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-? 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 ?-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 ?-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 infections in immunocompromised patients.

Public Health Relevance

The recent breakthrough of bioengineered chimeric antigen receptor (CAR) T-cell therapy for cancer has opened up a new horizon to target infectious disease-causing organisms such as viruses, bacteria, and fungi. This approach promises a great impact on the treatment of infectious agents in immunocompromised patients or those requiring long-term immunosuppressive drug therapy, such as transplantation recipients. The major advantages of this new CAR T-cell therapy are not only an immediate cure from the disease but also long-term benefits from the memory CAR T-cells, which will protect the host from future attack from foreign invaders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI127381-02
Application #
9392890
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Franceschi, Francois J
Project Start
2016-12-05
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030