The cancer-germline gene MAGE-3 codes for tumor-specific antigens recognized on many tumors by T lymphocytes. A MAGE-3 antigen presented by HLA-A1 has been used in several vaccination trials on metastatic melanoma patients. Only a small minority of patients have shown evidence of tumor regression. Attempts to correlate the tumor rejections with the cytotoxic T lymphocyte (CTL) response against the vaccine have been hampered by the low level of these responses. In noncancerous individuals, the frequency of the T cell precursors against antigen MAGE-3.A1 is Ϸ4 ؋ 10 ؊7 CD8 T cells. The diversity of the T cell receptor repertoire of these anti-MAGE-3.A1 precursors was analyzed in one individual. The results indicate that it is very likely that the repertoire comprises >100 clonotypes. On this basis, it is possible to use not only the frequency of CTL precursors in the blood but also the presence of dominant clonotypes to ascertain in patients the existence of anti-MAGE-3.A1 responses as low as 10 ؊6 of CD8. With this approach, we observed a correlation between tumor regression and anti-MAGE-3.A1 CTL responses in patients vaccinated with a recombinant virus encoding the antigen and also in patients vaccinated with peptide-pulsed dendritic cells. In contrast, for patients showing tumor regression after vaccination with peptide alone, CTL responses were almost never observed. It is possible that even those CTL responses that are below our present detection level can trigger a sequence of events that leads to tumor regression. S hared tumor-specific antigens encoded by cancer-germline genes such as those of the MAGE family have been used for therapeutic vaccination of cancer patients. A number of small clinical trials on metastatic melanoma patients have been performed with the MAGE-3 168-176 antigen EVDPIGHLY, which is presented by HLA-A1 (1, 2). Evidence of tumor regression was observed in Ϸ20% of the patients, but clinical benefit was limited to Ϸ10% of the patients.Our initial work suggested that in most vaccinated patients, even in those who displayed tumor regression, it was difficult to ascertain the existence of an antivaccine T cell response. We nevertheless felt that it was crucial to know whether low-level responses had occurred and whether such cytotoxic T lymphocyte (CTL) responses showed a correlation with tumor regression to understand why most patients failed to show any evidence of regression. We therefore developed a sensitive approach based on in vitro restimulation of blood lymphocytes with the antigenic peptide over 2 weeks, followed by labeling with tetramers. To evaluate precursor frequencies, these mixed lymphocyte-peptide cultures were conducted under limiting dilution conditions. Cells that were labeled with the tetramer were cloned, the lytic specificity of the clones was verified, and their diversity was analyzed by T cell receptor (TCR) sequencing (3).As the interpretation of these analyses was based on both the frequency and the diversity of the anti-MAGE-3.A1 CTL clones, it was necessary t...
'Cancer-germline' genes such as the MAGE gene family are expressed in many tumors and in male germline cells but not in normal tissues. They encode shared tumor-specific antigens, which have been used in therapeutic vaccination trials of metastatic melanoma patients. To establish whether there is a correlation between tumoral regressions and T-cell responses against the vaccine antigen, we evaluated the responses of patients vaccinated with a MAGE-3 antigenic peptide or a recombinant virus coding for the peptide. Blood lymphocytes were stimulated with antigenic peptide followed by detection with tetramer, T-cell cloning, and TCR analysis. In 4/9 regressor patients and in 1/14 progressors we found a low level, usually monoclonal cytolytic T lymphocyte response against the MAGE-3 peptide.
We observed two cases of Clostridium tertium bacteremia three months apart in the sterile unit of our department of hematology and oncology. One patient was being treated for first-relapse acute myeloblastic leukemia, while the second was receiving high-dose chemotherapy with hematopoietic stem cell support for non-Hodgkin lymphoma. At the time that C. tertium was identified, the first patient was completely asymptomatic, while the second was highly febrile. Both responded biologically and/or clinically to antibiotherapy. We discuss the epidemiology and pathology of C. tertium in the general and cancer patient population.
Oral mucositis is a frequent and devastating side effect of anticancer treatments. It impairs the patient's quality of life and also can be life threatening because severe infections and delayed or incomplete anticancer treatments may result. This problem has been largely overlooked and underestimated in the past. However, recently studies have been performed to precisely identify the epidemiology, cost, consequences, physiopathology, and treatments of oral mucositis. Clinical guidelines have recently been published to help the daily management of this frequent complication. In addition, some innovative new drugs, including palifermin, have been developed to prevent and treat this major side effect of cancer treatments. In this paper we summarize the recent developments of oral mucositis management.
Tumor infiltrating lymphocytes (TIL) display activation markers and their presence is often associated with a favorable outcome. The role of tumor antigens in T cell recruitment into tumors is unclear. In an attempt to address this issue, we purified lymphocytes from breast tumor or nontumor, mammary tissue from patients, and normal mammary tissue from healthy individuals. In all groups, including healthy individuals, the majority of cells displayed an effector/memory (CD45RA lo /CD27 1/2 ) phenotype and quite surprisingly the early and transient activation marker CD69, thus, questioning the tumor antigen specificity of TIL. Because the human repertoire is diverse, the T cells found in the tumors could recognize both self/tumor and environmental antigens through cross-reactivity. To test this hypothesis, we used two anti-male HY monospecific TCR transgenic mouse models. We found an infiltration of HY negative tumors by the CD4 1 and CD8 1 monoclonal T cells after priming with HY positive cells in the periphery. Thus, the presence of activated effector/memory T lymphocytes in tumors can be independent of reactivity against tumor antigens. These results suggest that to find activated effector T cells in a tissue does not always mean that a specific immune response is taking place. ' 2005 Wiley-Liss, Inc.Key words: human; rodent; tumor immunity; T cells; cell trafficking Tumor infiltrating lymphocytes (TIL) are found in different types of tumors and their presence has been correlated with a better outcome in patients with melanoma 1,2 and carcinoma of the kidney, 3 esophagus, 4 stomach, colon, 5,6 ovaries 7 and breast. 8,9 TIL are mostly T cells and a number of these have been demonstrated to be specific for tumor antigens. [10][11][12][13][14][15][16][17] Together with the discovery of tumor antigens, this led to the hypothesis that these TIL were actively fighting the tumor. 10,18 However, the proportion of tumor-specific vs. nonspecific T cells found in tumors is not known and the role of antigen in the intratumor accumulation of T cells is unclear. The intratumor T cells specific for tumor antigens are often viewed as the effector arm of the immunesurveillance model. This model is still challenged by 2 observations: (i) the increased incidence of tumors observed in immunodeficient patients is low for most common tumors, 19 (while it is high only for tumors that are virus-induced, such as HPV (Human papilloma virus)-induced skin and cervical cancers or EBV (Epstein-Barr virus)-related lymphoma) and (ii) the outcome of most common cancers in immunodeficient patients is comparable to that seen in immunocompetent patients. Moreover, some authors 20 argue against the increased tumor frequency observed by others 21 in immunodeficient mice, although these results have been disputed. 20 Taken together, these observations made in humans and mice call into question the fundamental role of the immune response to control tumor growth beside its antiviral activity.As breast cancer does not seem to be virally induced, the co...
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