research Institute is currently conducating preclinical research on the potential use of BCMA-directed dimerizing agent-regulated immune-receptor complex (DARIC) T-cells for the clearance of plasma cells, which could have applications in autoimmune disease. Peter Cook, PhD, a senior research scientist at Seattle Children’s Research Institute, presented early findings related to this goal at the American Society of Gene & Cell Therapy (ASGCT) 28th Annual Meeting, held May 13 to 17, 2024, in New Orleans, LA.

At the conference, CGTLive® interviewed Cook to learn more. He explained the rationale behind the use of the DARIC cells, discussed the key findings he presented, and touched on next steps for the research.

CGTLive: Can you give some background context about your presentation at ASGCT?

Peter Cook, PhD: We presented on work that we published earlier this year on developing a cell-based therapy specifically to target antibody-secreting plasma cells. It's a BCMA CAR T-cell that's actually drug inducible. The CAR T-cell won't work unless the patient is simultaneously delivered a small molecule drug, rapamycin, and the cells can be turned off by withdrawal of that drug.

What were the key findings that you presented?

We demonstrated our ability to produce these inducible BCMA CAR T-cells, which we call DARIC CAR T-cells. DARIC is an abbreviation for the drug-inducible CAR construct. We showed that by lentiviral transduction we can make cells that have equivalent activity to cells that express a traditional BCMA CAR, except that their activity is solely dependent on the presence of the dimerizer, which causes the CAR to come together. We showed that in vitro targeting multiple myeloma cancer cell lines, which express BCMA, and then also in vivo in mice that have multiple myeloma tumor cells, the tumor is cleared by the DARIC CAR T-cells only if the mice are simultaneously dosed with the drug.

Then what we were really interested in is whether we could use these cells to target normal plasma cells, which secrete antibodies. In some cases those antibodies can be bad actors, for example in solid organ transplantation if a patient has preexisting antibodies that cause organ rejection. We showed that in vitro with a plasma cell differentiation system that we had developed, these DARIC CAR T-cells could specifically kill only differentiated plasma cells and not undifferentiated B-cells, again, in the presence of the drug. Then, if we took those plasma cells and implanted them into mice, where they'll engraft and secrete human IgG, if those mice were then dosed with the DARIC cells, we saw a complete drop of human IgM and IgG titers in those mice.

How would you summarize the big picture implications you would want the broader healthcare community to take away from this?

I think we're in kind of the early days of using cell-based therapy for autoimmune disease to target antibody response that drives disease. There's already been tremendous excitement about using CD19 CAR T-cells, and there's been, in a very small number of patients, tremendous efficacy in lupus in that model. But as more people get involved, and we start expanding this therapy out to other disease indications, there will be cases where CD19 targeting isn't really what we want, and what we really want is something that's more specific to the plasma cells, which don't actually express CD19. The example I cited earlier of antibody rejection of solid organ transplants is one example. So we see that the BCMA DARIC cells could be a useful tool in the cell toolbox for use in autoimmune disease targeting antibodies that are acting as bad actors in that setting. In addition, the drug-inducible context can be useful specifically if you want to time things to the flare and remission cycle of autoimmune disease.

Are there any challenges that came up in this research that still need to be addressed?

I mean, the most obvious challenge for all of these cell-based therapies is probably cost of goods and complexity of the therapy. One thing that we're interested in is in vivo conversion of cells. For example, you could imagine a lentiviral construct that's been pseudotyped to target CD3 T-cells that would then deliver the BCMA DARIC. Then, instead of doing all of this complicated ex vivo engineering of the patient's cells and then redosing along with cytotoxic chemotherapy to improve engraftment, you would simply give the patient a dose of this lentiviral therapy package, which would then spontaneously convert their cells. Those cells with the DARIC construct would be nonfunctional unless you also gave the small molecule drug to turn them on, which could be an additional safety feature. That's sort of a challenge for the field, but I think there's a lot of interesting efforts to develop the technology to address that.

Are there any like future plans or next steps for this that you could discuss a little bit?

The strategy that I just described for developing an in vivo delivery system is certainly one next step. In our paper that we published, we didn't really use any disease models or organ transplant (you could imagine a skin graft model). We just showed that these cells can clear human plasma cells in engrafted mice. So moving it into actual relevant disease models, I think, would also be a clear next step for preclinical testing of this system.

Is there anything else you want to share?

I'll take a chance to plug the Center for Immunity and Immunotherapies at Seattle Children's Research Institute, where we have a tremendous and growing collection of investigators who are focused on developing therapies for autoimmune disease, many of them based on cell engineering around T-cells and B-cells and hematopoietic cells. I think it is just doing tremendous work in this field.

This transcript has been edited for clarity.

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REFERENCE
1. Cook P. Targeting human plasma cells using small molecule regulated BCMA CAR T cells eliminates circulating antibodies in humanized mice. Presented at: at ASGCT 28th Annual Meeting, held May 13 to 17, 2024, in New Orleans, LA. Abstract #1258