This month’s issue of Molecular Therapy– the premium journal covering developments in gene transfer- reports two deaths in recent cancer gene transfer studies. Both studies involved a similar anti-cancer strategy, in which a patient’s T cells are genetically modified to mount a strong and sudden immune attack against the patient’s cancer (the particular genetic modification is known as “CAR,” for chimeric antigen receptors). Both were phase 1 studies. Both patients died from what looks like “cytokine storm”- the same phenomenon that caused life threatening toxicity in the Tegenero TGN1412 study in 2005. In one case, the authors attribute death to the gene transfer; in the other, the authors categorize the death as possibly related to the gene transfer (the latter was previously described at ASGT in 2009).
In all likelihood, these patients (or at least, one of the patients) will be the third or fourth death in gene transfer that is clearly attributable to gene transfer. Don’t expect too much public hand-wringing or media coverage, however: in both cases, the patients were adults and had terminal cancer. I have not made a careful study of these particular trials or the strategies they employ. So the following thoughts about these deaths should be read with caution:
1- Unpredictability: These deaths point, once again, to the unpredictability of strategies aimed at training the immune system to respond against tumors. Immune systems are notoriously difficult to model in animals, and as a result, every human study is essentially a shot in the dark. The authors of one of the reports sagely urge that phase 1 studies using similar strategies begin at low doses.
2-Where’s the Toxicology? Neither report mentions anything about observing similar toxicities in preclinical studies. Indeed, neither report even mentions preclinical toxicology studies. One wonders why: were they done? how were they done? what was observed? For example, both studies involved immunosuppression co-interventions aimed at enhancing the effects of the T-cells (in one case, administration of the drug cyclophosphamide; in the other, use of nonmyeloablative conditioning). Were toxicology studies performed in animals receiving these immunosuppression treatments?
3-Did Investigators Give Preclinical Studies Their Best Shot at Producing Similar Toxicity? Both phase 1 studies were supported by preclinical studies using mice that lacked functional immune systems. One has to wonder how useful it is to test immunotherapies in mice that lack properly functioning immune systems. From what I can tell, in neither the first nor the second case did investigators perform preclinical studies that simultaneously delivered modified T-cells and immunosuppressive drugs.
4- Please: No More Gratuitous Appeals to the Integrity of the Investigators. An editorial by a leading expert on CARs accompanies the reports in Molecular Therapy andprovides a very helpful summary and context of the events. It ends, however, with the statement “it is a great credit to all investigators involved that they have been so forthcoming in providing detailed reports of serious adverse events.” I heard similar sentiments expressed when one of the deaths was presented at a scientific meeting last year. True- the research team did provide an unusually extensive report and investigation, including autopsy. However, careful and public reporting of serious adverse events is exactly what researchers are supposed to do in phase 1 studies involving highly innovative approaches; praising them for coming forward with this kind of information is a bit like congratulating Canada every time it holds a democratic election. One has to wonder whether there is a reserve of trial deaths that are never investigated or reported. (photo credit: Steve Kay 2008)
@Manual{stream2010-67,
title = {CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2010,
month = apr,
day = 22,
url = {http://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/}
}
MLA
Jonathan Kimmelman. "CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy" Web blog post. STREAM research. 22 Apr 2010. Web. 09 Nov 2024. <http://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/>
APA
Jonathan Kimmelman. (2010, Apr 22). CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy [Web log post]. Retrieved from http://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/
California’s Institute for Regenerative Medicine just announced a series of large funding awards to fund translational research initiatives involving (mostly) stem cells. The projects funded are telling with respect to what was funded, and what they will attempt to achieve.
First, notwithstanding a press release containing the words “bringing stem cell therapies to the clinic,” several projects are really dressed up gene transfer studies. Thus, one team will use gene transfer in hematopoietic stem cells for sickle cell anemia; another two will use gene transfer to stem cells for treating brain malignancies; another RNAi for HIV. All this is only further evidence that the field of stem cells is devouring gene transfer. Other projects are aimed more at getting “stem cells out of the clinic” by using small molecules or monoclonal antibodies to destroy stem cells causing malignancies.
