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Identification of immune mechanisms responsible for treatment failure or adverse events in cancer patients treated with immunotherapy checkpoint inhibitors

Grant number: 19/17705-3
Support type:Research Projects - Thematic Grants
Duration: May 01, 2021 - April 30, 2025
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal researcher:Kenneth John Gollob
Grantee:Kenneth John Gollob
Home Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil
Pesquisadores principais:
Israel Tojal da Silva
Assoc. researchers: Clóvis Antonio Lopes Pinto ; Emmanuel Dias-Neto ; Helano Carioca Freitas ; Jefferson Luiz Gross ; João Pedreira Duprat Neto ; Luiz Paulo Kowalski ; Milton José de Barros e Silva ; Rubens Chojniak ; Tiago da Silva Medina ; Vladmir Cláudio Cordeiro de Lima ; Walderez Ornelas Dutra

Abstract

The overall response rate (ORR) in patients treated with immune checkpoints varies greatly and ranges from 30% (Head and Neck cancer) to as high as 60% as a first line therapy in malignant melanoma. Non-small cell lung cancer (NSCLC) patients treated with checkpoint inhibition therapy is up to 45% as first line therapy. The elucidation of the factors responsible for treatment failure is fundamental for the development of new therapeutic approaches. In addition, severe adverse events (AEs) limit the treatment's use and cause significant morbidity in some patients and can require suspension of treatment. Two broad factors are essential for influencing the patient's response to treatment and development of AEs: 1) the nature of a patient's systemic and local tumor microenvironment (TME) immunoregulatory networks, including antigen presenting cells (APCs), T lymphocyte subpopulations and HLA type, and 2) the genomic landscape of the tumor itself, as indicated by mutational load, generation of potential neoantigens, and HLA allele loss, as well as the unique admixture of founder ethnicities including those of African, European, Indigenous and Asian origin found in the Brazilian population. We hypothesize that cellular immune activation, functional states, structural TCR/HLA aspects and immunoregulatory networks combine to drive response or failure to immunotherapy and development of adverse events (AEs), which can in turn be influenced by the tumor genomic landscape and the patient's genetic background. We propose to perform a non-interventional, prospective longitudinal cohort study evaluating the systemic (cellular and soluble) and TME immune status of melanoma (n=40) and NSCLC (n= 40) patients treated as a first line therapy with checkpoint inhibitors (anti-PD1/anti-CTLA-4 for melanoma and anti-PD1+chemotherapy for NSCLC), as well as a cohort of other cancer patients (Head and Neck, Kidney, and other lung cancers) treated with immune checkpoint inhibitors (n=120). The project will bring new findings to the field through the: 1) discovery of novel immune mechanisms behind immune checkpoint inhibitor therapy response or failure, 2) discovery of immune mechanisms behind the development of adverse events (AEs) in cancer patients treated with checkpoint inhibitors, and 3) identify potential immune biomarkers that predict which patients are most likely to benefit from immunotherapy using checkpoint inhibitors by predicting high likelihood of response to therapy and low likelihood of developing strong AEs. Specifically, we will investigate from the same patient their longitudinal (at least three timepoints, including before treatment begins) systemic cellular immune responses (using over 40 immune markers with 27 color high dimensional flow cytometry), soluble immune molecules (using 48 molecule Bioplex), and single cell RNAseq with TCR structural features, as well as the TME investigating the infiltrating immune cells, transcriptome and exome. This combination of three systemic and three tumor derived high dimensional datasets, together with excellent clinical patient data on response to therapy and AEs, are exactly the specific aspects of our study that sets it apart from all the other studies to date. The successful implementation of this project will generate models for response to therapy and development of AEs (for which very little has been published) that can be used for the subsequent development of novel therapies or adjuvant treatments to increase efficacy and safety of the immunotherapy checkpoint inhibitors, as well as discovery of possible biomarkers of clinical relevance. (AU)

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