Non‐clinical safety evaluation of single and repeated intramuscular administrations of MAGE‐A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys

The MAGE‐A3 recombinant protein combined with AS15 immunostimulant (MAGE‐A3 Cancer Immunotherapeutic) is under development by GlaxoSmithKline for the treatment of lung cancer and melanoma. We performed non‐clinical safety studies evaluating potential local and systemic toxic effects induced by MAGE‐A3 Cancer Immunotherapeutic in rabbits (study 1) and cynomolgus monkeys (study 2). Animals were allocated to two groups to receive a single (rabbits) or 25 repeated (every 2 weeks) injections (monkeys) of MAGE‐A3 Cancer Immunotherapeutic (treatment groups) or saline (control groups). All rabbits were sacrificed 3 days post‐injection and monkeys 3 days following last injection (3/5 per gender per group) or after a 3‐month treatment‐free period (2/5 per gender per group). Local and systemic reactions and MAGE‐A3‐specific immune responses (monkeys) were assessed. Macroscopic and microscopic (for rabbits, injection site only) post‐mortem examinations were performed on all animals. No systemic toxicity or unscheduled mortalities were recorded. Single (rabbits) and repeated (monkeys; up to four times at the same site) injections were well tolerated. Following five to seven repeated injections, limb circumferences increased up to 26% (5 h post‐injection), but returned to normal after 1–8 days. Three days after the last injection, enlargements of iliac, popliteal, axillary and inguinal lymph nodes, and increased incidence or severity of mononuclear inflammatory cell infiltrates was observed in injected muscles of treated monkeys. No treatment‐related macroscopic findings were recorded after the treatment‐free period. MAGE‐A3‐specific antibody and T‐cell responses were raised in all treated monkeys, confirming test item exposure. Single or repeated intramuscular injections of MAGE‐A3 Cancer Immunotherapeutic were well tolerated in rabbits and monkeys. Copyright © 2014 GlaxoSmithKline Vaccines. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.     

Ventilation/perfusion (V/Q) scanning in contemporary patients with pulmonary embolism: utilization rates and predictors of use in a multinational study

Journal of Thrombosis and Thrombolysis - Ventilation/perfusion (V/Q) imaging and computed tomography pulmonary angiography (CTPA) are common tools for acute pulmonary embolism (PE) diagnosis....     

Preferences for Conditional Economic Incentives to Improve Pre-exposure Prophylaxis Adherence: A Discrete Choice Experiment Among Male Sex Workers in Mexico

AIDS and Behavior - Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV but requires sustained adherence. Conditional economic incentives (CEIs) can improve medication-taking...     

Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation

Interactions between killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands influence development of natural killer (NK) cell repertoire and response to infection, cancer, and allogeneic tissue. As KIRs and HLA class I molecules are highly polymorphic, clinical allogeneic hematopoietic cell transplantation is predicted to frequently involve KIR mismatch, and thus to provide a unique system for study of human NK cell receptor repertoire development. Eighteen leukemia patients undergoing HLA-matched transplantation and their donors were analyzed for KIR genotype. Ten of 13 HLA-identical donor-patient pairs were KIR mismatched and 3 were matched; all HLA-matched unrelated pairs were KIR mismatched. Reconstitution of recipient NK cell repertoire following transplantation was examined using flow cytometry and monoclonal antibodies specific for KIR and CD94:NKG2A. These data form 3 groups. Six to 9 months after transplantation, 8 patients (group 1) reconstituted an NK cell repertoire resembling that of their donor, and for KIR-mismatched transplants, distinct from the recipient before transplantation. In the first year after transplantation, 5 patients (group 2) exhibited a generally depressed frequency of KIR-expressing NK cells and concomitant high frequency of CD94:NKG2A expression. By 3 years after transplantation, the frequency of KIR-expressing NK cells had increased to donor values, in the 3 patients from group 2 analyzed for this period. The remaining 5 patients experienced severe clinical complications following transplantation and displayed unique features in their NK cell receptor reconstitution. These results demonstrate that a majority of HLA-matched hematopoietic cell transplantations involve KIR mismatch and reveal differences in NK cell repertoire having potential impact for immune responsiveness and transplantation outcome.     

Maternal HLA class II compatibility in men with systemic lupus erythematosus

OBJECTIVE: Maternal-fetal cell transfer during pregnancy can lead to long-lasting microchimerism, which raises the question of whether microchimerism sometimes contributes to autoimmune disease later in life. In an experimental model, transfusion of parental lymphocytes homozygous for major histocompatibility complex alleles results in systemic lupus erythematosus (SLE). We identified male patients with SLE and healthy male subjects and their mothers in order to investigate the mother-son HLA relationship in SLE risk. Male subjects were selected in order to avoid confounding due to fetal microchimerism, which may occur in women. METHODS: HLA genotyping for DRB1, DQA1, and DQB1 was conducted for sons and their mothers. Thirty men with SLE and their mothers were compared with 76 healthy men and their mothers. RESULTS: Sons with SLE were HLA-identical with their mothers (bidirectionally compatible) for the basic HLA-DRB1 groups encoded by DRB1*01 through DRB1*14 more often than were healthy sons (odds ratio [OR] 5.0, P = 0.006). Each DRB1 group contains multiple allelic variants; male patients with SLE and their mothers often were identical for both DRB1 allelic variants (OR 3.2, P = 0.08). For DQA1 and DQB1, the ORs were 2.3 (P = 0.08) and 2.0 (P = 0.21), respectively. When analysis was limited to male subjects with SLE-associated HLA genes (encoding HLA-DR2 or HLA-DR3), the differences further increased for DRB1 basic groups (OR 7.2, P = 0.01), DRB1 alleles (OR 15.0, P = 0.018), DQA1 6.4 (P = 0.006), and DQB1 (OR 5.7, P = 0.027). No increase in (unidirectional) compatibility of the mother from the son's perspective was observed at any locus. CONCLUSION: We observed increased bidirectional HLA class II compatibility of male SLE patients and their mothers compared with healthy men and their mothers. This observation implies that maternal microchimerism could sometimes be involved in SLE and therefore merits further investigation.