Emerging Cell Therapies

Updates from The Keystone Symposium

The Keystone Symposium on Emerging Cellular Therapies, a joint conference with Stem Cells & Regeneration, commenced this past Thursday evening, January 25, 2024 in Santa Fe, New Mexico.

Keystone meetings are notoriously small – just a few hundred attendees, typically, and held in locations where one can easily access a ski hill. The schedule graciously features an afternoon break during which one can get outdoors. But the Santa Fe location is a bit different; the closest ski hill is up the road and not right out front like it is at Whistler and conference-goers seemed more inclined to enjoy the local posole, spend time at the spa, or fit in more work.

The conference opened with a keynote address from none other than the recent Nobel prize winner, Drew Weissman, who shared insights from his decades of research on mRNA and LNP delivery of therapies to different cell types. His lab has developed many of the modifications necessary for increasing expression and potency of mRNA-based delivery; which along with work by Katalin Karikó, “enabled the development of effective mRNA vaccines against COVID-19” and earned them both the Nobel in Physiology or Medicine in 2023. Dr. Weissman recalled that he used to attend HIV meetings decades ago and would talk to other translational researchers about his belief in the mRNA technology, and they would always tell him to “drop it.”

He also emphasized the importance of custom modifications for specific cell types, citing that expression in T cells or hematopoietic stem cells (for instance) might require very different modifications to achieve similar levels of expression of your cargo. These modifications could include changes to the 5’ or 3’ UTR. They are also investigating targeted delivery of LNP mRNA using conjugations of antibodies to the LNP. This could be an important advance for therapies that strive for in vivo delivery of payloads, such as gene editing or targeted cell activation.

On the topic of mRNA modifications, grad student Crystal Chen from Stanley Qi’s Lab at Stanford University gave a fascinating talk about a reporter system + screen looking for ways to engineer transcriptional control elements. Something we as cell engineers, I think, intuitively understand is that highly differentiated cell states such as T cells are under a number of regulation mechanisms that maintain that cell state; this happens on the DNA, RNA and protein level, from TFs to chromatin remodeling to RNA editing and beyond.

Chen’s studies screened and found a number of switches that can enhance expression in activated T cells. This is unpublished work, so I won’t speak on it further, other than to say I’ll be keeping an eye out for this publication in the future.

Also on the genetic engineering side, efficient genetic knock-in strategies have long needed optimization. Chris Chang, a grad student in Justin Eyquem’s lab at UCSF, presented a one-step enrichment strategy of engineered cells with multi-locus knock-ins using SEED selection (similar in flavor to SLEEK, if you are familiar.) Eyquem led efforts for genetic knock-in of CARs into the TRAC locus and others back when he was a postdoc in the Sadelain Lab. His group is carrying out several interesting CAR and T cell engineering efforts that I’ve been following.

Moving on to standout talks of cell therapies in the clinic for CNS, I was particularly impressed by the advances made by two companies, Neurona Therapeutics and BlueRock Therapeutics. Neurona’s Steve Havlicek presented updates on their clinical program for NRTX-1001 for a form of drug-resistant epilepsy. The therapy involves human embryonic stem cell-derived differentiation of a particular neuronal sub-type that is then injected into the epileptic region of the brain. Three patients’ data were presented, and all three have shown remarkable improvements with regards to their seizure activity post-treatment.

One limitation of this approach is that it requires invasive brain surgery. My main takeaway was, could there be a way to engineer the cells to traffic to the region you want instead of having to inject them directly into that region? Many of us in the field are always interested in how to make these therapies easier to deliver and thus more accessible for patients. This is also a common theme in the CAR T cell / oncology space where we are closely watching what will come out of ‘in vivo’ clinical programs.

Also on the CNS front, BlueRock Therapeutics shared clinical data from a small trial for Parkinson’s disease. The treatment is similar in methodology to Neurona’s: human embryonic stem cell-derived neurons, injected into the affected brain region. I was impressed by the consistent benefit shown for motor score improvement in the high-dose cohort. These motor-score improvements have been notoriously hard to show for Parkinson’s. Again, this was a small study. But just getting enrollment for these experimental treatments, consistent delivery of these cell types to that part of the brain, and then to observe safety and potential improvements to endpoints like motor score are all huge hurdles that have taken the collective efforts of many in the field to overcome. It was thrilling to see this data presented.

My passion for CNS treatments often feels sidelined by the cell therapy field’s fixation on treating oncology. But this is the first year where that fixation seems to be shifting to something else: autoimmune disease, which impacts around 4.5% of the population. Cassandra Willyard just put out a great article on the state of therapies targeting autoimmune diseases (Nature). Someone* made the realization that if we could engineer T cells to kill cancer cells that express B cell markers, we could also use them to kill B cells in autoimmune disorders caused by a rogue immune system. And a few companies are making headway in a clinical sector that is quickly being flooded by newcomers. Samik Basu, CSO of Cabaletta Bio, gave a great talk summarizing some of the risks and considerations one should take when approaching autologous CAR T therapies for autoimmune patients. The main takeaway for me was: the cancer patient state/baseline is quite different from an autoimmune patient. It might be hard to extrapolate what is happening in these two patient populations.

There were so many heavy-hitters presenting across the cell therapy space that I won’t be able to cover everything here. Katy Rezvani of MD Anderson presented an impressive update on her work engineering NK cells. She’s a pioneer for the field of CAR NKs and seems to have some kind of magic touch when it comes to getting them to work in the clinic. The same can be said for Dan Kaufman at UCSD, and the two had some interesting questions for one another. NK cells continue to have impressive safety profiles compared to their T cell counterparts; but durability and duration could use improvement. Many trials are relying on repeat dosing of large numbers of cells here to see a response, and attempting various ‘armoring’ or genetic knockouts to make the cells more potent.

Last but not least, Sonja Schrepfer of Sana Bio (and one of the organizers of the meeting) presented an impressive story of her work to generate hypoiummune allogeneic cell products. She’s been working on this problem since 2005, and walked the audience through a half dozen of her papers describing which genetic knockouts and activations are required to allow these donor cells to engraft and remain viable. Schrepfer presented some exciting updated preclinical data from a single NHP study in which they induced diabetes by killing the pancreatic cells and then transplanting hypoimmune beta-islets. The data was so convincing that Sana did not pursue treating additional NHPs and will move forward with a clinical trial at Uppsala University using cadaver-derived islets that have been genetically modified to evade the immune system. This, hopefully, will be an advance that allows patients to receive these valuable donor cells without immunosuppression.

Overall, this Keystone was an impressive but intimate meeting of the minds, filled with positive trends in preclinical and clinical data that left me hopeful for the field overall. There remain many biological mysteries to be solved in the world of cell therapy treatments, and I’m often left with the impression that the people who work in this area must have an affinity for complexity, for challenge. The hard problems, so to speak. But maybe, slowly, the field is moving forward, implementing the right genetic engineering approach, or carefully delivering to the right part of the brain, and for the betterment of patients across a diverse spectrum of disease.

Thank you to Dan Kaufman, Hans-Peter Kiem and Sonja Schrepfer for organizing this fantastic meeting!

*I would love to know who made this realization – I don’t know this side of the field very well.

All art made by Jocelynn Pearl using Midjourney.