Second is the sweeping ambition. As it stands today, only one clinical trial involving embryonic stem cell-derived tissues has been initiated. The projects funded under these awards are “explicitly expected to result in a filing with the FDA to begin a clinical trial.” Given that these projects are funded for four years, CIRM seems to be banking on the prospect of at least a few of these initiating phase 1 trials within five years. Four of these proposals involve goals of implanting embryo-derived tissues, and two of these involve non-lethal conditions–macular degeneration and type I diabetes (technically, other awarded projects involve nonlethal, though extremely morbid conditions). Another involves implantation of embryo-derived tissues for Amyotrophic Lateral Sclerosis. It will be interesting to see how many of these meet their translational objectives, and how investigators will navigate the ethical, regulatory, and social complexity of initiating clinical testing. (photo credit: Michael Ransburg, 2008)
@Manual{stream2009-80,
title = {California Dreamin: CIRM Announces New Stem Cell Awards},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = nov,
day = 5,
url = {http://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/}
}
MLA
Jonathan Kimmelman. "California Dreamin: CIRM Announces New Stem Cell Awards" Web blog post. STREAM research. 05 Nov 2009. Web. 09 Nov 2024. <http://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/>
APA
Jonathan Kimmelman. (2009, Nov 05). California Dreamin: CIRM Announces New Stem Cell Awards [Web log post]. Retrieved from http://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/
Last year’s “big ticket” item at ASGT was results from the first three patients in two gene transfer trials testing nearly identical products against a rare form of congenital blindness, Leber’s Congenital Amaurosis (LCA). I previously blogged (here and here and here and elsewhere) on the controversial decision to move the intervention into children, given the novelty of the intervention, that the trial is primarily a safety study, and that blindness is not a fatal condition.
Today, Jean Bennett of University of Pennsylvania presented an update on the first three patients (previously reported in New England Journal of Medicine) plus results on the next three patients. Here’s a synopsis. The first three patients continue to show dramatic improvement in objective measures like pupillometry (that is, their pupils are responding to flashes of light in a way that does not normally occur in patients with this form of blindness), and they show signs of improved vision.
The next three patients were children eight years or a bit older. Bennett showed dramatic footage of a child unable to find his way through a maze when using the uncorrected eye, and navigating a maze with relative ease with the corrected eye. She also showed data indicating retinal function in regions of the eye receiving vector. Improvements in vision were greater with the children than in the previous cohort- which she chalked up to the fact that retinal tissue was not as degenerated in younger patient-volunteers. The team did not observe any gene transfer-related adverse events.
The other two LCA trials were conspicuously missing from the meeting. Rumor has it that the Penn team has been far more successful recruiting patients with this rare disorder. Bennett flashed a slide at the beginning of her presentation showing that patients had been accrued from several continents- North America, Africa, Europe, and elsewhere. Patients in the second cohort, according to Bennett, are begging to have their second eye dosed. (photo credit: Ferran 2009).
@Manual{stream2009-96,
title = {The Vision Thing: Update on LCA},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = may,
day = 30,
url = {http://www.translationalethics.com/2009/05/30/the-vision-thing-update-on-lca/}
}
MLA
Jonathan Kimmelman. "The Vision Thing: Update on LCA" Web blog post. STREAM research. 30 May 2009. Web. 09 Nov 2024. <http://www.translationalethics.com/2009/05/30/the-vision-thing-update-on-lca/>
APA
Jonathan Kimmelman. (2009, May 30). The Vision Thing: Update on LCA [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/30/the-vision-thing-update-on-lca/
This year’s annual meeting of the American Society of Gene Therapy is in San Diego. I’ve been to several interesting talks thus far, and plan to post entries on a few. For now, here’s an overview of some major (or some not so major) clinical developments in gene transfer that are being reported at this meeting.
1- Last year, I predicted that the first gene transfer applications were nearing licensure. Not so fast. Because of concurrent sessions, I was unable to attend the entire talk given by Robert Shaw of the British biotech company Ark Therapeutics. Ark has developed a gene transfer approach, Cerepro, that uses adenovirus to treat malignant glioma (which is one of the most aggressive types of cancer). Ark recently applied to the European drug regulatory authority, EMEA, for registration of Cerepro. Why not FDA? Dunno (though the speaker stated that the review standards are more or less the same). The data behind the product are less than earth shaking. According to information available over the web [proviso- these data are from August 2008], the pivotal phase 3 study of Cerepro showed only a 42-day increase in survival for patients in the active drug arm. And the product caused “increases” in hemiparesis, aphasia, and fever.
2- Another somewhat discouraging indication of the challenges in reaching licensure for gene transfer products was a session titled “late stage industry clinical trials.” To me, late stage means phase 3. But three talks centered on phase 1/2 studies, and none presented phase 3 results. The first talk was given by Ceregene on their Parkinson’s disease product Cerepro. The product did not show any significant advantage over sham for their primary endpoint.
