Bio-engineered Cell Therapy to Treat Candidiasis

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Principal Investigator: Pappanaicken Rangasamy Kumar
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $251,250
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT ABSTRACT
Patients with hematological malignancies, and immunocompromised patients are highly susceptible to Candida
infection. Based on the immune status of the host, the infections may be mild to life- threatening. The goal is to
find novel treatment approaches to give long-term protection against opportunistic Candida spp. without
disturbing normal gut microflora. The rationale underlying this proposal is that the development of CAR-T cell
and CAR-Macrophage based cell therapies will target and recruit host immune system to protect against
opportunistic Candida infection. Recently chimeric antigen receptors (CAR) T-cell based therapy has
revolutionized cancer treatment strategy and showed overall success rate of more than 90% in hematological
malignancies. In pre-clinical studies Aspergillus specific CAR T cells has shown significant reduction in fungal
burden. Thus, the objective of this proposal is to develop CAR constructs to target systemic Candida infections
without disturbing normal gut microflora. We will generate CAR constructs by fusing extracellular domain of the
pattern recognition receptors with cytoplasmic domain of the activation receptors (CA-CAR). The central
hypothesis will
overcome barriers and immune evasion tactics imposed by the Candida spp.
 The central hypothesis will be tested by pursuing two specific aims.:
Aim 1). Generation and functional characterization of T-cells expressing CA-CARs:
Aim 2). Generation and functional characterization of macrophages expressing CA-CARs:
Aims 1 and 2 can be done simultaneously without being dependent on each other. These include (i)
generating CAR constructs by fusing Candida specific targeting domain with cell activating receptors; (ii)
expression of CARs in T cells and macrophages using molecular biology and tissue culture techniques; and
(iii) performing fungicidal assays by monitoring fungal growth real-time using image scanning microscope.
Functional efficacy studies will be done by co-culturing Candida yeast and Candia hyphae. In-vivo efficacy
studies will be done in NSG mice bearing systemic candidiasis. The proposed research is significant, because
it is the first cell-based therapy designed to target Candida that spares the normal commensals. It is also
significant because it will develop a platform that can be extended to study and control other opportunistic
infections. To protect patients from unanticipated CAR T cell/ CAR-Macrophage related toxicity, we will include
a mutant epidermal growth factor receptor (mEGFR) safety switch to induce apoptosis in CAR T cells. This can
be activated by targeting with mEGFR specific antibody. The results of this study will have an important
positive impact especially to overcome barriers such as virulence, antifungal resistance and recruit host
immune system for clearing pathogens. The expected outcomes are that this proposal will lay the groundwork
to develop suitable CARs to control other opportunistic pathogens and provide long-term benefit.

Terms: <Adaptive Immune System><Adverse effects><Age Years><Allogenic><Antibodies><Antigens><Aspergillus><Assay><Bioassay><Biological Assay><Biomedical Engineering><Blood granulocytic cell><C albicans><C. albicans><C. glabrata><C.albicans><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CD28><CD28 gene><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><Cancer Treatment><Candida><Candida albicans><Candida glabrata><Candida resistance><Candida resistant isolate><Candidiasis><Candidosis><Cell Body><Cell Therapy><Cell Wall><Cell secretion><Cells><Cellular Secretion><Circulation><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cross Presentation><Cytoplasmic Domain><Cytoplasmic Granules><Cytoplasmic Tail><DNA Molecular Biology><Death Rate><Development><Disseminated candidiasis><Disseminated candidosis><Drug resistance><Drugs><EGF Receptor><EGFR><ERBB Protein><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><External Domain><Extracellular Domain><Fungal Drug Resistance><Fungus drug resistant><GI microbiota><Gamma-delta T cells><Gastrointestinal microbiota><Generalized Growth><Generations><Goals><Grafting Procedure><Granular Leukocytes><Granulocytic cell><Growth><Growth Agents><Growth Factor><Growth Substances><HER1><Health><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hospital Infections><Hospital acquired infection><Human><Hyphae><Image><Immune Evasion><Immune system><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><In Vitro><Induction of Apoptosis><Infection><Inflammatory><Infusion><Infusion procedures><Life><Ligands><Macrophage><Malignant Hematologic Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Medication><Mice><Mice Mammals><Microscope><Modern Man><Molecular Biology><Monilia><Moniliasis><Monitor><Murine><Mus><Mφ><Nosocomial Infections><OKT3 antigen><Opportunistic Infections><Organ Transplantation><Organ Transplants><Outcome><Patients><Pattern recognition receptor><Phagocytosis><Pharmaceutical Preparations><Predisposition><Primary Immunodeficiency><Proteins Growth Factors><Receptor Activation><Receptor Protein><Research><Research Support><Resistant candida><Safety><Scanning><Solid><Susceptibility><System><Systemic candida><Systemic candida infections><Systemic candidiasis><T cells for CAR><T-Cell Receptor Therapy><T-Cell Receptor Treatment><T-Cell Receptor based Therapy><T-Cell Receptor based Treatment><T-Cells><T-Lymphocyte><T3 Antigens><T3 Complex><T3 molecule><T44><TCR Therapy><TCR based Therapy><TCR based treatment><TGF-alpha Receptor><Testing><Therapeutic Fungicides><Time><Tissue Culture Techniques><Tissue Growth><Torulopsis glabrata><Toxic effect><Toxicities><Transforming Growth Factor alpha Receptor><Urogastrone Receptor><Validation><Viral><Virulence><Yeasts><acquired immune system><anti-cancer therapy><anti-fungal><anti-fungal agents><anti-fungal drug><anti-fungal drug resistance><anti-fungal drug resistant><anti-fungal resistance><anti-fungal resistant><anti-microbial><antimicrobial><bio-engineered><bio-engineers><bioengineering><biological engineering><c-erbB-1><c-erbB-1 Protein><cancer therapy><cancer-directed therapy><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><congenital immune deficiency><congenital immunodeficiency><cytokine><dectin 1><dectin-2><developmental><drug resistant><drug/agent><efficacy study><enteric microbial community><enteric microbiota><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><fungicidal><fungicide><fungus drug resistance><gastrointestinal microbial flora><genetic immune defect><genetic immune deficiency><genetic immunodeficiency><granule><granulocyte><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><imaging><immune evasive><immunogen><immunological status><immunosuppressed patient><improved><in vivo><inborn errors in immunity><inborn errors of immunity><inborn immunodeficiency><infusions><inherited immune defect><inherited immune deficiency><inherited immunodeficiency><institutional infection><intervention design><intestinal flora><intestinal microbiota><intestinal microflora><intestinal tract microflora><microbe pathogen><microbial pathogen><mortality rate><mortality ratio><mouse dectin-2><mouse model><murine model><mutant><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><opportunistic pathogen><organ allograft><organ graft><organ xenograft><pathogen><pathogenic microbe><pre-clinical study><preclinical study><primary immune defect><primary immune deficiency><promoter><promotor><proto-oncogene protein c-erbB-1><receptor><recruit><resistance among Candida><resistance in Candida><resistance to Drug><resistance to anti-fungal><resistant Candida strains><resistant to Drug><resistant to anti-fungal><side effect><success><therapy design><thymus derived lymphocyte><time use><timeline><treatment design><treatment strategy><validations><vector><γδ T cells><γδT cells>