Thread by @Biotech2k1

For Whom does the Cell Toll? (A History of cell therapies)

A look at the history of cell therapies and editing.

1/ Engineering cells for cell therapies brings together the best of synthetic biology and genomics. Its about taking cells and reprogramming them into a therapy to treat disease.

2/ My focus in this space has been highly geared toward immune cells like T and NK cells. I will look at the evolution of cell therapies and where we are going.

3/ The first cell therapies where the autologous CAR-T therapies. This process took T cells from the patient, engineered them with a Chimeric Antigen Receptor (CAR), then put them back into the patient.

4/ These therapies were lead by companies like Kite, Juno and $BLUE. Both Kite and Juno were bought out for huge premiums. The promise of CAR-T therapies was revolutionary, but they still had some serious limitations.

5/ The challenges were time, cost and safety. It took weeks for these companies to extract cells, engineer them, expand them and administer them. Most patients had to spend weeks in the hospital under observation due to toxicity like CRS.

6/ The safety of these therapies improved as understanding of how they work lead to newer generations of autologous cell therapies. This left the challenges of time and cost. For the level of time involved, only a limited amount of these could be done in a year.

7/ Along came Allogeneic CAR-T therapies. This is where they take the T cells from a healthy donor, edit them and use them in a patient with their immune system depleted. Clearing the host immune system would prevent these foreign cells from being rejected.

8/ The promise of allogeneic CAR-T was short lived as they have shown very short durability of less then 6 months vs over 12 months with autologous. They did speed up the time for patients as they are available right away. They are manufactured ahead of time.

9/ Then came along solid tumor and the whole CAR-T excitement collapsed as these therapies failed over and over again in solid tumors. The problem was the way the CAR works. Its an antibody receptor which can only target cell surface antigens.

10/ Many of the antigens in solid tumor are inside the cells. They are mutated versions on normal proteins. This led to a shift away from CAR-T and toward NK and TCR therapies. The NK cells work without using a lot of cytokines and they don't use MHC.

11/ The early data in CAR-NK cells has shown data that is better then allogenic CAR-T and approaching the level of autologous CAR-T. Its still early. The question of whether they will do better in solid tumors is still open, but NK cells can combine with antibodies.

12/ When it comes to solid tumors, many companies have tested using TCR therapies. This takes healthy T cells from a donor, screens them to find ones that work for the antigens they desire and matches them to a patient who needs them.

13/ This proved to be just as time consuming as other allogeneic therapies, and it adds the limitation as they need to match the donor and recipient. It limits the amount of patients that can be helped. The technology here is advancing but its still not there yet.

14/ Companies like $ADAP and $IMTX are working on these kinds of therapies. They still have limited patients because they still need to match the donor to the patient base on HLA match.

15/ Then came the Tumor Infiltrating lymphocytes (TIL). They take part or all of a tumor from the patient. They break it down and get the specific antigens from that tumor and mix it with T cells from the patient.

16/ This is done in the lab to activate the cells toward the tumor specific antigens. This has a lot of promise for some patients. The companies working in this space are $IOVA and $TIL.

17/ With all these evolving approaches to cell therapies, the one thing that could not be address was manufacturing. It was always time consuming and costly. The number of therapies able to be done each year was still very limited.

18/ Then along came induced Pluripotent Stem cells (iPSC). This is where they use CRISPR to edit the DNA of the stem cell. Then they guide them down the development path to CAR-T or CAR-NK cells.

19/ This process allows for thousands of doses of cells to be produces at only a fraction of the price. The ability of this technology will change the way we manufacture immune cells in the future. Its also allows for the production of many other cells for therapies.

20/ The potential for iPSC to combine gene editing with cell development can be endless. The process is now evolving beyond immune cells to islet cells for Diabetes. They can make Glial cells, Heart cells and the potential is endless.

21/ Next up, I am going to dig deeper into the actual cell editing that goes into these Cell Therapies.