#29-Cell and Gene Therapy Today
Stay up to date with the latest developments in your field with our weekly digest of industry news and research articles.
I’m Pedro Silva Couto, and this is Cell and Gene Therapy Today. Here I will be sharing of the most recent news in CGT field as well as summarizing research articles focused on translational research, manufacturing and clinical studies featuring cell and gene therapy product candidates.
CGT News this week:
🤝 Cabaletta Bio receives US FDA clearance for IND application to treat systemic sclerosis with CABA-201 (news here). This is an anti-CD19 CAR-T product that aims at targetting autoimmune diseases such as Lupus Nephritis, The company’s product lead candidate is DSG3-CAART, currently being evaluated in a phase 1 clinical trial (NCT04422912).
💰 Laverock Therapeutics secures £13.5m funding to advance GEiGS® gene editing technology (news here). GEiGS® uses universal gene editing tools to minimally edit the host’s own non-coding genes and redirect their silencing activity (RNAi) towards any desired target gene or gene family. This substantial investment, led by Calculus Capital and supported by prominent investors including Mercia Ventures, Eli Lilly and Company, and Maven Capital Partners
🤝 Regeneron and Intellia Therapeutics announce expanded collaboration to advance CRISPR-based therapies for neurological and muscular diseases (news here). The focus of this collaboration seems to be focused on matching the AAV platform from Regeneron and the CRISPR/Cas9 designed by Intellias for precise modification of a target gene.
🔨 CDMO Resilience is set to manufacture BridgeBio’s lead investigational in vivo gene therapy products, BBP-631 and BBP-812 (news here). Both these products use the AAV platform (serotypes 5 and 9 respectively) an currently under clinical trial phase 1 evaluation for patients suffering from congenital adrenal hyperplasia (CAH) and Canavan disease.
🗃 US FDA launches START pilot program to accelerate rare disease therapeutic development (news here). The agency is announcing the opportunity for a limited number of sponsors to participate in a pilot program allowing for more frequent communication with FDA staff to provide a mechanism for addressing clinical development issues.
CGT Research this week:
Clinical Efficacy of CAR-T in Europe versus US
Large comparative study demonstrated inferior clinical outcomes of patients receiving CD19 CAR-T product in the Europe when compared to US with this discrepancy being attributed to longer vein-to-vein times, higher tumor burden and nonresponse to bridge treatment (study here).
This study featured the aggregate data of individual patient journeys (N=374) capturing baseline characteristics, CAR-T (either tisa-cel or axi-cel infusion-related data and survival outcomes. An analysis of region-specific differences highlighted the difference between vein-to-vein times that were on average 66 versus 50 for Europe and US, respectively. In general, European patients showed a higher risk profile prior to CAR-T therapy infusion consisting of higher tumour volume and more aggressive systemic inflammation levels. An analysis of the progress-free survival (PFS) revealed 3.1 versus 9.2 for Europe versus US-related patients, respectively. Other metrics such as the overall response rate and the complete response rate were also higher in the US when compared to Europe (74% versus 62% and 58% versus 38%, respectively. The authors then performed a multivariate model to understand which patient factors appear to be related to the limited clinical efficacy of the CAR-T product and the following ones emerged: (1) non-response to bridge therapy, (2) levels of ferritin at lymphodepletion and (3) C-reactive protein levels at lymphodepletion. One important piece of information from this paper was related to the fact that 80% of the studied population needing bridge therapy given the long vein-to-vein times remaining unclear whether bridge therapy benefits or leads to disappointing clinical outcomes.
Oncolytic adenovirus for combination therapy
Study demonstrated in vivo the synergistic effect of intratumoral injection of oncolytic adenovirus carrying IFN-α in combination with chemotherapy and radiation in pancreatic cancer (study here).
This study put forward a combination therapy prototype featuring, chemotherapy, radiotherapy and oncolytic adenovirus (OAd) expressing IFN for pancreatic cancer. The authors started by demonstrating that paclitaxel but not gemcitabine (chemotherapy drugs) enhanced replication of the OAd-IFN in vitro. Then proceeded with the in vitro to demonstrate that the product in combination with chemo suppressed pancreatic cancer cell proliferation in a dose-dependent manner. In the in vivo section of the work, the authors highlighted that combination therapy of OAd-IFN, chemotherapy and radiation was significantly more effective than any other combination of treatments. From the in vivo section of this article, it was demonstrated that combination therapy (OAd, chemotherapy and radiation) suppressed tumour growth in the absence of serious side effects compared to a higher extent than radiation+chemotherapy. This was associated with the product’s capability to trigger a local increase in the tumour-infiltrating lymphocyte score. The authors did not include much information on the manufacturing process used but highlighted two previous publications (here and here) where some information was disclosed. Although no information could be found on the upstream section of the process, OAd purification seemed to have been performed using purified by double CsCl density gradient ultracentrifugation with diafiltration used for buffer exchange using -80 °C as temperature storage conditions.
EV and CM pre-clinical applications
In an effort to understand the mechanism of action behind cell-free therapeutics (extracellular vesicles-EVs and conditioned medium-CM) in vivo study reported CM may have superior therapeutic effect than EVs when treating inflamed tenocytes (study here).
In this study, the authors take on a topical challenge of the EV field which is, related to their mechanism of action and namely which fraction(s) of the supernatant are responsible for the observed in vitro/in vivo potency. The authors used hMSCs to generate the cell-free materials and reported that both protein and particle number per unit of volume was higher in the CM compared to the EV fraction. More interestingly, the difference in particle number was only detected for particles larger than 195 nm but not for particles smaller than that. After, the authors used an in vitro model for tenocyte inflammation (used serum starvation and stimulation with TNFα and ILb1) and observed that the CM group led to the strongest treatment effect, leading to higher gene expression levels compared to the EV fraction. The application of CM also led to the highest number of differentially expressed genes relative to the inflamed control. The manufacturing methods used in this work featured a BM-MSC isolation using a ficoll-based approach followed by expansion in monolayer performed using DMEM supplemented with 10% FBS. Although the cells were expanded in a medium formulation containing serum, 48 hours prior to secretome collection, the cells were kept in DMEM with FBS. The CM fraction was generated after cell debris removal using a centrifugation cycle of 3000g for 20 minutes while the EVs were generated using a qEV10/35 nm column (size exclusion chromatography).
If you work in a lab and use adherent cells, it may be useful to understand how can you count them accurately and quickly using semi-automated tools. I have been using automated cell counters in my research (ex vivo hMSC manufacturing, coating for improved hMSC growth) and will do a webinar on this topic on October 12th at 1 pm BST (Free Registration Here).
This is it for this week’s Cell and Gene Therapy Today, which I aim to send you every Wednesday. If you found it valuable, please feel free to sign up or consider sending it to someone who finds this content useful!
I am currently a post-doctoral researcher at the University College London, and my project is focused on scalable CAR-T cell manufacturing using non-viral methods. You can find more about my research on my Google Scholar or my LinkedIn page.
Last but not least, this content was only possible to produce with the sponsorship of celltrials.org, the leading online portal tracking the clinical trial landscape of cell and gene therapy products. They have data packages on CAR-T, hMSCs, Extracellular Vesicles, and Cell-Free products, as well as in vivo gene therapy products (visit celltrials.org).