Therapeutic Cancer Vaccines in Combination with Conventional Therapy

The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination with chemotherapy may lead to improved clinical efficacy by clearing suppressor cells, reboot of the immune system, by rendering tumor cells more susceptible to immune mediated killing, or by activation of cells of the immune system. In addition, a range of tumor antigens have been characterized to allow targeting of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype can be targeted to specifically target cancer cells, but proteins targeted by immunotherapy may also simultaneously target cancer cells as well as suppressive cells in the tumor stroma

T-cell clonotypes in cancer

Cells of the immune system spontaneously recognize autologous tumor cells and T cells are believed to be the main effector cells for the immune surveillance of cancer. Recent advances in our understanding of basic and tumor immunology together with methodological developments implies that tumor specific T cells can now be studied functionally, phenotypically as well as molecularly. T cells recognize peptide antigens in the context of MHC molecules through the clonally distributed T-cell receptor (TCR), thus, the clonal distribution of the TCR offers the means to detect and track specific T cells based upon detection of the unique TCR. In this review, we present and discuss available data on TCR utilization of tumor specific T cells in murine models as well as spontaneous and treatment induced anti-tumor T-cell responses in humans

Characterization of Ex Vivo Expanded Tumor Infiltrating Lymphocytes from Patients with Malignant Melanoma for Clinical Application

Clinical trials of adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) to patients with advanced malignant melanoma have shown remarkable results with objective clinical responses in 50% of the treated patients. In order to initiate a clinical trial in melanoma, we have established a method for expanding TILs to clinical relevant quantities in two steps with in 8 weeks. Further characterization of expanded TILs revealed an oligoclonal composition of T-cells with an effector memory like phenotype. When autologous tumor was available, TILs showed specific activity in all patients tested. TIL cultures contained specificity towards tumor cells as well as peptides derived from tumor-associated antigens (TAAs) during expansion procedures

The Melanoma Inhibitor of Apoptosis Protein: A Target for Spontaneous Cytotoxic T Cell Responses

The identification of tumor antigens which expression is essential for the survival of tumor cells is a new avenue to prevent antigen loss variants emerging due to immunoselection, particularly during immune therapy. The melanoma inhibitor of apoptosis protein, ML-IAP (also named livin) counteracts apoptosis induced by death receptors, hypooxgenic conditions, or chemotherapeutic agents. Thus, elevated expression of ML-IAP renders melanoma cells resistant to apoptotic stimuli and thereby potentially contributes to the oncogenic phenotype. Here, we demonstrate that T cells in a large proportion of melanoma patients infiltrating the tumor or circulating in the peripheral blood specifically recognize ML-IAP-derived peptides. Interestingly, the responses against the peptide epitope ML-IAP280–289 were not restricted to melanoma patients but present among peripheral blood T cells in a few healthy controls. In situ peptide/HLA-A2 multimer staining, however, confirmed the infiltration of ML-IAP-reactive cells into the tumor microenvironment. Moreover, ML-IAP-reactive T cells isolated by magnetic beads coated with peptide/HLA-A2 complexes were cytotoxic against HLA-matched melanoma cells. In conclusion, out data strongly indicate ML-IAP as a suitable target for immunologic intervention

HLA-A24 and survivin: possibilities in therapeutic vaccination against cancer

Recently, it was described that an HLA-A24 restricted peptide derived from the survivin splice variant survivin-2B can be recognized by CD8(+) cytotoxic T-cells. The identification of an HLA-A24 epitope is critical for survivin-based immunotherapy as HLA-24 is the most frequent HLA allele in Asia. Consequently, this survivin-2B epitope is already a target in a clinical study in patients with advanced or recurrent colorectal cancer expressing survivin. However, the splice variant survivin-2B has been described to be pro-apoptotic, and is only expressed at low levels in most malignant tissues. Furthermore, survivin-2B expression are significantly decreased in later tumor stages and inversely correlated with tumor differentiation and invasion. Consequently, survivin is a more general vaccination candidate than the splice variant survivin-2B. Here, we on the basis of spontaneous immune responses in HLA-A24+ cancer patients describes that a HLA-A24-restricted survivin epitopes does indeed exist. Consequently, this epitope is an attractive target for the ongoing survivin-based peptide immunotherapy against cancer

Butyrate and propionate inhibit antigen-specific CD8⁺ T cell activation by suppressing IL-12 production by antigen-presenting cells

Abstract Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune responses. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8+ T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8+ T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8+ T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8+ T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8+ T cell function with possible implications in anti-cancer immunotherapy