Immunophenotyping and neoepitope mapping in relation to immunotherapy of cancer

Research output: Book/ReportPh.D. thesis

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Abstract

Cancer immunotherapy, specifically immune checkpoint inhibitors (ICIs), has emerged as a promising approach for treating various types of cancer. ICIs work by blocking inhibitory signals within T cells caused by interacting with cancer cells, so called immune checkpoints. Immune checkpoint blockade allows the T cells to recognize and attack the cancer cells. However, not all patients respond to this therapy, which may be due to cancer heterogeneity and the tumor mutational burden (TMB). While TMB has been linked to immunotherapy efficacy, some patient with cancers known to have low TMB respond while some with high TMB do not, indicating TMB alone cannot predict response. In this PhD thesis, we evaluated the immune response to immunotherapy in cancer patients with both low and high TMB.
We analyzed samples from patients diagnosed with recurrent glioblastoma (GBM) who were treated with PD-1 targeting ICI therapy. GBM is a type of brain cancer with a relatively low TMB, and immunotherapy has historically been largely ineffective for these patients. We therefore investigated the tumor microenvironment (TME), and particularly the T cell phenotypes after ICI therapy. Our findings revealed a distinct profile of intratumoral T cells with indications of increased activation, but also a more differentiated and exhausted profile, which may contribute to induced ICI resistance. Nonetheless, we were able to demonstrate tumor reactivity in tumor-infiltrating lymphocytes (TILs) in a small subset of the patients. Neoantigen-reactive T cells (NARTs) were further detected in both the tumor and blood samples of these responsive patients, indicating a potential for an improved clinical response to immunotherapy in this subgroup of patients. However, combination therapy may be necessary to achieve optimal results. In contrast, melanoma patients exhibit a high TMB and have generally demonstrated favorable responses to ICI therapy, however some patients do not respond. To address this issue, we evaluated a neopeptide vaccine administered to advanced melanoma patients in combination with anti-PD-1 therapy, with the goal to increase the NART repertoire in these patients. Our results showed that the neopeptide vaccine was safe for use and capable of inducing a T cell response towards vaccine peptides, primarily driven by CD4 T cells. However, due to the limited size of the patient cohort, we are unable to draw definitive conclusions regarding the vaccine's potential to increase clinical response.
All together, these studies emphasize the need for personalized and combinational therapy, even within the same cancer type and stage.
Original languageEnglish
PublisherDTU Health Technology
Number of pages171
Publication statusPublished - 2023

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