Cell therapy is the third and maybe final wave of medicines after small molecules (1st wave), and biologics (2nd wave). Cells are biocompatible robots that are capable of delivering medicines, orchastrating protocols/processes like wound healing, and acting on their own to address disease. Cells are finicky and have a lot of variability. Process is product.
Immulus is a company that was recently acquired by Lyell Immunopharma ($LYEL). The technology was developed in Dave Mooney’s Lab at Harvard/Wyss Institute and a company was formed around it in 2018, led by CEO Omar Ali. Essentially what they developed were micro scale beads coated and infused with various immunostimulatory molecules that can be used to expand and activate T-cells during the manufacturing process. These beads can be loaded with different molecules to interact with cells of interest in different ways. They essentially act as fake cells that sit and interact with real cells in a dish and help instruct the real cells how to grow and develop.
This company was interesting from an infrastructure perspective because:
Cellares: Cell therapy in a box
Basilard Biotech: Needles to deliver genetic payloads to cells
SQZ Biotech: Squeezing cells to deliver genetic payloads to cells
Mekonos: Cell therapy manufacturing on a chip
Indee Labs: Microfluidic vortex shedding for delivering payloads
Kytopen: Continuous fluid flow with electrical fields for delivering payloads
Berkeley Lights ($BLI): phenotyping assays for cell therapy
Morgify: Cell differentiation and phenotype maintenence platform
GC Therapeutics: Cell differentiation from stem cells
OriBiotech: Automation of CGT
Opportunities arise from unsolved problems. Teams with strong technology that address the following areas of need are interesting:
Clonal Expansion: Do T-cells continue to divide and grow in the body?
Memory: Are the infused T-cells able to ‘remember’ the tumor antigen long term to prevent relapse?
Tonic Signaling: What is the specificity of where the T-cells are activated?
Exhaustion: How long do the T-cells last in the blood before tiring out and become inactive?
These labs and companies are the hotbeds for talent and new ideas. Power law distributions apply here and a lot of biological risk. Founder background is important. Centers that run a lot of clinical trials and have experience directly working with cell therapies provide a real and substantive advantage.
Academic Labs:
Companies (large):
Lyell and Sana are the two big bets ARCH has made in the cell therapy space and represent the most ‘leaps and bounds’ approach that has been tried yet. While other companies have tried to minimize biological risk to get a product approved, these two companies have a longer timeline and hope to be the end all be all of cell therapy if successful.
Lyell’s goal is to develop cell therapies for solid tumors. Cell therapies have been very effective for ‘liquid cancers’ that affect circulating blood/immune cells like leukemia, but solid tumors are more difficult for many different reasons. Lyell took the best research (and researchers) from Fred Hutch, Stanford, and the NIH/NCI and have supposedly figured out a way to reprogram T-cells specifically to perform well in solid tumor settings. The work has been published for some time now, but has now matured enough to be taken to clinic. It is a big bet on the scientists and the culmination of knowledge that the de facto inventors of immunotherapy have acquired. This is perhaps in contrast to technology based approaches such as genetic circuits and auxiliary modifications of T-cells that give them extra functions. Perhaps a combination is optimal, but the results from Lyell’s clinical trials will be huge indicators for the fight against solid tumors using cell therapy.
Sana’s goal is to develop more elegent delivery for cell therapy. The current treatment regimen for cell therapy is difficult for patients to tolerate and come with a host of other manufacturing issues. Sana has developed two platforms to address this issue: 1. Fusogen delivery of genetic payloads in-vivo and 2. Immune evading cells for grafts. The fusogens allow you to target specific cell populations based on cell surface proteins, essentially a molecular barcode that allows genetic payloads to be delivered at high efficiencies in-vivo. The primary application for this is to reprogram T-cells directly in vivo, but many other cell therapies that are currently manufactured ex vivo have the potential to be replaced by the fusogen technology. The other platform addresses another key issue with cell therapy, which is graft vs host or host vs graft disease, essentially your immune system fighting against the implanted cells and the implanted cells fighting against your body. For other types of cell therapies that are stem cell or donor derived, their hypoimmune technology might be useful especially in applications in CNS, heart disease, and liver/pancreas/kidney diseases.
Aging Angle:
Before T cell therapies like CAR-T, hematopoetic stem cell transplant (HSC transplant) was the only approved cell therapy. Everything else and most prominently stem cell therapies for regeneration purposes has been seen as sort of a meme. HSC transplant basically is an immune system transplant, where you deplete your existing immune cells with intensive chemotherapy and get hematopoetic stem cells infused back into you. They graft in your bone marrow and repopulate your immune system, essentially a refresh. This is curative in some settings, especially blood cancers because the reintroduced cells are supposedly fresh and more reactive. In old age, our immune system undergoes senescence and its function is severely deteriorated. One of Lyell’s ideas is to do a sort of immune system transplant with rejuvenated T-cells to address age related pathologies. T-cells, and presumable other immune cells, can be rejuvenated using Yamanaka factors (same transcription factors used to make iPSCs from 2012 Nobel Prize) [pg. 36 of Lyell corporate presentation] and are supposedly healthier and better able to maintain homeostasis within the body and clear out junk like senescent cells.