mRNA-engineered iPSC-derived Cell Therapies Hold Potential for Tackling Solid Tumors

Kyle Garland, PhD

Solid tumors have remained a significant challenge in the field of cell therapy. Although many institutions and companies are attempting to replicate the success seen with chimeric antigen receptor T-cell (CAR-T) therapies in hematological malignancies in solid tumor indications, some investigators are turning to other types of cell therapies to address the problem.

Eterna Therapeutics and Factor Bioscience are among the companies exploring such approaches. The 2 companies, which are working collaboratively, presented data from their preclinical research across a total of 8 presentations at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16 to 20, in Los Angeles, California. Among the various approaches explored in these presentations were mRNA-engineered induced pluripotent stem cell (iPSC)-derived therapies, targeted gene insertion, and nucleic acid delivery.

In an interview with CGTLive™ at the conference, Kyle Garland, PhD, a senior scientist at Eterna Therapeutics, spoke about the findings being presented in some of these talks and the key takeaways for the healthcare community. He also touched on the need for stakeholders to put in extra effort to navigate through the existing regulatory frameworks that have not yet adapted to the rapidly changing landscape of advanced therapeutics.

CGTLive: What unmet needs are Eterna and Factor Bioscience focused on addressing with the research presented at ASGCT’s 2023 conference?

Kyle Garland, PhD: Thinking about FDA-approved autologous CAR T-cell therapies—these have really revolutionized the way in which we think about treating cancer. With that, however, there are still several critical limitations and challenges, including manufacturing complexities, reliability, lead time, and, perhaps most importantly, limitations to predominantly hematologic cancers. These are major challenges that we really seek to address with the work that we're presenting here at ASGCT.

What are some of the highlights and key findings covered by the presentations?

Together with our discovery partner Factor Bioscience, we're presenting a total of 8 presentations here at ASGCT that focus on nucleic acid delivery, targeted gene insertion, and the development of iPSC-derived cell therapies. We're particularly excited to highlight what we believe to be the first example of an iPSC-derived multicell-type therapeutic approach to target solid tumors. We're presenting on a platform that enables the generation of cell therapies comprising multiple immune cell types such as natural killer (NK) cells and T-cells, derived from iPSCs that have been reprogrammed with mRNA. Some of our in vitro work with iPSC-derived lymphoid and myeloid cells have shown synergistic cell killing of SK-OV-3 ovarian tumor cells. Furthermore, in order to improve the way in which our myeloid cells can target and engage tumor cells, we have transfected our myeloid cells with mRNA encoding a humanized ROR1 CAR protein. And notably, the ROR1-targeted myeloid cells have demonstrated robust engagement of ROR1 and cytotoxicity towards SK-OV-3 cells. We’re really excited about this new data and we believe that this novel approach has potential to form the foundation of an entirely new class of cell therapy that could be important for treating cancers—where we can sort of mimic the human immune response—the natural response to fight disease—and that is involving multiple cell types working together in a concerted manner. 

As for the nucleic acid focused posters, we've developed a library of multivalent ionizable lipids for the purposes of intracellular delivery of nucleic acid. We've screened those in several different formulations and have identified several lead candidates that we're very excited to further characterize and take forward.

Lastly, for our targeted gene insertion related posters, we are reporting a novel method for the production of single-stranded DNA for repair template insertion. We're also reporting a novel gene editing system that involves nickase functionality to induce single-strand breaks for insertion, rather than potentially problematic double-strand breaks that are often employed by earlier generation gene editing systems like CRISPR/Cas9. One thing that Dr. Jennifer Doudna, [PhD, a Nobel Laureate and professor of chemistry and biochemistry and molecular biology at Berkely College of Chemistry] just mentioned in her presidential symposium here at ASGCT is that chromosome loss is still a very serious issue. We hope that our technology can help address this.

What are the main takeaways from these presentations for the healthcare community?

I think that the main implications that should be taken away from this is that the field of mRNA cell engineering is advancing rapidly to provide the tools needed to address cancer and other diseases with unprecedented precision. What we expect is that many of these engineered cell therapies will be become available soon in the future. We expect that that will provide patients with really powerful new options for treating both hematologic cancers and solid tumors.

Have there been any notable challenges or limitations that have come up in these studies?

Absolutely. The main challenge that we foresee with advancing some of our technologies and cell therapeutic approaches is really the rapid advancement of the technologies combined with the existing regulatory framework not being able to adequately evaluate these novel cell therapies. In order to advance our technologies and cell therapies further, through clinical testing into patients in need, we're going to need to work very closely with regulators to help educate them on the characteristics of these novel cell therapies.

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

I’d just like to reiterate that Eterna Therapeutics is a life science company that is committed to realizing the potential of mRNA cell engineering and to hopefully providing patients with transformational medicines. As many of your audience will see with our work that we're presenting here, our technology has applications in many different fields of medicine. As such, to broadly deploy our technology will require deep collaboration in many different sectors of the healthcare community. I would just say that we encourage anyone with interest in potential collaboration to reach out and learn more.

Transcript edited for clarity.

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