T-cells are everywhere: An opinionated take on NEJM highlights for October 2018

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One century after the use of convalescent serum, convalescent T-cells

The use of tailored T-cells (e.g. CAR-T) is transforming our approach to (blood) cancers, but what about using T-cells against their raison d’être, intracellular pathogens such as viruses?  JC virus is the cause of Progressive Multifocal Leukoencephalopathy (PML), a fatal disease of the brain triggered by immunosuppression commonly occurring during cancer or auto-immune disease therapy. In a series of three consecutive patients with PML, scientists from MD Anderson infused in the spinal fluid T-cells that had been selected and expanded for their recognition of BK virus (an analog to JC virus) from HLA-matched donors. They observed a rapid decrease of JC viral loads, in-situ expansion of the donated T-cells as they went to work fighting the infection, and in two cases a regression of symptoms and brain lesions, and in the last case disease stabilization – impressive results in patients who were essentially at death’s door.  The days are not far when we will have libraries of T-cells against a wide variety of targets sitting on our shelves. Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy (subscriber access)

 

Foundational requirements for scalable precision medicine

Flagging an excellent review/thought piece on the informational infrastructure necessary for the scalable development of precision medicine. Well worth reading for the lucidity of the thinking. One key insight: the limitations created by hierarchical structures as embodied for example in ICD-10 where classifications consist of series of nested categories.  Precision medicine requires a broader relational structure that matches the real clinical world where pathological states have multiple descriptive and causal connections. Classification, Ontology, and Precision Medicine (subscriber access)

 

Mining the JAK pathways

Psoriasis is an auto-immune disease of the skin which in its severe form can be debilitating for patients and for which intravenous monoclonal antibodies directed against interleurkin / tumor necrosis factor are a mainstay of management. Safe and equally efficacious oral therapies would certainly be more convenient: the agent BMS-986165 aims to fill this gap and this phase 2 study shows a promising therapeutic effect although we will have to wait phase 3 to know whether the side-effect profile is acceptable (which is always the main question with agents that tweak the immune system).  But beyond that, BMS-986165 targets TYK2 of the JAK pathway for which four players are knows: JAK1, JAK2, JAK3, and TYK2, and we now have agents against every one of those – this begs the question, in diseases of inflammation which typically affect an entire signaling network, wouldn’t the answer lie in modulating many elements of the network rather than hammering a single node as is currently the approach?   Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis (subscriber access)

 

Good news for cystic fibrosis (CF) patients – and for Vertex

The most common CF-related mutation is Phe508del CFTR, and since both CFTR alleles must be impaired for CF to develop, the most common genotypes are either Phe508del-Phe508del or Phe508del-MF (where MF is some other mutation causing minimal function for CFTR). Unfortunately recent advances in CF through therapies aimed at recovering CFTR function, have had only small effectiveness for Phe508del-Phe508del and no effectiveness Phe508del-MF. There is hope that this will change as two parallel placebo-controlled phase 2 studies of VX-659 and VX-445 (both from Vertex) show an unambiguous significant benefit for the treatment arms. One caveat is that these studies were of short duration (one month) and that phase 3 programs to demonstrate long term benefits are on-going. VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles; VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles; Triple CFTR Modulator Therapy for Cystic Fibrosis (subscriber access)

 

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