# CRISPR against cancer in human trial

Mentor
First U.S. Patients Treated With CRISPR As Human Gene-Editing Trials Get Underway

The study takes immune cells out of the patient, modifies them with CRISPR in the lab to target cancer cells, and then puts them back into the patient. Two received this treatment so far, this study plans to have 18 patients in total. Several more studies plan to start this year.
"2019 is the year when the training wheels come off and the world gets to see what CRISPR can really do for the world in the most positive sense," says Fyodor Urnov, a gene-editing scientist at the Altius Institute for Biomedical Sciences in Seattle and the University of California, Berkeley.

atyy, Drakkith, pinball1970 and 4 others

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atyy
This seems to develop from earlier ideas - immune checkpoint inhibitors, and CAR-T and TCR. Immune checkpoint inhibitors and CAR-T therapies have been FDA approved. Current CAR-T involves T cells that have been genetically modified by a virus, whereas the newer effort mentioned in the OP uses CRISPR. The trial in the OP also mentions TCR rather than CAR-T, but both have common features.

BillTre
Ygggdrasil
Gold Member
2019 Award
The UPenn CRISPR clinical trial represents a pretty good opportunity to test the clinical applications of CRISPR gene editing for a variety of reasons:

1) As mentioned by @atyy, the trial is based off of well established cancer immunotherapy approaches, so the main untested component of the therapy is the CRISPR component.

2) The gene editing will be done ex vivo, that is, outside of the patient's body. This makes it easier for the scientists to perform the edits and characterize the effects of the edits on the modified T-cells before re-introducing the cells back into the patient.

BillTre, Steelwolf and jim mcnamara
wish this research will success in short years, look forward to see somedays cancle is just like normal cold

Laroxe and Steelwolf
Laroxe
This seems to involve similar processes to CAR T, which is still not widely available and which has been predicted to cost in the region of 1 to 1.5 million dollars per patient. The current cost of around 0.5 million is only possible because the staff costs are covered by research grants. There are already serious questions about the use of many new biological therapies, which have revolutionised the treatments of some cancers, based on their cost.

This new development seems to raise the spectre of a treatment that will only be available to the very rich and in particular settings.

The current study involves using CHRISPR targets two functional areas on T cells, one of these PD-1 already has a number of drugs available. The second TCR area has potential serious adverse effects which they are hoping this will control. However as more drugs become available that target various immune pathways it is difficult to see how a therapy like this could ever be considered cost effective. A major problem in cancer treatment is in the huge genetic variability within tumours which when acted upon by drugs acts as a selective force for more resistance. This is a major area of research and suggests more complex treatment combinations will be needed which will also be a significant problem in this therapy.

To become a useful addition to treatments this would need to show very significant advantages to be considered as a cost effective otherwise there would be no real motivation to develop it for a more general use. This would also have to occur as some of the biologics become available from generic sources at a lower cost.

