[Show abstract][Hide abstract] ABSTRACT: Oral mucositis (OM) is a painful complication of radiation therapy (RT) for head and neck cancer (H&NC). OM can compromise nutrition, require opioid analgesics and hospitalization for pain control, and lead to treatment interruptions. Based on the role of inflammatory pathways in OM pathogenesis, we investigated effect of cyclooxygenase-2 (COX-2) inhibition on severity and morbidity of OM.
[Show abstract][Hide abstract] ABSTRACT: Cancer is a disease of older age where genomic instability, impaired DNA repair, and weakened immune surveillance against cancer are recognized to play a causative role. Because the incidence of melanoma is increasing at a very fast pace in the elderly and there is a rapid expansion of the aging population, a large number of elderly patients with metastatic melanoma will be encountered in clinical practice. As a result, significant burden is expected to be placed on health care resources as effective treatment of this condition is sought. Because melanoma is an immunogenic tumor and promising immune-based treatments have acquired approval for treatment of metastatic melanoma, their successful use in elderly patients will require knowledge about aging and associated alterations in immune function. The spotlight will likely remain on antitumor immunity, its regulation and quality, and the profiles of the cytokines that shape the tumor microenvironment.
Clinics in dermatology 05/2013; 31(3):311-6. · 3.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Elderly cancer patients are often excluded from immune-based clinical trials and therapies based on the belief that they respond poorly to tumor antigens. Using melanoma as a model and melanoma related Mart-1 (27-35) epitope specific T cell receptor (TCR) engineered T cells as a tool we compared the T cell responses from young and elderly to the Mart-1(27-35) epitope, ex vivo. We also compared the natural Treg (nTreg) activities and the expression of a number of genes associated with immune response by real- time reverse Transcription Polymerase chain Reaction (qPCR) in formalin fixed primary melanomas, in situ. We detected a significant difference in CD8(+) T cell response to Flu antigen (influenza matrix peptide Flu MP(58-66)), but the responses of the two cohorts to melanoma antigen were comparable. nTreg activities in the elderly was significantly compromised. The qPCR analyses of tissues from elderly patients revealed lower levels of Fox-P3 expression but comparable levels of expression of IL-2, IFNγ, TNF α, IL-4, IL-10, IDO, and TGFβ. These findings indicate that elderly patients might be capable of responding to tumor antigens, and need not be excluded from immune-based therapies or clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Early diagnosis of cutaneous melanoma (CM) is associated with the finding of superficial tumors resulting in high cure rates with surgery, whereas those with deeply invasive tumors are at higher risk of recurrence and melanoma-specific mortality. Unfortunately, once metastatic to the visceral organs, CM is usually refractory to the presently available treatment modalities, resulting in uniformly poor outcomes in patients. Educating susceptible populations about the risk of developing CM has played an important role in preventive strategies despite the fact that benefits of primary skin screening are controversial. Although a number of reliable prognostic factors are recognized, clinical unpredictability is reflected by a small but significant proportion of patients who experience adverse outcomes from CM, even though lacking the known poor prognostic markers. Because CM is an immunogenic tumor, most of the new treatments have engaged in harnessing antimelanoma immunity, and recent advances in genomics have led to promising targeted therapies. A number of ethical issues have confronted health care providers when taking care of CM patients in different stages of the disease, which have included areas of primary prevention, early diagnosis, strategies to reduce recurrence of the tumor, and managing patients with advanced tumors. With the increasing incidence of CM in fair-skinned people, as well as the increasing recognition of CM in nonwhites, addressing the discussed ethical issues will be even more challenging and important as we provide comprehensive management of this disease.
