Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors

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A few further observations from the American Society of Gene Therapy Meeting…


A recurrent theme in this blog is the frequency with which novel research fields encounter safety problems that confound laboratory predictions. One presentation at the 2009 ASGT meeting brought this point home.

Recall my entry on May 12 discussing various refinements to retroviral gene transfer that are aimed at reducing risk of malignancy. Researchers have postulated that HIV-derived lentiviral vectors might not cause the same leukemia-inducing mutations as retroviruses, and RAC recently passed a favorable judgment on a lentiviral vector gene transfer protocol for X-SCID.

How confident can we be that lentiviruses will not trigger leukemias? Some indication is provided in a May 2009 review by John Rossi in Molecular Therapy. It concluded “overall, the results of these [safety] analyses [of lentiviral vectors] are highly encouraging…” but “clearly, more careful analyses… are warranted in appropriate animal models.”

At ASGT, researchers from France reported preliminary results from a phase 1 trial testing lentiviral vectors in patients with beta-thalassemia. The study involved two patients. Though no malignancies have been detected, tests in one patient showed signs that some cells were repopulating the patients blood much faster than others (what researchers call “clonal dominance”). This is a worrisome signal, as it might indicate a premalignant state.

The lessons here are not that lentiviral vectors are unsafe (we don’t know whether this will lead to a malignancy), or that such vectors shouldn’t be used in human beings (we can’t say anything yet about the risk-benefit balance). Instead, I think the lesson is: in novel research areas, be very wary of anyone who makes emphatic claims that their system provides safe harbor. Expect the unexpected. (photo credit: dark matter, 2005)

BibTeX

@Manual{stream2009-95,
    title = {Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = jun,
    day = 23,
    url = {http://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/}
}

MLA

Jonathan Kimmelman. "Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors" Web blog post. STREAM research. 23 Jun 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/>

APA

Jonathan Kimmelman. (2009, Jun 23). Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors [Web log post]. Retrieved from http://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/


Yellow Light on Gene Transfer Studies

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Among the greatest heartbreaks in the field of gene transfer have been problems encountered in trials involving a rare, hereditary immune disorder, X-SCID (known popularly as “Bubble Boy” syndrome).  As is well known, a team of researchers based in Paris– and then in London– successfully reversed severe immunodeficiencies in 20 or so children using retroviral gene transfer starting around year 2000.  Shortly thereafter, however, the Paris team began observing rare leukemic disorders that were causally related to the gene transfer. To date, the Paris team has reported 4 cases of leukemia, with one leading to death. The London team has reported one leukemia.


In response to these events, the U.S. Recombinant DNA Advisory Committee (RAC) recommended that investigators only use retroviral gene transfer in the most severe situations– namely, where patients are ineligible for even high risk alternative care options like haploidentical stem cell transplantation.  RAC’s recommendations were stricter than those in the U.K., which allowed children to enter a study even if they were candidates for haploidentical transplants.  

As reported in the current issue of Molecular Therapy, the RAC recently decided to liberalize its recommendations, allowing retroviral gene transfer in children who are eligible for halploidentical transplantation. RACs recommendations are still somewhat stricter than those of the UK, because the former recommends against retroviral gene transfer in children who are candidates for haploidentical transplantation but under 3.5 years age (children in this category respond better to haploidentical transplants). RAC additionally supported a similar trial involving a different vector that integrates its genome into the host’s (lentiviral vectors, which are derived from HIV).

Is this gentle liberalization of standards justified?  Some will argue that the benefits of haploidentical transplantation are variable and undependable, and that since initial leukemias have been reported, researchers have made progress in improving the safety of their vectors. All this might be true, if one were evaluating this as a clinical judgment.

However, the judgment is better viewed through the lens of research rather than therapy. Though laboratory testing indicates that new retroviral and lentiviral vectors are safer than the old ones, there remain substantial uncertainties. For example, current assays for determining the oncogenicity of integrating vectors are not well worked out. Neither the new retroviral vectors nor lentiviral vectors have been used in blood stem cell gene transfer in a pediatric population. The effect of lentiviral vectors on gene sequences near their integrating sites remains poorly understood. In short, the null hypothesis of new trials is that these new vectors are no better than the old ones.

What’s the safest way to refute this null hypothesis and confirm what many think, on laboratory evidence, will be the case? In my view, the safest approach– for patients as well as the field in general, which stands to lose much from another major toxicity– is to begin with the most narrow medical indication possible, which means excluding children who stand a chance of benefiting from standard (albeit suboptimal) care.  (photo credit: Jamelah 2007)

BibTeX

@Manual{stream2009-103,
    title = {Yellow Light on Gene Transfer Studies},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = may,
    day = 12,
    url = {http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/}
}

MLA

Jonathan Kimmelman. "Yellow Light on Gene Transfer Studies" Web blog post. STREAM research. 12 May 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/>

APA

Jonathan Kimmelman. (2009, May 12). Yellow Light on Gene Transfer Studies [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/


Burst Bubbles

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Among the greatest traumas for gene transfer was the development of leukemias in several children participating in trials using retroviral vectors against X-linked Severe Combined Immune Deficiency (X-SCID– also known as “bubble boy syndrome”).  About 20 or so children have had their immune systems fully restored by this gene transfer strategy.  Tragically, however, five children in two X-SCID studies (one in Paris, the other, London) developed T-cell leukemias that were causally linked to the gene transfer approach.


In the September 2008 issue of Journal of Clinical Investigation, Salima Hacein-Bey Abina and 28 other authors characterize the molecular nature of four of the adverse events, and report the outcome.  Before this article, it was known that one of the children died. This article now reports that the other three children have “sustained remission” after chemotherapy. 

The authors report that the vector inserted itself at the same genetic locus (LMO2) in 3 of the 4 cases.  In one case, vector inserted at a different genetic locus (CCND2); in another, vector inserted itself at LMO2 as well as a second locus, BMI1.  This suggests that LMO2 disruption is not the only path to causing cancer for this vector.  One other finding stood out.  Since the first leukemia was detected, many have speculated that the cancer was partly caused by the gene (rather than just the vector). However, the authors present evidence that the gene was expressed at normal levels in the children who developed leukemia. This lends support to the theory that the leukemias were not caused by the gene, but rather by some combination of the vector, the cell types used, and perhaps some characteristic of the underlying disease. (photo credit: concretecandy, boy in the bubbles, 2006)

BibTeX

@Manual{stream2008-124,
    title = {Burst Bubbles},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = nov,
    day = 6,
    url = {http://www.translationalethics.com/2008/11/06/burst-bubbles/}
}

MLA

Jonathan Kimmelman. "Burst Bubbles" Web blog post. STREAM research. 06 Nov 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/11/06/burst-bubbles/>

APA

Jonathan Kimmelman. (2008, Nov 06). Burst Bubbles [Web log post]. Retrieved from http://www.translationalethics.com/2008/11/06/burst-bubbles/


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