Intratumoral Delivery of Chimeric Antigen Receptor T Cells Targeting CD133 Effectively Treats Brain Metastases.

PURPOSE: Brain metastases (BM) are mainly treated palliatively with an expected survival of less than 12 months after diagnosis. In many solid tumors, the human neural stem cell marker glycoprotein CD133 is a marker of a tumor-initiating cell population that contributes to therapy resistance, relapse, and metastasis. EXPERIMENTAL DESIGN: Here, we use a variant of our previously described CD133 binder to generate second-generation CD133-specific chimeric antigen receptor T cells (CAR-T) to demonstrate its specificity and efficacy against multiple patient-derived BM cell lines with variable CD133 antigen expression. RESULTS: Using both lung- and colon-BM patient-derived xenograft models, we show that a CD133-targeting CAR-T cell therapy can evoke significant tumor reduction and survival advantage after a single dose, with complete remission observed in the colon-BM model. CONCLUSIONS: In summary, these data suggest that CD133 plays a critical role in fueling the growth of BM, and immunotherapeutic targeting of this cell population is a feasible strategy to control the outgrowth of BM tumors that are otherwise limited to palliative care. See related commentary by Sloan et al., p. 477.

A novel "in-situ tulip-bud deployment" method for transcatheter closure of secundum atrial septal defect.

OBJECTIVE: We devised a new technique for interventional closure of atrial septal defect (ASD) using the Amplatzer Septal Occluder (ASO), and validated this by comparing it with a cohort using the conventional method. BACKGROUND: Transcatheter closure of ASD is a widely accepted modality of treatment. Although the outcome is good, there are occasional technical difficulties encountered. METHOD: In this three-step technique, the device is protruded to form a "tulip bud." This "tulip bud" is then aligned adjacent to and along the plane of the ASD. The second step involves withdrawing the sheath in quick succession to deploy atrial discs over the septal defect. Finally, good placement of the occluder is checked before release. RESULTS: Twenty-seven consecutive patients (1.4-77.2 years of age, median = 15) underwent device closure by this method. Nineteen (70.4%) had a deficient aortic rim (< 5 mm). Mean (+/- SD) ASD size by transesophageal echocardiography (TEE) was 16.0 +/- 5.1 mm. The chosen ASO size was 122 +/- 8% of the ASD size. The mean (+/- SD) duration of deployment and of deployment to release was 1.27 +/- 1.91 minutes and 5.18 +/- 2.63 minutes, respectively. The total fluoroscopy and procedure time was 9.93 +/- 5.61 minutes and 68.67 +/- 28.39 minutes, respectively. Twenty-one out of 27 patients (77.8%) had closure in one attempt. Comparing these 27 patients with the previous 48 consecutive patients with a deficient aortic rim by the conventional method, there was no difference in age, body weight, Qp/Qs, ASD size and ASO size or degree of oversizing (p > 0.05). The percentage of patients with aortic root deficiency was slightly higher in "tulip-bud" group compared to the conventional group (63.2% vs. 58.4%; p = 0.039). No complications were observed in either series. CONCLUSION: This is a promising new method to circumvent some of the difficulties associated with closure of large ASDs and deficient aortic rim.

Directed ortho metalation-cross coupling strategies. N-cumyl arylsulfonamides. Facile deprotection and expedient route to 7- and 4,7-substituted saccharins.

By using the powerful N-cumylsulfonamide directed metalation group (DMG), a series of 2-substituted derivatives were prepared according to the directed ortho metalation (DoM) tactic (Table 1). Mild conditions for N-decumylation and other simple transformations of the products have been achieved (Scheme 2). The 3-silyloxy sultam 12 undergoes further DoM to give formyl, thiomethyl, iodo, and amide derivatives 13a-g of potential value for saccharin synthesis (Table 2). An effective route to target 7-aryl saccharins via Suzuki cross coupling (Table 3) followed by further metalation-carbamoylation and cyclization (Table 5) is described. 4,7-Disubstituted saccharins have been obtained by similar sequences (Scheme 3). Mild TFA-mediated N-decumylation furnishes substituted primary arylsulfonamides (Table 4).

Rapid assembly of the bicyclo[5.3.1]undecenone core of penostatin F: a successive Diels-Alder/Claisen reaction strategy with an efficient stereochemical relay.

The first synthesis of the tricyclic core of Penostatin F (1) using a stereocontrolled Diels-Alder reaction and a Claisen rearrangement in succession has been achieved in nine steps from commercially available methyl acetoacetate and (E)-2-decenal. Penostatin F is a metabolite isolated from a fungal strain of Penicillium sp., OUPS-79, separated from the marine alga Enteromorphia intestinalis and exhibits significant cytotoxicity against cultured P388 Leukemia cells (ED(50) = 1.4 micromol/mL). [reaction: see text]