Engineered Plasma Cells Show Potential in Leukemia Mouse Model

Richard James, PhD

Following the great success seen with T-cell therapies in hematological cancers, many companies and institutions are now engaged in research on alternative cell therapy methods, based on other cell types, to address gaps and limitations seen with currently available T-cell therapy options. One such approach is utilizing engineered plasma cells that secrete therapeutic proteins.

Investigators from the lab of Richard James, PhD, an associate professor at the University of Washington and a principal investigator at Seattle Children's Research Institute, gave multiple presentations on their ongoing preclinical research in this area at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California. During the conference, CGTLive™ spoke with James about the key findings from this research coming out of his lab and the main takeaways for the healthcare community.

CGTLive: Can you discuss the research from your lab that was presented at ASGCT’s 2023 conference?

Richard James, PhD: My lab is working on developing a new type of cell therapy where we use antibody-secreting plasma cells as a delivery vector for protein therapeutics and other biologics. The way it works is we take B-cells from your blood, edit them with CRISPR-Cas9 reagents and AAV-based repair templates so that they can express a therapeutic protein, and then we differentiate them into plasma cells, whereupon those would get transferred to a recipient, who has a disease of some sort. The idea is that because plasma cells can live for greater than 20 years at times, that the cells would migrate to the bone marrow and be able to be a stable source of this therapeutic protein for a really long period of time without needing a redose or a different therapy.

We have a talk and a poster [being presented at the conference]. The talk is about a proof-of-concept into a new method that we've developed to link protein secretions with genomic sequence. We're using this, as a screening tool, to figure out ways to make biologics that express more protein. In the poster, which is perhaps more exciting to your audience, we've engineered B-cells to produce blinatumomab, which is a bispecific T-cell engager. What we've done is we've engrafted these B-cells into an immune-deficient mouse model that has been previously engrafted with an acute lymphocytic leukemia graft. We've shown that these cells are able to produce this bispecific T-cell engager and when the mice are then exposed to allogeneic T-cells, the tumor is completely cleared. This was really exciting and it's good proof-of-concept that this B-cell-mediated therapy has potential to work in people. B-cells producing therapeutic proteins could be a new [type of] cell therapy that will be—in the midterm anyway—coming to clinical trials. These types of results show that it’s possible that that'll happen.

Were there any challenges or limitations in this research, or areas of interest for future research that you'd like to see explored further?

One of the things we found, getting back to the talk we had, is that we go and express a protein, and we think it's going to be great, and one of the big problems is that we don't get as much expression as we'd like. Developing ways to identify changes we can make to the cells or changes we can make to the protein so that it secretes better in a B-cell context are really important. 

The other thing that we've been working very extensively on is trying to figure out how to improve engraftment of the cells. We get about 5% engraftment now of the cells that are really long-lived—they all engraft, but only 5% of the long-lived ones do. What we're thinking is that if we can either change our culture conditions so that we can make more of the long-lived cells or find ways to improve engraftment of those cells, that will greatly improve the potential of this therapy because we will need fewer cells to get the same response. 

Obviously, there's also manufacturing concerns that need to be worked out. That work is ongoing.

Is there anything else you’d like to share with the audience?

Pay attention to the biotech companies—Be Biopharma and other ones—that are working on generating B-cells that produce therapeutic proteins because I think in the near-to-mid-term there's going to be a therapy that hopefully will be exciting to the clinical community.

Transcript edited for clarity.

REFERENCE
Seattle Children’s Researchers Share Progress at American Society of Gene and Cell Therapy Annual Meeting. Website. Seattle Children’s Research Institute. Accessed October 12, 2023. https://www.seattlechildrens.org/research/featured-research/asgct-2023/