Modification of T cells with CAR to control the expansion of neoplastic B cells and the invasive form of Candida spp.

• Grant number: 24/00060-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2024
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Thiago Aparecido da Silva
• Grantee: Júlia Garcia Guimarães
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Invasive candidiasis (IC) has become a growing concern for global public health, with the main species causing IC being classified by the WHO as critical and high priority fungal pathogens. IC frequently occurs in immunocompromised patients, and cases of hematological malignancies are risk factors for the incidence of IC, with antifungal resistance representing a significant challenge in the clinical management of these patients. The high incidence of IC associated with B cell neoplasms arises from the patient's immunocompromised state, leukemia/lymphoma treatments, and the prophylactic antifungal treatment protocol that favors the selection of resistant fungal species. In addition to this, the virulence factors of Candida spp. they mediate the escape/subversion of the host's immune system by compromising the effective action of the different profiles of CD4+ T cells and CD8+ T cells. Cellular therapy with modification of T cells with chimeric antigen receptor (CAR) for the treatment of B cell neoplasms, through CD19-CAR, also presents the challenge of containing cases of invasive fungal infections. Our research group and collaborators demonstrated the ability to use CAR technology to control invasive fungal infections and, recently, the proponent of the proposal characterized a CAR capable of redirecting T cells to different species of Candida spp., called M-CAR. In this sense, the present project proposes to associate the application of cell therapy with CAR in the control of B cell neoplasms and invasive candidiasis. Therefore, the current proposal aims to modify the signal transduction domain of M-CAR to enhance the cytotoxic effect of T cells against Candida spp. and, in addition, promote an increase in the affinity of the antigen recognition domain present in M-CAR through the specific alteration of the polypeptide sequence of the scFv used in M-CAR. A new CAR targeting ²-glucan will be generated to expand the target molecules present in the fungal cell wall for CAR cell therapy. Using the M-CAR variants and the ²-glucan-specific CAR construct, human T cells will be modified with these constructs in association with CD19-CAR to act directly in the control of invasive candidiasis and in reducing the expansion of neoplastic B cells. The evaluation of the therapeutic effect of T cells expressing CD19-CAR and fungus-specific CAR will be carried out in in vitro assays and in the NSG murine model.