Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSP-mediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 x 10(7) to 3.0 x 10(12) viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 x 10(12) VP and transient grade IV thrombocytopenia at the dose of 3.0 x 10(12) VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4(+) and CD8(+) T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.
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PMID:A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients. 1909 59

Differences in CD8(+)CD57(-) and CD8(+)CD57(+) lymphocyte lifespan have been documented. Lower numbers and shorter lifespan are characteristic of CD8(+)CD57(+) in normal individuals. However, CD8(+)CD57(+) are expanded in certain disease states including T cell large granular leukemia and other hematologic malignancies. The mechanisms responsible for the differences in CD8(+)CD57(-) and CD8(+)CD57(+) lifespan remain elusive. In this study, we demonstrate that the small heat shock protein (Hsp) 27 is a key regulator of CD8(+)CD57(+) lymphocyte lifespan. We found that Hsp27 expression is significantly lower in CD8(+)CD57(+) than in CD8(+)CD57(-) lymphocytes. In contrast, Hsp60 and Hsp70 are expressed at comparable levels. Unlike other antiapoptotic Bcl-2-like molecules, the expression of Hsp27 tightly correlates with CD8(+)CD57(+) and CD8(+)CD57(-) lifespan. We demonstrate that Hsp27 overexpression in CD8(+)CD57(+) lymphocytes to levels found normally in CD8(+)CD57(-) lymphocytes decreased apoptosis. Accordingly, silencing of Hsp27 in CD8(+)CD57(-) lymphocytes increased apoptosis. Collectively these results demonstrate that Hsp27 is a critical regulator of normal CD8(+)CD57(+) lifespan supporting its use as a marker of lifespan in this lineage, and suggest a mechanism responsible for the decreased apoptosis and clonal expansion characteristic of certain disease states.
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PMID:The small heat shock protein 27 is a key regulator of CD8+ CD57+ lymphocyte survival. 2038 76

Patients undergoing treatment for glioblastoma multiforme are routinely placed on prophylactic treatment for Pneumocystis jirovecii pneumonia because of significant therapy-induced lymphopenia. In patients with sulfa allergies, dapsone prophylaxis is often used due to its efficacy, long half-life, cost effectiveness, and general safety at low doses. However, dapsone may uncommonly induce a hemolytic anemia, particularly in patients deficient of glucose-6-phosphate dehydrogenase. This hemolysis is thought to be a result of oxidative stress on red blood cells induced by dapsone metabolites which produce reactive oxygen species that disrupt the red blood cell membrane and promote splenic sequestration. A single case report of dapsone-induced hemolytic anemia in a patient with glioblastoma multiforme has been reported. We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone. There are several potential mechanisms by which histone deacetylase inhibition may alter dapsone metabolism including changes in hepatic acetylation or N-glucuronidation leading to an increase in the bioavailability of dapsone's hematotoxic metabolites. In addition, vorinostat may lead to increased hemolysis through inhibition of heat shock protein-90, a chaperone protein that maintains the integrity of the red blood cell membrane cytoskeleton. The potential interaction between dapsone and vorinostat may have important clinical implications as more than 10 clinical trials evaluating drug combinations with vorinostat in patients with malignant glioma are either ongoing or planned in North America.
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PMID:Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone. 2457 44

Tumor relapse is the primary cause of mortality in patients with hematologic cancers following autologous hematopoietic stem cell transplantation (HSCT). Vaccination early after HSCT can exploit both the state of lymphopenia and minimal residual disease for generating antitumor immunity. Here, multiple vaccinations using lymphoma cells engineered to secrete heat shock protein fusion gp96-Ig within 2 weeks of T cell-replete syngeneic HSCT led to cross-presentation and increased survival of lymphoma-bearing mice. To enhance vaccine efficacy, interleukin (IL)-2 was directed to predominantly memory phenotype CD8(+) T lymphocytes and natural killer (NK) cells via administration bound to anti-IL-2 monoclonal antibody clone S4B6 (IL-2S4B6). Combination therapy with gp96-Ig vaccination and coordinated infusions of IL-2S4B6 resulted in marked prolongation of survival, which directly correlated with ~500% increase in effector CD8(+) T-cell numbers. Notably, this dual regimen elicited large increases in both donor CD8(+) T and NK cells, but not CD4(+) T lymphocytes; the former 2 populations are essential for both vaccine efficacy and protection against opportunistic infections after HSCT. Indeed, IL-2S4B6-treated HSCT recipients infected with Listeria monocytogenes exhibited decreased bacterial levels. These preclinical studies validate a new strategy particularly well suited to the post-HSCT environment, which may augment adaptive and innate immune function in patients with malignant disease receiving autologous HSCT.
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PMID:Heat shock protein vaccination and directed IL-2 therapy amplify tumor immunity rapidly following bone marrow transplantation in mice. 2468 86