Genome-wide approaches and analysis of circulating tumor DNA for detection of predictive biomarkers of response to oncological treatment with immune checkpoint inhibitors

• Grant number: 24/13129-6
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: CNPq
• Principal Investigator: Dirce Maria Carraro
• Grantee: Gabriel Bandeira Do Carmo
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated research grant: 24/02226-0 - Abordagens genômicas amplas e análise de DNA tumoral circulante para detecção de biomarcadores preditivos de resposta ao tratamento oncológico com inibidores de checkpoint imunológico, AP.R

Abstract

Immunotherapeutic drugs, such as immune checkpoint inhibitors (ICIs), have revolutionized cancer treatment, significantly increasing patient survival. These drugs stimulate defense cells to fight the tumor and can promote long-lasting effects, possibly by inducing immunological memory in patients (Rui et al., 2023). However, many aspects are still unknown and represent challenges for the most effective use of immunotherapy in cancer. A considerable portion of patients do not respond to treatment or present relapse after an initial response, indicating the need for new immuno-oncological targets and effective biomarkers to predict response to ICIs.The development of ICIs is based on the advancement of knowledge about the mechanisms of interaction between tumor and the immune system, resulting in substantial advances in immuno-oncology. ICIs such as anti-CTLA4 and anti-PD1 have significantly altered the natural course of several types of cancer, although approximately 60% of treated patients are resistant, depending on the type and stage of the disease (Sharma et al., 2020). The research of predictive biomarkers for immunotherapy has mainly targeted tumor-intrinsic biomarkers (such as PD-1/PD-L1 and tumor mutational burden (TMB)), tumor microenvironment (such as tumor infiltrating lymphocytes (TILs)) and systemic biomarkers (such as circulating factors and microbiota) (Liu et al., 2021; Waldman et al., 2020). However, none of them have demonstrated adequate sensitivity and specificity to efficiently predict response to immunotherapy, which is essential to personalize and improve treatment with these drugs.Motivated to address the unmet needs in cancer treatment with immunotherapy, the Center for Research in Immuno-Oncology (CRIO) was created, linked to the postdoctoral scholarship proposal (Process: 2021/00408-6, led by Dr. Kenneth Golob, where Dr. Dirce Carraro acts as Principal Investigator (PI)).CRIO aims to study suppression mechanisms in the tumor microenvironment to identify therapeutic targets and characterize molecular and genomic alterations that may be predictive biomarkers of response to immunotherapy. We have developed a scientific research platform with three plans: 1) identification of potential targets through studies in animal and cellular models; 2) use of multi-omics approaches to discover new immunomodulatory targets and predictive biomarkers of response in prospective and retrospective tumor samples; and 3) validation of targets and biomarkers in cellular/animal models or patient series.We prioritize cancers such as colorectal, non-small cell lung cancer (NSCLC), and oral cavity tumors, due to their global relevance and impact on health (Ferlay et al., 2024; Mendonça et al., 2023). Despite the approval of immunotherapy for these cancers, there is still a lack of effective therapeutic options for many patients.The Pós-doutorado Junior (PDJ) proposal falls under plan 2 and focuses on genomic approaches to discover predictive biomarkers of response. Our hypothesis is that genomic characterization of tumor tissue, combined with monitoring of circulating tumor DNA (ctDNA), will allow the discovery of predictive biomarkers of response to oncological treatment, including ICIs. Complementarily, CRIO's multidisciplinary approaches will provide clues about the mechanisms of resistance to ICIs, opening new perspectives in this promising area.