Casgevy: bioethical concerns should not be written off just yet — even though the treatment has been approved

On BioEdge, Dr Patrick Foong and I quickly run through the bioethical perturbations that have come with the relatively rapid approval of Casgevy, the first-ever approved genome-editing therapy that utilises CRISPR/Cas 9. In some ways, it could be said that Casgevy is the first-ever approved genome therapy ‘full-stop’, because other categories of gene therapy have not been understood to create ‘edits’ to the human genome, as such.

For instance, Luxturna (and other AAV therapies) are used to ‘swap out’ mutated genes with ‘healthy’ or unmutated versions of the same. While this may seem like an ‘edit,’ it is also arguably a form of “gene replacement therapy.”

Similarly, forms of therapy using CAR T cells have been characterised as therapies that use cell reprogramming or engineering, rather than cell ‘editing,’ to create their therapeutic effects. This is because the immune cells that are extracted from a patient in a CAR T therapy process, and then reprogrammed to recognise and target cancer cells, is not as much a process by which genes or cells are ‘edited’ as much as one in which they are adapted, ex vivo.

As I have noted previously on Cells and Statutes, one of the most concerning aspects of the process in which Casgevy was approved was that the admitted lack of acceptable data about so-called off-target effects was not deal-breaker: neither for the FDA in the United States nor the MHRA in the United Kingdom.

Closer to home, it will be interesting to see what happens when an evidence dossier lands with the Australian regulator: the TGA. Given the ongoing pivot towards making cell and gene therapies faster to approve, the broader governmental investment in cell and gene therapies (see the 2021 senate inquiry on the future of cell and gene therapy here), and the historical tendency of the TGA to follow the FDA’s decisions, both for scientific and regulatory reasons, I suspect it will be approved without too much agony.

Updates from ‘Cellular Horizons’

Medical Research Future Fund project investigating how to to improve decisions about accessing cellular therapies

I recently presented updates from our MRFF project, which investigates how to improve decision-making, primarily among patients, about how and whether to access cellular therapies. The project has so far focused primarily on mesenchymal stem cell interventions: ie, ‘regenerative medicine’ treatments for osteoarthritis and conditions involving cell dysfunction. As a chief investigator in the ‘legal and regulatory affairs’ sub-team on the project, my focus has been on how these treatments are regulated.

New cellular therapies

However, as new cell-based interventions emerge as we speak, the project will likely also consider these novel interventions. In a very recent trial, immune cells (CAR-T cells) have been ‘programmed’ to attack cancerous T-cells by means of CRISPR ‘base editing.’ Specifically, this trial is aimed at treating a patient with T-cell acute lymphoblastic leukemia, or T-ALL.

There have been two issues for treating this disorder in the past.

The first relates to what is called T-cell aplasia. This is a process whereby the antigens on the T-cells are attacked, which destroys not only the cancerous T-cells but also destroys the normal T-cells. The means that T-cell numbers are decreased significantly.

Cell aplasia happens when patients undergo CAR T-cell therapy. Thus, when the cancer is a B-cell malignancy, the patient will generally experience B-cell aplasia. However, with B-cell aplasia, immunoglobulin replacement therapy can be administered to manage the problem. This is not so for T-cell aplasia. T-cell aplasia is not generally tolerated in humans, and persistent T-cell aplasia is life threatenting. Therefore, CAR T-cell therapy has generally not been possible for T-ALL.

The second issue is that CAR-T cells programmed to recognise and destroy T-cell antigens will inevitably attack healthy T-cells too in what is described as ‘T-cell fratricide.’ Sometimes, this problem is called ‘T v T’ fratiricide. This is described in the video below, which is a basic introduction to base editing published by Great Ormond Street Hospital:

While it is an extremely complicated molecular process, in CRISPR base editing, nucleotide bases in donor cells are edited at the atomic level so that the gene for CD7 (a genetic marker in blood cancers) is changed from cytosine to a thymine. In this process, the base editing produces a so-called ‘stop codon’ that terminates the production of CD7 (acting like a molecular ‘full-stop’). These edited cells are then transplanted into the patient to treat relapsed lymphoblastic leukaemia.

In an article published in Leukemia, authored by the team that are conducting the trial, the authors write that

Base editing offers the possibility of seamless disruption of gene expression of problematic antigens through creation of stop codons or elimination of splice sites. We describe the generation of fratricide-resistant T cells by orderly removal of TCR/CD3 and CD7 ahead of lentiviral-mediated expression of CARs specific for CD3 or CD7. Molecular interrogation of base-edited cells confirmed elimination of chromosomal translocations detected in conventional Cas9 treated cells.

https://doi.org/10.1038/s41375-021-01282-6

While it is far too early to determine whether base editing might present an option to patients with T-ALL and whose options are exhausted, it is promising to see that base editing appears to be possible in humans. Using CRISPR base-edited cells in humans represents a new form of cellullar therapy — it could be called somatic cell genome editing; the only other trial for SCGE that I’m aware of is the trial for exagamglogene autotemcel  or exa-cel (formerly known as CTX-001); however, that is not a base-edited genome therapy. Rather, Exa-cel uses CRISPR to treat blood disorders (hemoglobinopathies) such as sickle-cell disorder.

Unlike T-ALL base editing treatment above, where base editing is applied to donor cells, exa-cel edits the patient’s own cells (ie, it is an autologous treatment), which are removed prior to the treatment. With the cells removed, the patient is given ablative therapy while the hematopoietic stem cells are edited using CRISPR-Cas9 to produce high level of fetal hemoglobin. This treatment promises to ensure that vaso-occlusive crises (blocked blood flow, depriving tissues of oxygen, and usually caused by the ‘sickle’ shape of the red blood cell), which is a symptom of the blood disorders, is avoided.

New Priority Review Pathway for Biologicals

In the context of such cellular therapies emerging in recent times, the Australian drug regulator, the Therapeutic Goods Administration, has recently introduced new expedited pathways for drug sponsors and manufacturers to fast-track novel biological therapies (another name for therapies involving cell and tissue products) through the approval process. In a recent article published in the Journal of Law and Medicine, our team analysed the new ‘priority pathway,’ which has since been approved. We also wrote a submission to the TGA, which can be found here.

In early December, I presented some of our work on these matters to another team of experts working on cellular therapies in Australia. Presentation slides from that meeting are available here.

Earlier in the year, in April, I presented a brief introduction on the same subject to our internal team. That presentation is also made available here.