3- Last year, the “buzz” at ASGT was the preliminary results from three studies testing AAV vectors for a form of congenital blindness, LCA. I also discussed the somewhat ethically controversial decision to move this study into children. I will look forward to attending Jean Bennett’s talk on Friday; her abstract reports that her LCA study has enrolled “9 children and young adults” ranging from age 8 to 26 years. The abstract claims improvement in “subjective and objective” measures of vision. To be continued… (photo credit: slack12, 2008)
@Manual{stream2009-99,
title = {ASGT in San Diego},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = may,
day = 28,
url = {http://www.translationalethics.com/2009/05/28/asgt-in-san-diego/}
}
MLA
Jonathan Kimmelman. "ASGT in San Diego" Web blog post. STREAM research. 28 May 2009. Web. 09 Nov 2024. <http://www.translationalethics.com/2009/05/28/asgt-in-san-diego/>
APA
Jonathan Kimmelman. (2009, May 28). ASGT in San Diego [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/28/asgt-in-san-diego/
Why is gene transfer going cellular? The publicly stated reasons are two fold. First is a recognition that gene transfer has always involved “cell transfer.” For instance, ADA-SCID and X-SCID protocols– for that matter, all ex vivo protocols– involve modifying cells outside the body, and returning them to the volunteer.
A second reason is to have a more “inclusive” society, and an “expanded membership base.” I suspect this partly reflects a concern that cell-types might affiliate with groups like ISCT (International Society of Cell Therapy), which has a “gene therapy” committee, or perhaps also ISSCR (International Society of Stem Cell Research).
Of course, this raises the question of what ASGCT means by “CT.” Does the society intend “American Society of Gene AND Cell Therapy,” or is it “OR Cell Therapy (which would include protocols that do not involve genetic modification). I can’t help but wonder what the realignment will mean for gene transfer. Since its founding, “gene transfer” has represented a kind of “invisible college” – an international network of collaborations and co-citations with a common set of concerns. Does renaming represent the demise of the gene transfer invisible college, as “genes” are absorbed under the more powerful social category of “cells?” Or does it represent a promising extension of the network? Is this simply a reflection that in the first decade of the 21st century, “cells” are, in terms of scientific capital, what “genes” were to the 1990s? (photo credit: I like 2008)
@Manual{stream2008-117,
title = {Soft Cells and C-Sections},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = dec,
day = 10,
url = {http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/}
}
MLA
Jonathan Kimmelman. "Soft Cells and C-Sections" Web blog post. STREAM research. 10 Dec 2008. Web. 09 Nov 2024. <http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/>
APA
Jonathan Kimmelman. (2008, Dec 10). Soft Cells and C-Sections [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/
Since it’s issuance in 1998, Canada’s Tricouncil Policy Statement (Canada’s policy on the ethics of human research) has had an influence on the practice of research ethics that has outsized Canada’s population. The three research councils– CIHR, NSERC, and SSHRC– are presently revising the Tricouncil, and a few days ago, a revised draft was presented on the CIHR web site.
There is much to commend the newest version. There are also a number of disappointments. I won’t dwell on these here, however. Instead, I will focus on Tricouncil’s revised language on phase 1 and gene transfer research.
The revised Tricouncil contains a definition of phase 1 that, in my view, is somewhat outmoded and not much of an improvement on the old version. Both emphasize the role of phase 1 in toxicity and dose determination, but do not encompass the many other purposes to which phase 1 trials are put (e.g. for deciding whether to pursue phase 2, for gathering evidence of biological effects, etc.). On the other hand, the new Tricouncil requires prospective registration of all trials– including phase 1. And it contains a lengthy discussion of “therapeutic misconception,” which it defines as “the tendency of trial participants to believe that the primary intention of research tests and interventions is to provide a therapeutic benefit to the patient-participant.” The document urges research ethics boards and researchers to “emphasize which specific elements of a clinical study are required for research purposes, as well as the differences between research and the standard clinical care they might otherwise receive.” Bravo.
The new Tricouncil also, for the most part, replaces the old language of “gene therapy” with the more neutral “gene transfer.” In a section on “Gene Transfer,” the new draft warns about therapeutic misconception. It shrinks from any ethical statement on germline modification by deferrinng to Canada’s Assisted Human Reproduction Act. The remainder of the text notes the irreversibility of genetic alterations (not quite accurate), the potentially latent nature of gene transfer risks (a point I agree with), and states that research and ethical debate is evolving rapidly (a point I mostly agree with). Somewhat disappointingly, there is no mention of the need for centralized, transparent, or specialized review of such protocols.
