An opinionated take on NEJM highlights for the second quarter of 2024

The quest for solid tumor CAR-T

For all their success in hematological cancers, the track record of CAR-Ts against solid tumors has been disappointing (though see here for an exception). One key obstacle has been access by CAR-Ts to the tumor site. Here, a Mass General team reports on their experience treating 3 patients afflicted with glioblastoma multiforme (GBM, a nearly always fatal brain malignancy) positive for a variant of the EGFR receptor. In each case they prepared (autologous) CAR-Ts against the EGFR variant, and delivered them directly into the appropriate lateral ventricle of the brain, in proximity to the tumor.  In all three cases there was rapid regression of the tumor, though two concurrent phenomena must unfortunately temper our enthusiasm. First, as measured by circulating tumor cells, the EGFR variant marker rapidly decreased, indicative of selective pressure on the tumor, but also of a potential mechanism for escape. Second, the CAR-Ts did not appear to be persistent – possibly readily explained since there was no formal preconditioning for marrow engraftment.  Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma


When the CRISPR way may be the better way

We have followed in this series the parallel gene therapy approaches to sickle cell disease and thalassemia (here, and here) followed by Bluebird (introducing a functional copy of the defective hemoglobin gene with a lentivirus vector) and Vertex/CRISPR Therapeutics (disabling the gene responsible for repression of functional fetal hemoglobin post birth). This time, it is phase 3 results for the latter approach that are presented in the Journal, and they are spectacular: 29/30 sickle cell patients were free of painful vaso-occlusive crises for the following 1.5 years, and 32/35 patients with beta thalassemia and at least 12 months of follow-up became transfusion independent. Both the Bluebird therapy (Lyfgenia, Zynteglo) and the Vertex therapy (Casgevy) are approved and competing in the marketplace, but at least from the analysts’ tea-leaves, Casgevy looks favored.

Are there broader lessons? From a technical perspective, now that we have CRISPR tech, it will usually be easier to disable a gene than repair/supplement a defect. So, when there is an option to achieve restoration of function via the former method, as was the case in sickle cell and thalassemia by disrupting the repressor of fetal hemoglobin production, it probably ought to be the first one to try.

Another question mark was the question of whether the use of CRISPR editing might lead to off-target effect but in a letter to the editor in the same issue of the journal, investigators report on an extensive analysis that looked at the 5,000 most likely sites for off-target editing (based on sequence homology with the CRISPR guide) and these were intact. This raises an interesting question: right now, the therapy relies on apharesis, ex-vivo editing, and re-infusion (with conditioning), a complex process. Could a similar therapy be administered directly in-vivo? Exagamglogene Autotemcel for Severe Sickle Cell DiseaseExagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia; Specificity of CRISPR-Cas9 Editing in Exagamglogene Autotemcel


Using genetics to understand Alzheimer’s disease

Population genetic work in Alzheimer’s disease (AD) has tended to be oriented toward the identification of genetic risk factors for AD, rather than protective factors, because the latter is a lot harder to do even though it may have more straightforward impact on the invention of therapies.  In Columbia, there exists a large kindred where a substantial fraction of the family carry a dominant variant of the gene PSEN1 which invariably causes an Alzheimer type dementia in the late 40s. In a prior study of this family, an individual carrier was found to be normal in their 70s, and further analysis showed that were homozygous for the so-call Christchurch variant of APOE3. Because it is not a common variant, homozygosity is extremely rare, but in a follow-up study of the family, 27 out of about ~1000 carriers of PSEN1 mutations with clinical histories were found to be heterozygous for APOE3ch, and in aggregate, for these individuals, the onset of AD is delayed by about 5 years.  Whether this potentially translates to a therapeutic approach is not clear, but it’s a step in the long road to understand this disease. APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease


Let’s hope this is a one-off …

A letter to the editor reporting a case of avian flu in a US dairy worker with no contact with birds or poultry, and where cows have been known to be affected. Fortunately, the worker had relatively mild disease, but in the past, cases of human infections by avian flu have had high mortality. So, we have moved from [Bird -> Human] and [Bird -> Cattle] to [Cattle -> Human].  Let’s hope we manage to stay one step short of [Human -> Human]. Highly Pathogenic Avian Influenza A(H5N1) Virus Infection in a Dairy Farm Worker


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.

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