Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma

Valentini, Davide; Rao, Martin; Landenberg, Anna von; Bártek, Jiří; Sinclair, Georges; Paraschoudi, Georgia; Jäger, Elke; Harvey-Peredo, Inti; Dodoo, Ernest; Maeurer, Markus

doi:10.18632/oncotarget.24955

Cited by 11 publications

(13 citation statements)

References 45 publications

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“…Many groups have used immunoproteomics to discover TAAs using autoantibodies against immunogenic antigens expressed by tumor cells (either on the surface or in the cytosol) (69). These antigens may be entirely unidentified proteins (neoantigens) or peptides that are mutated from the wild type (neoepitopes) (70). A few examples of TAAs identified using proteomics include the markers PSMA1, LAP3, ANXA3, and maspin, which were identified by one group as biomarkers for colon cancer (71).…”

Section: Finding the Tumor: Tumor Associated Antigens Expression Levmentioning

confidence: 99%

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

2019

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Chimeric antigen receptor (CAR) T cells, T cells that have been genetically engineered to express a receptor that recognizes a specific antigen, have given rise to breakthroughs in treating hematological malignancies. However, their success in treating solid tumors has been limited. The unique challenges posed to CAR T cell therapy by solid tumors can be described in three steps: finding, entering, and surviving in the tumor. The use of dual CAR designs that recognize multiple antigens at once and local administration of CAR T cells are both strategies that have been used to overcome the hurdle of localization to the tumor. Additionally, the immunosuppressive tumor microenvironment has implications for T cell function in terms of differentiation and exhaustion, and combining CARs with checkpoint blockade or depletion of other suppressive factors in the microenvironment has shown very promising results to mitigate the phenomenon of T cell exhaustion. Finally, identifying and overcoming mechanisms associated with dysfunction in CAR T cells is of vital importance to generating CAR T cells that can proliferate and successfully eliminate tumor cells. The structure and costimulatory domains chosen for the CAR may play an important role in the overall function of CAR T cells in the TME, and “armored” CARs that secrete cytokines and third- and fourth-generation CARs with multiple costimulatory domains offer ways to enhance CAR T cell function.

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Section: Finding the Tumor: Tumor Associated Antigens Expression Levmentioning

confidence: 99%

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

2019

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“…The exact characterization of tumor-infiltrating lymphocytes (TILs) can even have therapeutic relevance. Neoantigenspecific immune reactivation of TILs, unique for each patient, is currently considered a method of personalized anticancer treatment [35].…”

Section: Tumor Infiltrating Lymphocytes and Their Prognostic Value Inmentioning

confidence: 99%

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

2020

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Background Tumor initiation and subsequent progression are usually long-term processes, spread over time and conditioned by diverse aspects. Many cancers develop on the basis of chronic inflammation; however, despite dozens of years of research, little is known about the factors triggering neoplastic transformation under these conditions. Molecular characterization of both pathogenetic states, i.e., similarities and differences between chronic inflammation and cancer, is also poorly defined. The secretory activity of tumor cells may change the immunophenotype of immune cells and modify the extracellular microenvironment, which allows the bypass of host defense mechanisms and seems to have diagnostic and prognostic value. The phenomenon of immunosuppression is also present during chronic inflammation, and the development of cancer, due to its duration, predisposes patients to the promotion of chronic inflammation. The aim of our work was to discuss the above issues based on the latest scientific insights. A theoretical mechanism of cancer immunosuppression is also proposed. Conclusions Development of solid tumors may occur both during acute and chronic phases of inflammation. Differences in the regulation of immune responses between precancerous states and the cancers resulting from them emphasize the importance of immunosuppressive factors in oncogenesis. Cancer cells may, through their secretory activity and extracellular transport mechanisms, enhance deterioration of the immune system which, in turn, may have prognostic implications.

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“…In 2015, however, functional lymphatic vessels were reported to line the dural sinuses of mice, with potentially analogous structures also observed in human dura. 40,41 Also of note, classical dendritic cells have been identified within glioblastoma tumor tissue 29 and could transport tumor antigen to draining lymph nodes for T-cell priming.…”

Section: Opportunities and Limitations For Priming Of Tumor-specific mentioning

confidence: 99%

“…Indeed, despite multiple local and systemic immunosuppressive mechanisms, growing evidence indicates that glioblastoma patients can prime tumor-specific T-cell responses. 40,41…”

Section: Opportunities and Limitations For Priming Of Tumor-specific mentioning

confidence: 99%

“…This may result from some level of CAR-T cell-induced tumor cell death, which could generate endogenous immune responses via 'antigen spreading' and then lead to complete tumor eradication as demonstrated in pre-clinical models of other cancer types. 92 Evidence for endogenous immune priming in glioblastoma exists with the generation of de novo T-cell responses, 40,41 which can be rescued from adaptive immune resistance by anti-PD1 therapy. [25][26][27][28] Another recent example is a clinical trial of patient-specific glioblastoma vaccines comprising multiple 'non-self' neoepitopes in which vaccine-specific T-cell responses were only found in the two patients who had not received dexamethasone during priming.…”

Section: Possibility Of Car-t Cell Induction Of Endogenous Antitumor mentioning

confidence: 99%

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Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

2019

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Chimeric antigen receptor (CAR)‐T cell therapy is now approved in the United States and Europe as a standard treatment for relapsed/refractory B‐cell malignancies. It has also been approved recently by the Therapeutic Goods Administration in Australia and may soon be publicly reimbursed. This advance has accentuated scientific, clinical and commercial interest in adapting this exciting technology for the treatment of solid cancers where it is widely recognised that the challenges of overcoming a hostile tumor microenvironment are most acute. Indeed, CAR‐T cell technology may be of the greatest value for those cancers that lack pre‐existing immunity because they are immunologically ‘cold’, or have a low somatic tumor mutation load, or both. These cancers are generally not amenable to therapeutic immune checkpoint blockade, but CAR‐T cell therapy may be effective because it provides an abundant supply of autologous tumor‐specific T cells. This is achieved by using genetic engineering to re‐direct autologous T‐cell cytotoxicity towards a tumor‐associated antigen, bypassing endogenous T‐cell requirements for antigen processing, MHC‐dependent antigen presentation and co‐stimulation. One of the most challenging solid cancers is glioblastoma, which has among the least permissive immunological milieu of any cancer, and which is almost always fatal. Here, we argue that CAR‐T cell technology may counter some glioblastoma defences and provide a beachhead for furthering our eventual therapeutic aims of restoring effective antitumor immunity. Although clinical investigation of CAR‐T cell therapy for glioblastoma is at an early stage, we discuss three recently published studies, which feature significant differences in target antigen, CAR‐T cell phenotype, route of administration and tumor response. We discuss the lessons, which may be learned from these studies and which may guide further progress in the field.

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Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma

Cited by 11 publications

References 45 publications

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

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