Advances in Chimeric Antigen Receptor T-Cell Therapies for Solid Tumors.

In 2017, the US Food and Drug Administration approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CARs), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed living drugs for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted. This state-of-the-art review will focus on the challenges, advances, and novel approaches being used to implement CAR T-cell immunotherapy for the treatment of solid tumors

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. TRIAL REGISTRATION: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer

Prolapsed Uterus in a Cow

On July 22, 1941, a three year old purebred Holstein cow had an apparently normal calving. Following parturition, the cow was allowed to drink approximately five gallons of warm water, and for a period of three hours was left unnoticed

Porcelain tableware

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Immunological Comparison of Rat Liver Tumors with Normal Rat Livers

Antisera were developed against centrifugal supernates and crude ribonucleoprotein fractions of normal rat livers and liver tumors. These antisera were tested with the homologous fractions of both the rat liver tumor and normal rat liver in agar-diffusion reactions. In no case was a definite reaction of nonidentity observed although a liver tumor antigen spur was sometimes observed in the reactions that utilized antisera directed against centrifugal supernates of liver tumors. The results indicate a qualitative similarity of a number of antigens derived from liver tumors and normal rat livers

CONSOLIDATED EDISON THORIUM REACTOR PHYSICS DESIGN

The nuclear characteristics of the CETR are described. Core operating lifetime, control-rod worth, and powerdensity distribution are discussed in relation to maximizing the core operating life. Other objectives of nuclear design are to minimize the power-density variation and to assure control of the reactor. (J.R.D.

Understanding patients' satisfaction with physician assistant/associate encounters through communication experiences: a qualitative study in acute hospitals in England.

BACKGROUND: Physician assistants/associates (PAs) are a recent innovation in acute hospital teams in England and many other countries worldwide. Although existing evidence indicates generally high levels of patient satisfaction with their PA hospital encounters, little is known about the factors associated with this outcome. There is a lack of evidence on the process of PA-patient communication in hospital encounters and how this might influence satisfaction. This study therefore aimed to understand patients' satisfaction with PA acute hospital encounters through PA-patient communication experiences. METHODS: A qualitative study was conducted among patients and representatives of patients seen by or receiving care from one of the PAs working in acute hospital services in England. Semi-structured interviews were undertaken face-to-face with study participants in the hospital setting and shortly after their PA encounter. Data were coded and analysed using thematic analysis. The study was framed within a theoretical model of core functions of medical encounter communication. RESULTS: Fifteen patients and patient representatives who had experienced a PA encounter participated in interviews, across five hospitals in England. Four interrelated communication experiences were important to participants who were satisfied with the encounter in general: feeling trust and confidence in the relationship, sharing relevant and meaningful information, experiencing emotional care and support, and sharing discussion on illness management and treatment. However, many participants misconceived PAs to be doctors, raising a potential risk of reduced trust in the PA relationship and negative implications for satisfaction with their PA encounter. Participants considered it beneficial that patients be informed about the PA role to prevent confusion. CONCLUSIONS: PA encounters offer a constructive example of successful clinician-patient communication experiences in acute hospital encounters from the patient's perspective. Study participants were generally naïve to the PA role. Hospital services and organisations introducing these mid-level or advanced care practitioner roles should consider giving attention to informing patients about the roles

Photosensitizer Drug Delivery via an Optical Fiber

: An optical fiber has been developed with a maneuverable miniprobe tip that sparges O2 gas and photodetaches pheophorbide (sensitizer) molecules. Singlet oxygen is produced at the probe tip surface which reacts with an alkene spacer group releasing sensitizer upon fragmentation of a dioxetane intermediate. Optimal sensitizer photorelease occurred when the probe tip was loaded with 60 nmol sensitizer, where crowding of the pheophorbide molecules and self-quenching were kept to a minimum. The fiber optic tip delivered pheophorbide molecules and singlet oxygen to discrete locations. The 60 nmol sensitizer was delivered into petrolatum; however, sensitizer release was less efficient in toluene-d8 (3.6 nmol) where most had remained adsorbed on the probe tip, even after the covalent alkene spacer bond had been broken. The results open the door to a new area of fiber optic-guided sensitizer delivery for the potential photodynamic therapy of hypoxic structures requiring cytotoxic control