PubMed Health⌕ Search

Biomedical subjects

Mark D McKee

Publications and source records attributed to Mark D McKee.

9 recordsLinked to original sources
PubMed2007

T cell immunotherapy.

Adoptive T cell immunotherapy is the isolation of tumor-specific T cells from a cancer patient, in vitro activation and expansion of these T cells, and re-infusion of the T cells to the patient. In a small percentage of patients with tumor types susceptible to immune modulation, adoptive therapy has proven to be highly effective. The use of adoptive therapy has several limitations which are being actively investigated today. T cells from various sources are being isolated for adoptive therapy: lymphocytes can be isolated from tumor lesions, from lymph nodes draining the tumor or a tumor vaccine site, or from peripheral blood lymphocytes stimulated with tumor antigens in vitro. Recent advances in T cell therapy include enhanced efficacy of T cell therapy following non-myeloablative chemotherapy and genetic modification of T cells for use in adoptive therapy. Clinical trials using gene-modified T cells with improved activation, lifespan, and tumor targeting are on the horizon. It is likely that adoptive immunotherapy will remain a fertile area for investigation resulting in advances in the fields of T cell biology and gene therapy. Adoptive therapy for cancer will become widespread only after its clinical benefit for sizeable patient populations has been established.

Animals↗
PubMed2006

Identification of a hepatitis C virus-reactive T cell receptor that does not require CD8 for target cell recognition.

Hepatitis C virus (HCV) has been reported to elicit B and T cell immunity in infected patients. Despite the presence of antiviral immunity, many patients develop chronic infections leading to cirrhosis, hepatocellular carcinoma, and liver failure that can require transplantation. We have previously described the presence of HLA-A2-restricted, HCV NS3-reactive cytotoxic T lymphocytes (CTL) in the blood of HLA-A2- liver transplantation patients that received an HLA-A2+ liver allograft. These T cells are analogous to the "allospecific" T cells that have been described in hematopoietic stem cell transplantation patients. It has been speculated that allospecific T cells express high-affinity T cell receptors (TCRs). To determine if our HCV-reactive T cells expressed TCRs with relatively high affinity for antigen, we identified and cloned a TCR from an allospecific HLA-A2-restricted, HCV:NS3:1406-1415-reactive CD8+ T cell clone and expressed this HCV TCR in Jurkat cells. Tetramer binding to HCV TCR-transduced Jurkat cells required CD8 expression, whereas antigen recognition did not. In conclusion, based on the reactivity of the TCR-transduced Jurkat cells, we have identified a TCR that transfers anti-HCV reactivity to alternate effectors. These data suggest this high affinity HCV-specific TCR might have potential new immunotherapic implications.

CD8 Antigens↗
PubMed2005

T cell avidity and tumor recognition: implications and therapeutic strategies.

In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell-tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR) affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell-tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.

Journal Article↗
PubMed2005

Antigen recognition and T-cell biology.

Despite the wealth of information that has been acquired regarding the way T cells recognize their targets, we are left with far more questions than answers regarding how to manipulate the immune response to better treat cancer patients. Clearly, most patients have a broad repertoire of T cells capable of recognizing their tumor cells. Despite the presence of these tumor reactive T cells and our ability to increase their frequency though vaccination or adoptive transfer, patients still progress. From the T cell side, defects in T cell signaling may account for much of our failure to achieve significant numbers of objective clinical responses. In spite of these negatives, the horizon does remain bright for T cell based immune therapy of cancer. The periodic objective clinical response tells us that immune therapy can work. Now that we know that cancer patients have the capacity to mount immune responses against their tumors, current and future investigations with agents which alter T cell function combined with vaccination or adoptive T cell transfer may help tip the balance towards effective immune therapies.

Animals↗
PubMed2004

The prognostic significance of margin width for extremity and trunk sarcoma.

BACKGROUND AND OBJECTIVES: To evaluate the significance of resection margin for soft tissue sarcoma (STS), we determined local recurrence-free interval (LRFI), distant metastases-free interval (DMFI), and overall survival (OS) for primary extremity and truncal STS with clear margins (> or =10 mm), close margins (1-9 mm), and positive margins (0 mm). METHODS: Patients were evaluated via review of charts and tumor specimens. RESULTS: Among 111 patients, tumors were predominantly high grade (86%), > or =5 cm (76%), and deep (81%). A minority of patients received adjuvant radiation (38%) and/or adjuvant chemotherapy (34%). Margin width was > or =10 mm (48%), 1-9 mm (40%), or 0 mm (12%). Margins > or =10 mm were less common for large (P = 0.009) or deep (P = 0.02) tumors. By multivariate analysis, independent factors for LRFI were tumor size (P = 0.04) and margin width (P = 0.03). Independent factors related to DMFI were tumor grade (P = 0.002), size (P = 0.007), and patient age (P = 0.02). Independent factors relating to OS were tumor grade (P = 0.001), size (P = 0.004), and depth (P = 0.03). CONCLUSIONS: Margins > or =10 mm independently predicted longer LRFI and are optimal for extremity STS resection. Adjuvant radiotherapy should be considered for all STS resected with margins <10 mm, and margin width should be considered when reporting and interpreting LR outcomes for these patients.