Clinics in dermatology 09/2012; 30(5):501-10. · 3.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cutaneous melanoma (CM) is a highly curable skin cancer of melanocytes if diagnosed early. Unfortunately, its invasion into the deeper dermis increases the risk of it spreading to the lymph nodes and distant organs. Spread of metastatic melanoma (MM) to other organs is among one of the most dangerous conditions that is almost uniformly fatal for the majority of patients with the currently available treatment modalities. Since melanoma is an immunogenic tumor, developing novel immune strategies will continue to play a critical role in designing effective treatment modalities for those at high risk of recurrence and those with distant metastasis. While older age is believed to be a poor prognostic marker for CM, rapid expansion of the aging population and its projected increase in the coming decades is expected to result in a large number of elderly melanoma patients seeking treatment in all stages of disease. This will not only bring with it unique management challenges in this population, but also an increased burden on communities to provide financial and social resources. Comprehensive efforts will need to be directed towards early diagnosis, as well as developing safe and effective treatment. Renewed interest in the cancer immune surveillance theory coupled with recognition of aging-associated weaknesses in the immune system has put the spotlight on immunsenescence as a important risk factor for the rising incidence of CM in the aging population. Comprehensive assessment of the aging immune system might shed light, not only on weaknesses of individual components of the adaptive immune system, but also on the critical imbalances resulting from these weaknesses on anti-melanoma immunity. Identifying these imbalances might help harness novel immune-based treatment of MM in selected elderly patients. This article describes our experience of treating elderly patients with MM and the issues unique to them, with particular emphasis on insights into the aging immune system.
Expert Review of Pharmacoeconomics & Outcomes Research 04/2011; 11(2):185-93. · 1.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MHC class I-restricted human melanoma epitope MART-1(27-35) specific TCR-engineered CD4+CD25- T cells synthesize Th1 type cytokines and exhibit cytolytic effector function upon cognate stimulation. A detailed characterization of such TCR-engineered CD4+CD25- T cells now reveals that they are multifunctional. For example, they undergo multiple rounds of division, synthesize cytokines (IFN-gamma, TNF-alpha, IL-2, and MIP1ss), lyse target cells, and "help" the expansion of the MART-1(27-35) specific CD8+ T cells when stimulated by the MART-1(27-35) peptide pulsed DC. Multiparametric analyses reveal that a single TCR-engineered CD4+ T cell can perform as many as five different functions. Nearly 100% MART-1(27-35) specific TCR expressing CD4+ T cells can be generated through retroviral vector-based transduction and one round of in vitro stimulation by the peptide pulsed DC. MHC class I-restricted tumor epitope specific TCR transduced CD4+ T cells, therefore, could be useful in immunotherapeutic strategies for melanoma or other human malignancies.
[Show abstract][Hide abstract] ABSTRACT: The rapidly expanding segment of the aging population with its rising incidence of cutaneous melanoma will present major challenges in therapeutic management. Immune strategies will be important in designing effective treatment of melanoma because it is a highly immunogenic tumor. Aging, however, is associated with dysregulation of the immune system and is likely to affect the success of melanoma treatment in the elderly population. This population represents an ideal in vivo model to study the effects of the aging immune system on the natural history of melanoma in the elderly. We review the epidemiology, histopathologic features, and treatment outcomes of elderly melanoma patients with reference to their immune function. Various components of the normal immune system are described, and the immune response to melanoma is recapitulated. Particular emphasis is placed on the growing understanding of the innate, adaptive, and regulatory arms of the aging immune system.
Clinics in dermatology 11/2009; 27(6):537-44. · 3.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For tumor vaccine-based immunotherapy of cancer, the expansion of tumor antigen-specific cytotoxic T lymphocytes (CTL) in the patients by blocking induced regulatory T (Treg) cells is the most important objective now. Fludarabine (FLU), a known anticancer drug, has been shown to downregulate Treg cells in vivo in chronic leukemia patients. Melanoma tumor antigen Mart-1(27-35)-specific CD8+ CTLs generated in vitrowith total peripheral blood lymphocytes (PBL) lose their activity within 14-21 days with concomitant expansion of Treg cells. When CD4+ cells are removed from PBL and CTL are generated with purified CD8+ cells, the CTL survive and maintain their activity for a significantly longer period.
We used a low dose of FLU in the cultures in Mart-1-specific CTL generation assays with total PBL. Blood samples were taken from HLA-A2-positive melanoma patients and normal donors. Autologous matured dendritic cells pulsed with Mart-1(27-35) peptide were used to generate CTL responses using purified CD8+ cells or total PBL.
