# Redirected T Cell Therapy to Cure Invasive Fungal Infections

> **NIH NIH R33** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $447,011

## Abstract

Project Summary
Chimeric antigen receptor (CAR) T-cell therapy give new hope to patients suffering from drug-resistant infectious
organisms such as Aspergillus, Candida, or Mucor. This is the first time that a pattern-recognition receptor
(Dectin-1) has been adapted to redirect T-cell specificity to control fungal infection. Dectin-1 CAR (D-CAR) can
activate the cytolytic machinery, and likely the perforin/granzyme and granulysin pathway, of genetically modified
T-cells. The production of IFN- from the D-CAR+ T-cells may further augment innate immunity to invasive fungal
infections if recombinant IFN-γ is administered pharmacologically or derived from CD4+ helper T-cells or natural
killer cells.
In the R21 phase, 2 major factors that limit immediate clinical applications of CAR T-cell therapy will be
addressed: (1) generation of rapidly proliferative β-glucan-specific D-CAR+ T-cells and (2) long-term in vivo
persistence to control invasive fungal infection.
Several types of CARs are currently used in clinical trials to control B-cell malignancy. Because it is not yet
apparent which CAR design provides fully competent T-cell activation for a given patient, we have developed an
approach for screening multiple CAR molecules. Our team has developed the EZ-CAR platform for generating
multiple CARs by mixing and matching components derived from known T-cell activating receptors while keeping
the targeting domain intact. Using this approach, we will generate about 21 D-CARs with the Dectin-1 fungal
targeting domain. Rapid production (within 10 days of PBMC collection from donor) may improve the therapeutic
potential of the manufactured T-cells because it avoids the replication-mediated T-cell senescence and terminal
differentiation that is associated with loss of in vivo persistence.
In the R33 phase, the study will be expanded to target a wide variety of clinically important opportunistic molds
(Mucor, Scedosporium) and yeasts (Candida). Drug-resistant isolates identified in MD Anderson clinical
laboratories will be used for validating the therapeutic efficacy of the D-CAR+ T cells. In some fungi, such as
Rhizopus (Mucorales family), the β-glucan layer is masked by the glycosaminoglycans (GAG) layer. D-CAR+ T-
cell therapy will be used in combination with fungal cell wall biosynthesis inhibitors such as caspofungin to disrupt
the glycosaminoglycans layer, which will allow better recognition and activation of the D-CAR+ T-cell therapy.
In summary, patients suffering from invasive fungal infections due to primary immunodeficiencies such as genetic
mutations and secondary immunodeficiencies such as human immunodeficiency virus infection, cancer, and
transplantation are highly likely to benefit from immune adjuvant therapy. Development of single-engineered T-
cells that can target various pathogens, such as D-CAR+ T-cells cells, which redirect T-cell specificity to
Aspergillus, Candida, and Mucor species, is highly warranted to combat invasive fungal infe...

## Key facts

- **NIH application ID:** 9837412
- **Project number:** 5R33AI127381-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** DIMITRIOS P KONTOYIANNIS
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,011
- **Award type:** 5
- **Project period:** 2016-12-05 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837412

## Citation

> US National Institutes of Health, RePORTER application 9837412, Redirected T Cell Therapy to Cure Invasive Fungal Infections (5R33AI127381-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837412. Licensed CC0.

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