The identification of tumor antigens, which are essential for the survival of tumor cells is a new avenue to prevent antigen loss variants emerging due to immunoselection, particularly during immune therapy. In the search for such immunogenic tumor antigens, we recently identified spontaneous cytotoxic lymphocyte (CTL) responses against the inhibitor of apoptosis protein survivin. Thus, we identified two HLA-A2-restricted, survivin-derived CTL epitopes, which both were targets for spontaneous CTL responses in melanoma, breast cancer, and CLL. Here, we extend these data and describe the characterization of novel HLA-A1-, HLA-A2-, HLA-A3-, and HLA-A11-restricted survivin epitopes on the basis of spontaneous CTL responses in cancer patients. These epitopes significantly increase the number of patients eligible for immunotherapy based on survivin derived peptides. Additionally, the collective targeting of several restriction elements is likely to decrease the risk of immune escape by HLA-allele loss.

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Activating BRAF somatic missense mutations within the kinase domain are present in 60 -66% of melanomas. The vast majority of these represent a single substitution of glutamate for valine (V599E). Here, we demonstrate spontaneous HLA-B*2705-restricted cytotoxic T-cell responses against an epitope derived from V599E BRaf. These T-cell responses were mutation specific as the corresponding epitope derived from wildtype BRaf was not recognized. The loss of the V599E BRAF genotype during progression from primary to metastatic melanoma in patients with V599E BRaf specific T-cell responses suggests an active immune selection of nonmutated melanoma clones by the tumor-bearing host.

B-cell lymphoma 2 (Bcl-2) is a pivotal regulator of apoptotic cell death and it is overexpressed in many cancers. Consequently, the Bcl-2 protein is an attractive target for drug design, and Bcl-2-specific antisense oligonucleotides or small-molecule Bcl-2 inhibitors have shown broad anticancer activities in preclinical models and are currently in several clinical trials. The clinical application of immunotherapy against cancer is rapidly moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of "therapeutic" vaccines. The overexpression of Bcl-2 in cancer and the fact that immune escape by down-regulation or loss of expression of this protein would impair sustained tumor growth makes Bcl-2 a very attractive target for anticancer immunotherapy. Herein, we describe spontaneous T-cell reactivity against Bcl-2 in peripheral blood from patients suffering from unrelated tumor types (ie, pancreatic cancer, breast can- IntroductionIn recent years, research into the interplay between cancer cells and cells of the immune system has conveyed a detailed understanding of the capacity of the immune system to recognize and destroy cancer cells. To this end, a large number of peptide antigens derived from tumor-associated antigens (TAAs) have been applied in immunotherapeutic trials for the treatment of various malignancies (eg, melanoma; cancers of the breast, prostate, and kidney; in addition to hematologic cancers). 1 In some cases the response rates have been impressive and no adverse autoimmunity has been observed. 2 A major strategic difficulty associated with the abovementioned trials relates to the choice of the best-suited peptide antigens. Many of the peptide epitopes used in vaccination trials are melanocyte specific and these peptides can only be applied for melanoma. 3 More important, the vast majority of the antigens described thus far are not vital for survival and growth of the tumor cells, and immunoselection of antigen-loss variants may therefore prove to be an additional obstacle for the clinical applicability of most of the known peptide epitopes. In this respect, the development of acquired antigen loss during immunotherapy has been demonstrated in several cases. 4,5 Obviously, the development of loss-variant tumor cells implies that these cells acquire a pronounced growth advantage and are left unaffected by further treatment. The development of peptide vaccines with a broader immunotherapeutic potential and with a low probability of acquisition of immune escape over the course of treatment therefore awaits the molecular characterization of more appropriate antigens. The identification of tumor antigens, which are essential for the survival of tumor cells, represents a new avenue to prevent antigen loss variants emerging due to selection, particularly during therapy.Resistance to a wide variety of chemotherapeutic agents poses a major obstacle in the treatment of cancer. To this end, intrinsic or acquired drug resistance represents a general character...