On balance, these two sets of modifications are pretty good, though rather than anticipate the issues that are likely to arise in the next 5-10 years while this draft is in force, I worry a little that instead the draft represents a policy that I and others wish we might have had in the previous 5-10 years. Onwards and upwards! (photo credit: Studiolit 2006)
@Manual{stream2008-118,
title = {Northern Lights? Canada and the New Tricouncil Draft},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = dec,
day = 8,
url = {http://www.translationalethics.com/2008/12/08/northern-lights-canada-and-the-new-tricouncil-draft/}
}
MLA
Jonathan Kimmelman. "Northern Lights? Canada and the New Tricouncil Draft" Web blog post. STREAM research. 08 Dec 2008. Web. 09 Nov 2024. <http://www.translationalethics.com/2008/12/08/northern-lights-canada-and-the-new-tricouncil-draft/>
APA
Jonathan Kimmelman. (2008, Dec 08). Northern Lights? Canada and the New Tricouncil Draft [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/08/northern-lights-canada-and-the-new-tricouncil-draft/
“Since 2005, we’ve started seeing the big 20 pharma corporations making investments [in gene therapy],” says a deputy head in European Medicine Agency (EMEA) in the October 2008 issue of Nature Biotechnology (“Ark floats gene therapy’s boat, for now,” by Randy Osborne). “When you want to know what season is there and when the weather will change, you have to see which birds are flying.”
All this should be very encouraging for the field. Yet the story also describes the many travails of companies seeking regulatory approval for their gene transfer products. One is Introgen, which sought approval for its adenovirus-p53 cancer product Advexin. FDA returned Introgen’s submission with a “refuse to file” letter indicating that the materials were incomplete. The study on which this filing was based was presented at the American Society of Gene Therapy meeting last Spring. As I indicated in my June 10 posting, a major concern with this study was that its efficacy claims were based on a subgroup analysis of genetic profiles. Others, like TheStreet.com columnist Adam Feuerstein, have been far less guarded in their assessment of Advexin; Feuerstein called Introgen “a living textbook for what investors need to be wary of when considering a biotech investment.”
The second product profiled in the Nature Biotechnology story is Ark’s Cerepro, which uses herpes simplex virus vectors to deliver a gene, thymidine kinase, to the tumor bed of patients with malignant glioma (a highly aggressive form of brain cancer); the gene then converts a pro-drug, ganciclovir, into a toxin that kills tumor tissue. Ark is reportedly planning to file a license application to EMEA. Preliminary data in a randomized controlled trial against standard of care vs. standard of care + Cerepro indicate a median extension of survival by 42 days (with serious side effects).
One last product profiled briefly is Amsterdam Molecular Therapeutic’s product, Glybera, for a very rare genetic disease lipoprotein lipase deficiency. Amsterdam intends to file for licensure “later this year.”
The fortunes of clinical gene transfer might indeed be flying North. But with some lead products showing such incremental gains in survival and dependence on combination with standard care, clinical application seems less likely to arrive with a bang than with a modest honk. (photo credit: denis collette, 2007)
@Manual{stream2008-130,
title = {Northward Migration?},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = oct,
day = 14,
url = {http://www.translationalethics.com/2008/10/14/northward-migration/}
}
MLA
Jonathan Kimmelman. "Northward Migration?" Web blog post. STREAM research. 14 Oct 2008. Web. 09 Nov 2024. <http://www.translationalethics.com/2008/10/14/northward-migration/>
APA
Jonathan Kimmelman. (2008, Oct 14). Northward Migration? [Web log post]. Retrieved from http://www.translationalethics.com/2008/10/14/northward-migration/
This month’s issue of Molecular Therapy– the premium journal covering developments in gene transfer- reports two deaths in recent cancer gene transfer studies. Both studies involved a similar anti-cancer strategy, in which a patient’s T cells are genetically modified to mount a strong and sudden immune attack against the patient’s cancer (the particular genetic modification is known as “CAR,” for chimeric antigen receptors). Both were phase 1 studies. Both patients died from what looks like “cytokine storm”- the same phenomenon that caused life threatening toxicity in the Tegenero TGN1412 study in 2005. In one case, the authors attribute death to the gene transfer; in the other, the authors categorize the death as possibly related to the gene transfer (the latter was previously described at ASGT in 2009).
