Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma


Treatment of Malignant Pleural Mesothelioma by Fibroblast Activation Protein-specific Re-directed T cells

Malignant pleural mesothelioma (MPM) results from chronic exposition to asbestos in at least 70% of the cases. Fibroblast activation protein (FAP) is predominantly expressed on the surface of reactive tumor-associated fibroblasts as well as on particular cancer types. Because of its expression on the cell surface, FAP is an attractive target for adoptive T cell therapy. T cells can be re-directed by retroviral transfer of chimeric antigen receptors (CAR) against tumor-associated antigens (TAA) and therefore represent a therapeutic strategy of adoptive immunotherapy.

FAP re-directed CD8+ T cells showed antigen-specific functionality in vitro and in vivo. Furthermore, FAP expression was verified in all MPM histotypes. Therefore, our data support performing a phase I clinical trial in which MPM patients are treated with adoptively transferred FAP-specific re-directed T cells.


Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells

“Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8+ T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell–inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3+ regulatory T cells (Tregs), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8+ T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of Tregs, in the tumor microenvironment depended on the presence of CD8+ T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell–inflamed tumor microenvironment.”


Genetic Ablation of Epidermal EGFR Reveals the Dynamic Origin of Adverse Effects of Anti-EGFR Therapy

“Cancer patients treated with anti-EGFR (epidermal growth factor receptor) drugs often develop a dose-limiting pruritic rash of unknown etiology. The aims of our study were to define causal associations from a clinical study of cutaneous and systemic changes in patients treated with gefitinib and use these to develop and characterize a mouse model that recapitulates the human skin rash syndrome caused by anti-EGFR therapy. We examined the patients’ plasma before and after treatment with gefitinib and documented changes in chemokines and leukocyte counts associated with the extent of rash or the presence of pruritus. We established a parallel mouse model by ablating EGFR in the epidermis. These mice developed skin lesions similar to the human rash. Before lesion development, we detected increased mRNA expression of chemokines in the skin associated with early infiltration of macrophages and mast cells and later infiltration of eosinophils, T cells, and neutrophils.”


The Calcineurin-NFAT-Angiopoietin-2 Signaling Axis in Lung Endothelium Is Critical for the Establishment of Lung Metastases

“The premetastatic niche is a predetermined site of metastases, awaiting the influx of tumor cells. However, the regulation of the angiogenic switch at these sites has not been examined. Here, we demonstrate that the calcineurin and nuclear factor of activated T cells (NFAT) pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. Upregulation of the calcineurin pathway via deletion of its endogenous inhibitor Dscr1 leads to a significant increase in lung metastases due to increased expression of a newly identified NFAT target, Angiopoietin-2 (ANG2). Increased VEGF levels specifically in the lung, and not other organ microenvironments, trigger a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR1 or the ANG2 receptor, soluble TIE2, prevents the activation of lung endothelium, inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the premetastatic niche and offer targets for lung metastases.”


Lung Tumor NF-κB Signaling Promotes T cell–Mediated Immune Surveillance

We investigated the role of cancer cell NF-κB activity in T cell–mediated antitumor responses. In tumors rendered immunogenic by model antigen expression or following administration of antitumor vaccines, we found that high NF-κB activity leads to tumor rejection and/or growth suppression in mice. NF-κB activity mediates immune surveillance and promotes antitumor T cell responses in both murine and human lung cancer.


Gene-Engineered T Cells for Cancer Therapy

“T cells have the capacity to eradicate diseased cells, but tumours present considerable challenges that render T cells ineffectual. Cancer cells often make themselves almost ‘invisible’ to the immune system, and they sculpt a microenvironment that suppresses T cell activity, survival and migration. Genetic engineering of T cells can be used therapeutically to overcome these challenges. T cells can be taken from the blood of cancer patients and then modified with genes encoding receptors that recognize cancer-specific antigens. Additional genes can be used to enable resistance to immunosuppression, to extend survival and to facilitate the penetration of engineered T cells into tumours. Using genetic modification, highly active, self-propagating ‘slayers’ of cancer cells can be generated.”


Gene-Engineered T Cells for Cancer Therapy

“T cells have the capacity to eradicate diseased cells, but tumours present considerable challenges that render T cells ineffectual. Cancer cells often make themselves almost ‘invisible’ to the immune system, and they sculpt a microenvironment that suppresses T cell activity, survival and migration. Genetic engineering of T cells can be used therapeutically to overcome these challenges. T cells can be taken from the blood of cancer patients and then modified with genes encoding receptors that recognize cancer-specific antigens. Additional genes can be used to enable resistance to immunosuppression, to extend survival and to facilitate the penetration of engineered T cells into tumours. Using genetic modification, highly active, self-propagating ‘slayers’ of cancer cells can be generated.”


Gene-Engineered T Cells for Cancer Therapy

“T cells have the capacity to eradicate diseased cells, but tumours present considerable challenges that render T cells ineffectual. Cancer cells often make themselves almost ‘invisible’ to the immune system, and they sculpt a microenvironment that suppresses T cell activity, survival and migration. Genetic engineering of T cells can be used therapeutically to overcome these challenges. T cells can be taken from the blood of cancer patients and then modified with genes encoding receptors that recognize cancer-specific antigens. Additional genes can be used to enable resistance to immunosuppression, to extend survival and to facilitate the penetration of engineered T cells into tumours. Using genetic modification, highly active, self-propagating ‘slayers’ of cancer cells can be generated.”