Chemotherapy, Adjuvant↗
PubMed2003

CD8-independent tumor cell recognition is a property of the T cell receptor and not the T cell.

The CD8 coreceptor enhances T cell function by stabilizing the TCR/peptide/MHC complex and/or increasing T cell avidity via interactions with the intracellular kinases Lck and LAT. We previously reported a CD4(+) T cell (TIL 1383I), which recognizes the tumor-associated Ag tyrosinase in the context of HLA-A2. To determine whether CD8 independent tumor cell recognition is a property of the TCR, we used retroviral transduction to express the TIL 1383I TCR in the CD8(-) murine lymphoma, 58 alpha(-)/beta(-). Immunofluorescent staining of TCR-transduced cells with human TCR V beta subfamily-specific and mouse CD3-specific Abs confirmed surface expression of the transferred TCR and coexpression of mouse CD3. Transduced effector cells secreted significant amounts of IL-2 following Ag presentation by tyrosinase peptide-pulsed T2 cells as well as stimulation with HLA-A2(+) melanoma lines compared with T2 cells alone or HLA-A2(-) melanoma cells. Further analysis of TCR-transduced clones demonstrated a correlation between T cell avidity and cell surface expression of the TCR. Therefore, the TIL 1383I TCR has sufficient affinity to mediate recognition of the physiologic levels of Ag expressed by tumor cells in the absence of CD8 expression.

Animals↗
PubMed2002

Provider case volume and outcome in the evaluation and treatment of patients with mammogram-detected breast carcinoma.

BACKGROUND: Practice volume may affect the outcome of patients with breast carcinoma. Defining factors that influence the relation of volume and outcome for the diagnosis and treatment of breast carcinoma is important, because breast carcinoma is common, and care is decentralized. METHODS: Community-wide diagnosis and treatment of mammogram-detected breast carcinoma was examined using claims data from a single insurer representing 25% of the regional population. Among 1001 mammogram-directed breast biopsies, the rate of breast carcinoma diagnosed by stereotactic core needle biopsy (SCNB) or excisional biopsy with needle localization (EBNL) and the rate at which breast-conserving surgery (BCS) was used were analyzed. Outcome and practice volume were examined for surgeons, radiologists, and medical centers. RESULTS: Two hundred twenty-four tumors were diagnosed by EBNL (604 diagnoses) and SCNB (397 tumors), for a 22.4% positive biopsy rate. The median number of procedures per physician was one. Positive biopsy rates for radiologists, surgeons, and medical centers did not correlate with practice volume. Positive biopsy rates for high-volume physician providers and medical centers ranged from 9% to 46%. The BCS rate was 45% and 64% for surgeons treating one or more than one claim, respectively. Tumor stage and surgeon case volume were the only independent predictors of BCS (P < 0.05). CONCLUSIONS: There is wide variation in diagnosis and treatment outcomes for patients with mammogram-detected breast carcinoma. Overall, practice volume was correlated with the use of BCS but not with the rate of positive biopsy. A wide variation in the positive biopsy rate among high-volume providers and medical centers suggests that volume of practice is not a surrogate for quality in the diagnosis of breast carcinoma.

Biopsy↗
PubMed2002

Effects of interleukin 2 therapy on lymphocyte magnesium levels.

Interleukin 2 (IL-2) can cause partial or complete tumor regression in approximately 20% of patients with renal cell carcinoma. Among the many physiologic effects of IL-2, decreased serum levels of the divalent cations magnesium (Mg) and calcium have been demonstrated, with corresponding decreases in their urinary excretion. We investigated the effect of IL-2 on lymphocyte Mg levels among patients receiving three different dosing regimens. Twenty-eight patients with metastatic renal cell carcinoma were treated with high-dose intravenous, low-dose intravenous, or subcutaneous IL-2 therapy. Serum ionized Mg, urinary Mg, and peripheral blood mononuclear cell Mg levels were measured in samples from patients during treatment and compared with pretreatment levels. Serum Mg and ionized Mg levels decreased for all patients within 12 hours of treatment (P <.005) and remained low for the duration of therapy. Urinary Mg decreased in parallel with serum levels in all patients (P <.005). The peripheral blood mononuclear cell Mg content per cell increased within 24 hours of treatment (P <.005). The magnitude of these changes was similar during the first week of treatment for patients receiving intravenous or subcutaneous administration of IL-2. During IL-2 therapy, lymphocyte Mg increases coincident with serum Mg depletion. Mg availability may have functional implications for lymphocyte proliferation and integrin function.

Adult↗