34 research outputs found
Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer?
Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent 'cancer immunoediting' has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment
EGFR T790M Mutation as a Possible Target for Immunotherapy; Identification of HLA-A*0201-Restricted T Cell Epitopes Derived from the EGFR T790M Mutation
Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, has achieved high clinical response rates in patients with non–small cell lung cancers (NSCLCs). However, over time, most tumors develop acquired resistance to EGFR-TKIs, which is associated with the secondary EGFR T790M resistance mutation in about half the cases. Currently there are no effective treatment options for patients with this resistance mutation. Here we identified two novel HLA-A*0201 (A2)-restricted T cell epitopes containing the mutated methionine residue of the EGFR T790M mutation, T790M-5 (MQLMPFGCLL) and T790M-7 (LIMQLMPFGCL), as potential targets for EGFR-TKI-resistant patients. When peripheral blood cells were repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific IFN-γ secretion, T cell lines responsive to T790M-5 and T790M-7 were established in 5 of 6 (83%) and 3 of 6 (50%) healthy donors, respectively. Additionally, the T790M-5- and T790M-7-specific T cell lines displayed an MHC class I-restricted reactivity against NSCLC cell lines expressing both HLA-A2 and the T790M mutation. Interestingly, the NSCLC patients with antigen-specific T cell responses to these epitopes showed a significantly less frequency of EGFR-T790M mutation than those without them [1 of 7 (14%) vs 9 of 15 (60%); chi-squared test, p = 0.0449], indicating the negative correlation between the immune responses to the EGFR-T790M-derived epitopes and the presence of EGFR-T790M mutation in NSCLC patients. This finding could possibly be explained by the hypothesis that immune responses to the mutated neo-antigens derived from T790M might prevent the emergence of tumor cell variants with the T790M resistance mutation in NSCLC patients during EGFR-TKI treatment. Together, our results suggest that the identified T cell epitopes might provide a novel immunotherapeutic approach for prevention and/or treatment of EGFR-TKI resistance with the secondary EGFR T790M resistance mutation in NSCLC patients
Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines
New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines
Malignant inflammation in cutaneous T-cell lymphoma: a hostile takeover
Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL
Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy
Cytotoxic T lymphocytes directed against a tumor-specific mutated antigen display similar HLA tetramer binding but distinct functional avidity and tissue distribution
We have previously identified an antigen (Ag) recognized on a human large cell carcinoma of the lung by a tumor-specific cytotoxic T lymphocyte clone derived from autologous tumor infiltrating lymphocytes (TILs). The antigenic peptide is presented by HLA-A2 molecules and is encoded by a mutated α-actinin-4 (ACTN4) gene. In the present report, we have isolated two anti-α-actinin-4 T cell clones from the same patient TIL and from his peripheral blood lymphocytes (PBLs) by using tetramers of soluble HLA-A2 molecules loaded with the mutated peptide. Although all of the clones displayed similar tetramer labeling, those isolated from PBL showed lower avidity of Ag recognition and killed the specific target much less efficiently, indicating that tetramer staining does not correlate with clone avidity/tumor reactivity. T cell receptor (TCR) analysis revealed that α-actinin-4-reactive clones used distinct α and β chain rearrangements, demonstrating TCR repertoire diversity. Interestingly, TCRβ chain gene usage indicated that only Ag-specific clones with high functional avidity were expanded at the tumor site, whereas a low-avidity clone was exclusively amplified in patient peripheral blood. Our results point to the existence of distinct but overlapping antitumor TCR repertoires in TIL and PBL and suggest a selective in situ expansion of tumor-specific cytotoxic T lymphocyte with high avidity/tumor reactivity
In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census
Killer inhibitory receptor (CD158b) modulates the lytic activity of tumor-specific T lymphocytes infiltrating renal cell carcinomas.
In this study, we showed that renal tumors contain substantial subsets of CD8(+) p58(+) T cells. From 1 of these tumors, T cells were amplified in mixed lymphocytes-tumor cell cultures and p58(+) T cells were selected immunologically. After expansion, phenotypic and functional features of p58(+) and p58(-) T cells were examined. The p58(+) T cells expressed p58.2 receptor and corresponded to CD3(+), CD8(+), T-cell receptor (TCR) alpha/beta(+) T cells that were CD56(+) and CD28(-). Functionally, p58(+) T cells showed a low level of lytic activity against autologous tumor cells that was dramatically and specifically increased by anti-p58.2 monoclonal antibody. On the other hand, p58(-) CD8(+) T cells did not lyse autologous tumor cells and had non-major histocompatibility complex-restricted cytotoxicity against K562 and Daudi cells. A p58(+) cytotoxic T lymphocyte (CTL) clone (4C7) with the same characteristics as the p58(+) T-cell line was derived. This CTL clone did not lyse autologous normal B cells but lysed several HLA-A1(+) renal tumor cell lines. Analysis of TCR repertoire diversity showed that the p58(+) T-cell line contained 3 TCR rearrangements, whereas the TCR repertoire of p58(-) T cells was polyclonal. Interestingly, TCR transcripts of p58(+) T cells and of CTL clone 4C7 were detected as prominent ex vivo in tumor cells but not in peripheral blood mononuclear cells, suggesting that these cells are antigen specific and amplified at the tumor site. (Blood. 2000;95:2883-2889