CAR-T is an immunotherapy that is currently used to treat blood cancers and is in clinical trials to treat other cancers as well. This treatment requires harvesting a patient’s T cells from their blood, genetically modifying them to be more efficient in attacking cancer cells, growing them in the lab and then infusing them back into the patient. Because the first-generation CAR-T therapies are autologous – based on cells from the patient the therapy is intended for – these therapies are limited by the cost, time and infrastructure required to handle each person’s cells. Genomic editing expands the landscape of CAR-T cell-based therapies, and CRISPR/Cas9 provides the capability of further streamlining immune cell-based therapies by enabling an off-the-shelf option.
CRISPR Therapeutics has been exploring an allogeneic CAR-T program with the potential for a large-batch “universal” therapy based on donor cells as opposed to a customized batch for an individual patient. Large-batch production would alleviate the need for health centers to maintain their own infrastructure and technology to develop patient-specific CAR-T therapies and would also be much faster and far less expensive – making it accessible for a patient population vs an individual patient.
Safety First
The first batch of data from CRISPR Therapeutics’ research shows 58% of the 26 large B-cell lymphoma patients who received the therapy saw their tumors shrink and that 38% had no signs of cancer whatsoever. This response is close to that of autologous CAR-T therapies such as Novartis’s Kymriah and Gilead’s Yescarta and is an early indication that off-the-shelf could be a viable option from an efficacy standpoint … but what about safety?
Autologous CAR-T therapies have been associated with cytotoxic release syndrome (CRS), a potentially fatal side effect where a patient’s immune system goes into a “dangerous overdrive.” In the 26 patients involved in CRISPR Therapeutics’ Phase I trial, investigators saw no cases of grade three or higher CRS, and there was only one case of neurotoxicity in a patient who already had brain inflammation from a rare herpes infection. Just after this data was released, another allogeneic CAR-T research program by Allogene Therapeutics was put on clinical hold due to a chromosomal abnormality in one of their study participants. It should be noted that the patient was responding to treatment, and the clinical significance of the abnormality is not yet known. Allogene suspects it may have been related to a gene editing enzyme that CRISPR Therapeutics doesn’t use. While the safety outlook has been very positive in the early phase trials of CRISPR Therapeutics’ research, there are other hurdles to consider.
Durability in Question
The clinical trials underway suggest the CRISPR/Cas9 CAR-T cell-based therapies do not have the desired staying power. Prior to the clinical hold, an Allogene trial showed that more than half of its initially responding patients relapsed within six months. That same timeframe applied for CRISPR Therapeutics, when all but three initial responders had relapsed within six months and one of these was just one month following treatment. This leads to the inevitable question – what are the implications of repeat dosing?
On the positive side, the ability to manufacture an off-the-shelf CAR-T therapy makes repeat dosing much easier. On the downside, both Allogene and CRISPR Therapeutics had mixed results when they redosed the relapsed subjects in their trials.
Of the seven subjects who had relapsed on CRISPR Therapeutics’ treatment, plus an eighth who had not initially responded, there were three non-responders and five new remissions … all of whom relapsed shortly thereafter. When Allogene’s five relapsed patients were redosed, all went into remission but two relapsed again.
The prospect of redosing has several issues associated with it, the least of which is the added costs of administering the therapy again. Every time a patient receives treatment, they need to undergo lymphodepletion to wipe out their immune system – something patients and doctors will likely not want to do more than once.
Will Technology Evolve to Address These Issues?
It is easy to forget that CAR-T therapies and CRISPR/Cas9 are relatively new, and there is still so much to be learned before we can assess the full potential of the technology. Just as there was no way to predict that CRISPR/Cas9 would enable allogeneic manufacturing, we can’t foresee all the possible applications of CRISPR technology as it evolves.
In October, Prime Medicine announced the latest in new CRISPR technology, now being referred to as CRISPR 3.0. This will differ from its progenitor, CRISPR 2.0, which could only do base editing. With base editing researchers can repair individual DNA bases, but only in four out of the 12 possible ways: C-to-T, T-to-C, A-to-G, and G-to-A. CRISPR 3.0’s prime editing, however, can make all 12 of the possible changes.
David Liu, the Harvard researcher who was instrumental in developing the CRISPR 2.0, was instrumental in showing how CRISPR 3.0 can insert, delete, or replace long stretches of DNA in any cell type and at any spot on the genome. The earlier CRISPR systems need to tether themselves to molecular anchors, which are only located in select regions of the genome.
The nicknames of CRISPR 2.0 and 3.0 may be misleading, because these are not potential replacements for older technology – they are more likely to become a collection of tools to choose from depending on the disease or condition being treated. Early-stage pipelines will likely continue to see an influx of CRISPR-based therapies, and researchers will continue to drive progress without waiting for results of those in earlier projects. We can only wait and see if these candidates all live up to their potential.
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