This is the second part of my overview of the most significant events in cell therapy in 2016.
CRISPR-modified cells go clinical
This year, for the first time, CRISPR gene-edited cells were used in human. Chinese oncologists from Sichuan University used CRISPR editing method to knockout PD-1 gene on autologous T-cells of the patient with metastatic lung cancer. The first patient was a part of clinical trial, which partially supported by company Chengdu MedGenCell. The outcome of the first case(s) was not reported as of today. Three more clinical trials, involved CRISPR-based PD-1 knockout of auto- T-cells in bladder, prostate and renal cancer are registered in NCT database. These 3 trials is a collaboration between Peking University and company Cell Biotech.
In US, a group from University of Pennsylvania proposed the first clinical trial, where T-cells from patients with multiple myeloma will be modified with CRISPR-based gene editing technology. The trial design was presented at NIH RAC and was recommended for approval. Parker Institute will fund Penn’s CRISPR project. RAC decision on Penn’s trial triggered debate on ethical and potential safety issues.
CAR-T cell therapy toxicity
Toxicity, related to highly efficacious CAR-T cell therapies, was one of the hottest and highly discussed topics the year. If in previous years, deaths due to cytokine release syndrome led to temporary suspension of few clinical trials by FDA, this year, fatal neurotoxicity came upfront and dominated the news. US-based company Juno Therapeutics reported at least 5 deaths from cerebral edema in their pivotal trial ROCKET. After the first 3 deaths, reported in July, FDA lifted the trial hold in a week after protocol amendment. However, this change did not have beneficial effect and 2 more deaths were reported in November. Unfortunately, the causes of fatal cerebral edema remain unknown. The trial, more likely, will be terminated. Investors dumped Juno’s stock and criticized company’s CEO, who sold $6M worth stock between June and November.
Fatal neurotoxicity added more to heated debate on safety of CAR-T cell therapies. Even though, other developers did not observed fatal cases of cerebral edema, some critics think that field is not ready to go on a market. Despite FDA’s support and effort to understand CAR-T cell-related toxicities through creation of database, Juno’s trial deaths may have negative ripple effect on the whole field.
Big failures of clinical trials
Few academic and industry-sponsored clinical trials failed in late stage. First, pan-European Phase 3 trial, evaluated transplantation of autologous hematopoietic stem/ progenitor cells in patients with refractory Crohn’s disease failed to demonstrate efficacy and was terminated due to toxicity.
Second, Belgian company Celyad released results of their Phase 3 cardiac cell therapy pan-European trial CHART-1. Even though, exploratory analyses suggested potential benefit in fraction of patients, study failed to meet primary end point.
Third, South Korean Phase 3 clinical trial, assessing efficacy if autologous bone marrow-derived mesenchymal stem cells in patients with chronic spinal cord injury was terminated in the middle due to futility. Only 2 patients out of 16 analyzed showed functional improvement. The study was supported by company Pharmicell.
Also, I’d like to note that results of 2 failed cardiac cell therapy clinical trials (both involve autologous CD34+ cells) were published this year: PreSERVE-AMI (Caladrius), RENEW (Baxter).
ChondroCelect withdrawal from European market
This year Belgian cell therapy company Tigenix announced plans for voluntary withdrawal of their autologous chondrocytes implantation product ChondroCelect from European market. This is business decision, due to competitors on a market and lack of reimbursement. ChondroCelect received EMA marketing authorization in 2009 and since that received reimbursement only in 3 countries. ChondroCelect withdrawal brings failure rate of ATMPs post-marketing adoption in Europe to 50%. This is an alarming trend.
CAR-T goes outside of oncology
This year, we saw the first attempts of getting CAR-based technology outside of oncology field. French company TxCell started several collaborations for development of CAR-Tregs for therapy of autoimmune diseases. Their ENTrIA platform describes the concept behind. Researchers from UPenn described so-called CAAR cells , which able to eliminate auto-reactive B-cells.
Best strategic acquisitions
This year was very productive for strategic acquisition in the field. I’d like to mention here the most interesting: Astellas acquired Ocata Therapeutics ($384M), GE acquired Biosafe, Pfizer acquired Bamboo Therapeutics ($150M), Allergan acquired RetroSense ($60M).
Islet transplantation in diabetes to become standard of care
Human pancreatic islets transplantation in type 1 diabetes has been on trials in selected medical centers for about two decades. This year, results of large multicenter Phase 3 clinical trial were reported. Clinical and manufacturing protocols were successfully reproduced by 8 centers. The study met primary end points, demonstrating glycemic control, freedom of severe hypoglycemic events and insulin-independence. Results of this study will be submitted as BLA for marketing authorization. This is historic and intriguing moment for the field! Because trial was academic, it is unclear who will own license and how technology will spread globally.