The presence of FLU in the cultures with PBL helped to generate a significantly higher number of antigen-specific CTLs as detected by Mart-1 HLA-A2 tetramer staining. Specificity of such CTLs was determined by IFN-gamma secretion or by cytotoxicity against the target cells bearing the specific antigen. The presence of FLU stopped the expansion of IL-10-producing CD4+ Treg cells in the cultures with PBL. Analyses of expanded CD4+ cells isolated from PBL in vitro cocultures with FLU showed a Th1 type of function. Those cells secreted higher amounts of IFN-gamma and very low levels of IL-10, or no IL-10 at all, upon restimulation.
The observations of the study are as important for adaptive immunotherapy of cancer as they are for vaccine-based approaches.
[Show abstract][Hide abstract] ABSTRACT: Cytolytic T lymphocytes (CTL) play an important role in defense against viral infections. Following clonal expansion and effector functions, a vast majority of the antigen-specific CTL undergoes programmed cell death to maintain homeostasis. We have shown earlier that melanoma epitope-specific CTL are quite sensitive to activation-induced cell death (AICD) even on the secondary encounter of the antigen. Excessive sensitivity of viral antigen-specific CTL to AICD, however, would be counterproductive. It might be argued that although CTL for a "self" epitope might be more prone to AICD for maintaining self-tolerance, viral antigen-specific CTL are likely to be less sensitive to AICD. We show here that influenza matrix protein-derived MP(58-66) epitope-specific CTL, activated in vitro and bearing a memory phenotype, are just as sensitive to AICD. The AICD in these CTL is not blocked by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone or by soluble Ig-Fc chimeras of the death receptors [Fas, TNF receptor (TNF-R), TRAIL-RI, TRAIL-RII]. However, the MP(58-66)-specific CTL can be rescued from AICD by the c-jun-N-terminal kinase (JNK) inhibitor SP600125. These results have implications for immunotherapeutic intervention in rescuing viral epitope-specific CTL from AICD.
Journal of Leukocyte Biology 03/2007; 81(2):539-47. · 4.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CD4+ T cells naturally expressing CD25 molecules (natural T regulatory cells (Tregs)) have a role in maintaining self tolerance and in regulating responses to infectious agents, transplantation Ags, and tumor Ags. CD4+ Tregs induced from CD4+CD25- precursors (induced Tregs) also regulate immune responses in the periphery. However, which of these Tregs is a major impediment in generating antitumor CTL responses is not clear. We show that although the CD4+CD25+ subsets isolated from peripheral blood-derived lymphocytes do suppress the proliferation of CD4+CD25- effector T cells, they do not suppress the activation and expansion of the self but melanoma-associated, melanoma Ag-reactive T cell 1 (MART-1)27-35-specific CD8+ T cells stimulated by the respective peptide-loaded matured dendritic cells in vitro. The CD4+CD25- counterparts, in contrast, lead to the generation of CD25+ glucocorticoid-inducible TNFR+-Forkhead/winged helix transcription factor+ populations and efficiently suppress the activation and expansion of the MART-127-35 epitope-specific CTLs. Our data suggest that when CTL precursors are optimally stimulated, natural Tregs are not a formidable constraint toward generating a robust antitumor CTL response, but induced Tregs could be.
The Journal of Immunology 02/2006; 176(2):984-90. · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The functional phenotype of a cell results from the simultaneous action of many thousands of genes, which until recently could not be assessed using standard molecular biological techniques. Indeed, molecular genetics and cellular biology inadequately explain the molecular physiology of normal and diseased cells and provide a fragmented view of the role of various genes and their products. Recent advances in techniques of large-scale gene expression allow simultaneous study of thousands of genes of interest in a specific tissue/tumor of interest, and the ability to identify expression signatures associated with functional phenotypes. The application of gene expression profiling to lymphomas has already led to identification of distinct expression signatures associated with a germinal center cell and activated B-cell phenotype, and to the differentiation of tumor cells based on these stages of development. The differentiation of two stages of developmental arrest in large B-cell lymphomas suggests that this subtype is comprised of two diseases, albeit of similar histologic and immunophenotypic character, which were shown to have dramatically different outcomes following chemotherapy. Important information will also be obtained through the association of genes of unknown activity with functional cellular phenotypes and expression signatures, possibly leading to identification of new genes involved in lymphomagenesis and new targets for treatment.
Current Oncology Reports 06/2001; 3(3):243-9. · 2.87 Impact Factor