After seeing a dramatic increase in the development and use of immunotherapy and precision medicine over the past few decades, oncological care now embraces the start of the adoptive cell therapy (ACT) era. This impulse towards a new treatment paradigm has been led by chimeric antigen receptor (CAR) T cells, the only type of ACT medicinal product to be commercialized so far. Brought about by an ever-growing understanding of cellular engineering, CAR T cells are T lymphocytes genetically modified with an appropriate DNA construct, which endows them with expression of a CAR, a fusion protein between a ligand-specific recognition domain, often an antibody-like structure, and the activating signaling domain of the T cell receptor. Through this genetic enhancement, CAR T cells are engineered from a cancer patient’s own lymphocytes to better target and kill their cancer cells, and the current amassed data on clinical outcomes point to a stream of bright developments in the near future. Herein, from concept design and present-day manufacturing techniques to pressing hurdles and bright discoveries around the corner, we review and thoroughly describe the state of the art in CAR T cell therapy.

Objective: The most common forms of migraine are complex disorders characterized by significant clinical diversity. The genetic basis of migraine has been the subject of many studies but remains largely unknown. We present the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility risk loci through a case-control study, in order to unravel population-specific variants. Methods: Genotyping was conducted on 380 individuals using the Applied Biosystems Axiom™ PMDA array. A vast dataset of 8,031,293 single-nucleotide polymorphisms (SNPs) was available, providing a comprehensive scope for GWAS analysis. PRS models were created and tested on subsets of the genotyping data, and the optimal statistical significance threshold was assessed. Results: We detected nine risk loci corresponding to nine lead SNPs ( ZNF385D , YTHDF3 , NPS , RAP1A/INKA2 , CTA-481E9.4/CTA-481E9.3 , AC092079.1 , PPHLN1 , SMYD3 and AL355597.1 (near ADARB2 )). Additionally, eleven variants, without any previous association to pathogenicity in migraine, were highlighted by the chosen PRS model. Among our results, a new locus within the NPS gene, representing a novel association with migraine, is a potential new target directly related to recent and effective migraine treatments. Conclusions: These findings reinforce the importance of neurotransmitter release and synaptic transmission, as well as the involvement of vascular components, in migraine pathophysiology. This work underscores that GWAS can provide novel, clinically valuable insights into populational and disease-associated genetic landscapes, enabling therapeutic developments and bolstering personalized medicine strategies.

Common forms of migraine are complex disorders characterized by significant clinical diversity. Their genetic basis has been extensively studied but remains unclear. This study represents the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility loci through a case–control study and unravel population-specific variants. Genotyping data was acquired with Applied Biosystems Axiom™ PMDA array, producing 12,035,248 single-nucleotide polymorphisms (SNPs) post-imputation, providing a comprehensive scope for GWAS analysis. PRS models were created and tested using a k-folds cross-validation framework and the optimal significance threshold was assessed. We detected 12 potential risk loci corresponding to 12 lead SNPs (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3, RAP1A, TIGD4, CADPS2, RP11-46E17.6, RP4-569D19.5, RP11-398K14.1, PCBP1-AS1, TCF15, IL6R and UNC13A). The top three variants (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3 and RAP1A) were also supported by the PRS model. We highlight that several variants present putative biological relevance to migraine pathophysiology, reinforcing the importance of neurotransmitter release, synaptic transmission and the involvement of vascular components in migraine pathophysiology.