Aarti Mathur

Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA(-) and CD45RO(+) after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA(+) and CD45RO(-) phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate-antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175.

New, effective therapies are needed for pancreatic ductal adenocarcinoma. Ipilimumab can mediate an immunologic tumor regression in other histologies. This phase II trial evaluated the efficacy of Ipilimumab for advanced pancreatic cancer. Subjects were adults with locally advanced or metastatic pancreas adenocarcinoma with measurable disease, good performance status, and minimal comorbidities. Ipilimumab was administered intravenously (3.0 mg/kg every 3 wk; 4 doses/course) for a maximum of 2 courses. Response rate by response evaluation criteria in solid tumors criteria and toxicity were measured. Twenty-seven subjects were enrolled (metastatic disease: 20 and locally advanced: 7) with median age of 55 years (27 to 68 y) and good performance status (26 with Eastern Cooperative Oncology Group performance status =0 to 1). Three subjects experienced ≥ grade 3 immune-mediated adverse events (colitis:1, encephalitis:1, hypohysitis:1). There were no responders by response evaluation criteria in solid tumors criteria but a subject experienced a delayed response after initial progressive disease. In this subject, new metastases after 2 doses of Ipilimumab established progressive disease. But continued administration of the agent per protocol resulted in significant delayed regression of the primary lesion and 20 hepatic metastases. This was reflected in tumor markers normalization, and clinically significant improvement of performance status. Single agent Ipilimumab at 3.0 mg/kg/dose is ineffective for the treatment of advanced pancreas cancer. However, a significant delayed response in one subject of this trial suggests that immunotherapeutic approaches to pancreas cancer deserve further exploration.

ConspectusPhotoelectrochemical water splitting is a promising avenue for sustainable production of hydrogen used in the chemical industry and hydrogen fuel cells. The basic components of most photoelectrochemical water splitting systems are semiconductor light absorbers coupled to electrocatalysts, which perform the desired chemical reactions. A critical challenge for the design of these systems is the lack of stability for the majority of desired semiconductors under operating water splitting conditions. One strategy to address this issue is to protect the semiconductor by covering it with a stabilizing insulator layer, creating a metal–insulator–semiconductor (MIS) architecture, which has demonstrated improved stability. In addition to enhanced stability, the insulator layer may significantly affect the electron and hole transfer, which governs the recombination rates. Furthermore, the insertion of an insulator layer leads to the introduction of additional insulator/electrocatalyst and insulator/semiconductor interfaces. These interfaces can impact the system’s performance significantly, and they need to be carefully engineered to optimize the efficiencies of MIS systems. In this Account, we describe our recent progress in shedding light on the critical role of the insulator and the interfaces on the performance of MIS systems. We discuss our findings by focusing on the concrete example of planar n-type Si protected by a HfO2 insulator layer and coupled to a Ni or Ir electrocatalyst that performs the oxygen evolution reaction, one of the water splitting half-reactions. To improve our fundamental understanding of the insulator layer, we precisely control the HfO2 insulator thickness using atomic layer deposition (ALD), and we perform a series of rigorous electrochemical experiments coupled with theory and modeling. We demonstrate that by tuning the insulator thickness, we can control the flux and recombination of photogenerated electrons and holes to optimize the generated photovoltage. Despite optimizing the thickness, we find that the maximum generated photovoltage in MIS systems is often significantly lower than the upper performance limit, i.e., there are additional losses in the system that could not be addressed by optimizing the insulator thickness. We identify the sources of these losses and describe strategies to minimize them by a combination of improving the semiconductor light absorption, removing nonidealities associated with interfacial defects, and finding alternative insulators with improved charge carrier selectivity. Finally, we quantify the improvements that can be obtained by implementing these specific strategies. Our collective work outlines strategies to analyze MIS systems, identify the sources of efficiency losses, and optimize the design to approach the fundamental performance limits. These general approaches are broadly applicable to photoelectrochemical materials that utilize sunlight to produce value-added chemicals.