BillTre and atyy
Mentor
The human genome project took a few billion dollars, today you can sequence a whole genome for under $1000 (not the same task, but gives an idea of the difference). I would be surprised if the treatment cost for the first few patients tells us much about how much this might cost in 10-20 years. Laroxe and BillTre Laroxe Science Advisor The human genome project took a few billion dollars, today you can sequence a whole genome for under$1000 (not the same task, but gives an idea of the difference). I would be surprised if the treatment cost for the first few patients tells us much about how much this might cost in 10-20 years.
I really hope your right but the estimates were from people in the field and much of the cost would be based on the types of facilities needed, the various staff, the time involved before we even look at the medical costs or the profits the companies will expect. The current cost of a single dose of a PD-1 inhibitor a biologic therapy that is now widely used and usually weekly for a period of time is somewhere around $33,000. This technology goes well beyond these first treatments and is much more complex and I have little faith that reducing the cost is a priority of the manufacturers. But then, I'm just an old cynic. :) Mentor and I have little faith that reducing the cost is a priority of the manufacturers If cost is what prevents a widespread use? Demand at a lower price should be there if this works well. Laroxe Laroxe Science Advisor If cost is what prevents a widespread use? Demand at a lower price should be there if this works well. In countries that support medical costs in some way they normally buy drugs for the whole healthcare system under contracts, these days the decision as to whether to include new drugs is based on a cost benefit analysis. A new cytotoxic drug used in cancer treatment would need to show some advantages over what was available and there would be estimates of its effectiveness usually based on measures like improved quality of life and whether it delays death. A new drug that on average extended life by 1 month, that might cause significant side effects and was expensive would be unlikely to be recommended. Pembrolizumab a checkpoint inhibitor of PD-1 was an early biologic the received approval in the USA in 2014, a review by NICE in the UK in 2017 maintained that there was still insufficient information about its effectiveness to recommend it for widespread use, though it was available in particular cases based on specific criteria. Rather unusually this drug proved to be significantly more effective than originally though and was recommended for widespread use in 2018. These sorts of decisions are common in European countries but can seriously effect a drug companies profits, the costs of the drugs are also negotiated by each country, but this can also offer advantages to companies. Many of the new drugs produced by companies that have no advantage other than providing the company with greater profits and exclusive production rights are never licenced in Europe and really rely on direct to customer advertising to sell, the US is one of two countries in the world that allows such advertising. The nature of cancer treatment means a lot of drugs are associated with public campaigns to make them available on the basis you shouldn't put a price on any period of extended life. It is thought that some of these campaigns are promoted by the companies who produce the drugs and many are simply ill informed. We have to consider that the cost of these new biologic drugs, if made widely available would bankrupt some third world countries and in an effort to improve the perception of fairness would need significant support from richer countries increasing the costs. As populations across the globe are seeing significant improvements in life expectancy, they are also seeing cancer rates increasing because of it. I have read recently that there are already discussions in the USA about allowing health insurers greater flexibility in what they are obliged to cover. This revolution in treatments is only getting started really and wouldn't help much if health insurers are pushed into bankruptcy. The US in particular will need to take greater control over costs, just to maintain the competitive development, otherwise health insurance could become unaffordable. Last edited by a moderator: BillTre russ_watters Mentor If cost is what prevents a widespread use? Demand at a lower price should be there if this works well. This revolution in treatments is only getting started really and wouldn't help much if health insurers are pushed into bankruptcy. The US in particular will need to take greater control over costs, just to maintain the competitive development, otherwise health insurance could become unaffordable. The issue I see is that it's my understanding that these drugs are limited or even single-patient designer drugs. That makes economy of scale in production difficult to achieve. There's not much difference in cost for growing something in a 1L fermenter vs a 1,000L fermenter, so if you make 1/1000th the drug it will have to cost 1000x as much. There's some exciting progress on the horizon, but also I think some tough conversations about the expected/accepted standard and cost of care. Ygggdrasil Ygggdrasil Science Advisor Gold Member 2019 Award The issue I see is that it's my understanding that these drugs are limited or even single-patient designer drugs. That makes economy of scale in production difficult to achieve. There's not much difference in cost for growing something in a 1L fermenter vs a 1,000L fermenter, so if you make 1/1000th the drug it will have to cost 1000x as much. There's some exciting progress on the horizon, but also I think some tough conversations about the expected/accepted standard and cost of care. Yes, one of the biggest problems with CAR-T therapy is that it requires a specialized team of scientists to engineer the patient's cells for the therapy. The logistics of the process can be quite complex: One of the first CAR-T treatments to reach the marketplace will probably come from Novartis. The Swiss drug giant last year completed a global test of children with leukemia in which 82 percent of the kids saw their tumors evaporate, and many stayed cancer-free. Novartis will apply for permission to sell the treatment this year, but the company isn’t too happy with how the therapy is made. For its study, Novartis says that it air-shipped patients’ cells back and forth to a single cell-processing factory it owns in Morris Plains, New Jersey, with the help of Cryoport, a company specializing in shipping frozen cells. It’s logistically complex, labor-intensive, expensive, and potentially unpredictable, since no two people’s cells are the same. What’s more, Novartis isn’t certain how many patients it will actually be able to treat. https://www.technologyreview.com/s/603762/this-lab-in-a-box-could-make-gene-therapy-less-elitist/ One potential solution is to automate the process of genetically engineering T-cells as the Technology review quoted above discusses. See also: https://www.biopharma-reporter.com/...o-slash-the-cost-of-CAR-T-manufacturing-Cesca russ_watters and Laroxe Laroxe Science Advisor I think as more single gene products and ways of controlling gene expression become available the need for these far more complex & expensive approaches will disappear. I see these reports as being part of the research effort to increase our understanding of these processes but I think its premature to be even considering such approaches as becoming commonly available. The fact that the biological agents are already making huge changes in things like cancer treatments puts people who are suffering from the disease now in a very difficult position, there is the hope that the developments will help them personally and a degree of despair at how long new developments take to become established treatments. Dealing with uncertainty can be far more difficult than dealing with a bad certainty. Ygggdrasil Science Advisor Gold Member 2019 Award With regard to whether the cost of CAR-T therapies could go down enough in the future for them to become widespread, it is instructive to consider the example of in vitro fertilization, a procedure that also involves extracting cells from a patient, manipulating them in the lab, and putting them back into the patients body. When it was first introduced in the 1978, the procedure was very expensive and not very effective: Treatment was expensive with each cycle of IVF costing £3,000, at a time when the average annual income was around £6,000. Fertility treatment was restricted to those who could pay, and were willing to undergo this radical new technique. [...] With success rates in the early years averaging 12%, most women who went to Steptoe and Edwards did not end up with a baby https://www.theguardian.com/society/2013/jul/12/story-ivf-five-million-babies(according to online inflation calculators £3,000 in 1978 would be the equivalent of about £17,000 or$22,000 today).

Now, however, the procedure is performed fairly routinely, and it is estimated that since the first IVF birth in 1978, five million babies have been born through this procedure. Still progress has been slow. The costs can still be prohibitive (costing ~£5,000 per treatment in the UK, though researchers are working to reduce these costs to ~£200 per treatment). A ~3-fold reduction in cost for CAR-T might put it more in line with other anti-cancer treatments, but these costs might still be prohibitive for very wide use.

That said, we are also still very early in the days of cancer immunotherapy and it is possible to image other therapies (e.g. cancer vaccines), that could potentially be cheaper than genetically engineering T-cells.