The Principles of Engineering Immune Cells to Treat Cancer

Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell com...

Notch Signaling in Development, Tissue Homeostasis, and Disease

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies-and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it.

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Is autoimmunity the Achilles' heel of cancer immunotherapy?

Cellular therapies using regulatory T (Treg) cells are currently undergoing clinical trials for the treatment of autoimmune diseases, transplant rejection and graft-versus-host disease. In this Review, we discuss the biology of Treg cells and describe new efforts in Treg cell engineering to enhance specificity, stability, functional activity and delivery. Finally, we envision that the success of Treg cell therapy in autoimmunity and transplantation will encourage the clinical use of adoptive Treg cell therapy for non-immune diseases, such as neurological disorders and tissue repair. Therapies based on adoptive cellular transfer of regulatory T (Treg) cells are currently undergoing clinical trials for autoimmune diseases, graft-versus-host disease and the prevention of transplant rejection. This Review provides an overview of Treg cell biology and discusses the latest approaches to enhance Treg cells for therapeutic purposes.

Treg cell-based therapies: challenges and perspectives.

Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors

Many microbiota-based therapeutics rely on our ability to introduce a microbe of choice into an already-colonized intestine. In this study, we used genetically barcoded Bacteroides thetaiotaomicron (B. theta) strains to quantify population bottlenecks experienced by a B. theta population during colonization of the mouse gut. As expected, this reveals an inverse relationship between microbiota complexity and the probability that an individual wildtype B. theta clone will colonize the gut. The polysaccharide capsule of B. theta is important for resistance against attacks from other bacteria, phage, and the host immune system, and correspondingly acapsular B. theta loses in competitive colonization against the wildtype strain. Surprisingly, the acapsular strain did not show a colonization defect in mice with a low-complexity microbiota, as we found that acapsular strains have an indistinguishable colonization probability to the wildtype strain on single-strain colonization. This discrepancy could be resolved by tracking in vivo growth dynamics of both strains: acapsular B.theta shows a longer lag phase in the gut lumen as well as a slightly slower net growth rate. Therefore, as long as there is no niche competitor for the acapsular strain, this has only a small influence on colonization probability. However, the presence of a strong niche competitor (i.e., wildtype B. theta, SPF microbiota) rapidly excludes the acapsular strain during competitive colonization. Correspondingly, the acapsular strain shows a similarly low colonization probability in the context of a co-colonization with the wildtype strain or a complete microbiota. In summary, neutral tagging and detailed analysis of bacterial growth kinetics can therefore quantify the mechanisms of colonization resistance in differently-colonized animals.

Fitness advantage of Bacteroides thetaiotaomicron capsular polysaccharide in the mouse gut depends on the resident microbiota

Dirk Schüler für die ausgezeichnete Be-treuung und seine kontinuierliche Unter-stützung während meiner Zeit als Doktoran-din bedanken. analysis of the magnetosome island in Magnetospirillum gryphiswaldense: the mamAB operon is sufficient for mag-netite biomineralization. PLoS One 6:e25561 [3] Kolinko I, Lohsse A, Borg S et al. (2014) Biosynthesis of magnetic nanostructures in a foreign organism by transfer of bacterial magnetosome gene clusters. Im Gegensatz zum Wildtyp-Stamm von Rhodospirillum rubrum (A) kann der rekombinante Stamm mit inserierten Magnetosomen-Genen (B) mithilfe eines Magneten ange-reichert werden. C, Transmissionselektronenmikroskopische Aufnahme einer Mischkultur des magnetischen R. rubrum-Stamms (R. rubrum_ABG6X_feo) und des Donorstamms Magnetospiril-lum gryphiswaldense mit Magnetosomen (vergrößerte Ausschnitte) (aus [3]).

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Isabel Kolinko

Papers

Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors

Fitness advantage of Bacteroides thetaiotaomicron capsular polysaccharide in the mouse gut depends on the resident microbiota

Heterologe Synthese von Magnetosomen in einem phototrophen Bakterium