The design of an NMR excitation scheme, whether selective or nonselective, is essentially the simultaneous inversion of an array of Bloch equations driven by magnetic fields which differ according to well-defined constraints. We find that if relaxation effects are negligible, nearly exact inversion of the Bloch equations is straightforward when performed in a special time-varying frame of reference. Repeated inversions of the Bloch equations for small perturbations provide the basis for arbitrarily large, optimal adjustments of the magnetization response to an applied time-varying magnetic field. Choice of the target response to be sought at each iteration is not trivial if overall adjustments of more than one-half rotation are required. We present the analysis both formally and in geometric terms and show how it leads to a general algorithm for the optimization of NMR excitation schemes. The unprecedented efficiency of the algorithm and its ability to generate novel pulses from distant starting approximations are demonstrated in the optimization of slice-selective pi pulses for inversion and refocusing, and a prefocused slice-selective pi/2 pulse. Other applications are discussed, including use of the algorithm to compensate for instrumental imperfections such as radiofrequency inhomogeneity.

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SUMMARYChimeric antigen receptor (CAR) T cell immunotherapy has the potential to revolutionize cancer medicine. However, excessive CAR activation, lack of tumor-specific surface markers, and antigen escape have limited the safety and efficacy of CAR T cell therapy. A multi-antigen targeting CAR system that is regulated by safe, clinically-approved pharmaceutical agents is urgently needed, yet only a few simple systems have been developed, and even fewer have been evaluated for efficacy in vivo. Here, we present NASCAR (NS3 ASsociated CAR), a collection of induc-ible ON and OFF switch CAR circuits engineered with a NS3 protease domain deriving from the Hepatitis C Virus (HCV). We establish their ability to regulate CAR activity using multiple FDA-approved antiviral protease inhibitors, including grazoprevir (GZV), both in vitro and in a xenograft tumor model. In addition, we have engineered several dual-gated NASCAR circuits, consisting of an AND logic gate CAR, universal ON-OFF CAR, and a switchboard CAR. These engineered receptors enhance control over T cell activity and tumor-targeting specificity. Together, our com-prehensive set of multiplex drug-gated CAR circuits represent a dynamic, tunable, and clinically-ready set of modules for enhancing the safety of CAR T cell therapy.

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