Developing Inhibitory Chimeric Antigen Receptors for Mitigating CAR T Cell On-Target, Off-Tumor Toxicity- [electronic resource]
Developing Inhibitory Chimeric Antigen Receptors for Mitigating CAR T Cell On-Target, Off-Tumor Toxicity- [electronic resource]
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214101924
- ISBN
- 9798380851114
- DDC
- 616.079
- 서명/저자
- Developing Inhibitory Chimeric Antigen Receptors for Mitigating CAR T Cell On-Target, Off-Tumor Toxicity - [electronic resource]
- 발행사항
- [S.l.]: : University of California, Los Angeles., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(127 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-05, Section: B.
- 주기사항
- Advisor: Witte, Owen N.
- 학위논문주기
- Thesis (Ph.D.)--University of California, Los Angeles, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Chimeric antigen receptor T cell (CAR T) therapy has shown extraordinary success in the treatment of hematological malignancies. However, its application to solid tumors has been largely limited by the immunosuppressive tumor microenvironment and toxicities. Because most CAR targets are tumor associated antigens, they are also expressed on normal tissues that are killed by CAR T cells in a process known as on-target, off-tumor toxicity. To mitigate this toxicity and increase specificity, Boolean logic gates have been applied to CAR T cells to regulate activity based on multiple antigenic signals. The AND-NOT-gate utilizes an inhibitory chimeric antigen receptor (iCAR) to downregulate T cell activation after normal tissue antigen recognition. Our study found that an iCAR with a single PD-1 domain shows a kinetic delay in inhibition. This delay can be ameliorated by increasing the avidity but not the affinity of the iCAR. Alternatively, the PD-1 domain can be replaced with alternative inhibitory domains from BTLA, LAIR-1, and SIGLEC-9. To further enhance inhibition, we developed a dual-signaling inhibitory CAR (DiCAR) that combines the PD-1 domain with one of these alternative domains. These DiCARs are more efficient at inhibiting cytotoxicity than an iCAR with a single PD-1 domain. Furthermore, preliminary studies have shown that these DiCARs can inhibit cytotoxicity in vivo.
- 일반주제명
- Immunology.
- 일반주제명
- Molecular biology.
- 일반주제명
- Bioengineering.
- 일반주제명
- Cellular biology.
- 일반주제명
- Pharmacology.
- 키워드
- Immunotherapy
- 키워드
- Logic-gated CARs
- 키워드
- Prostate cancer
- 기타저자
- University of California, Los Angeles Molecular and Medical Pharmacology 0639
- 기본자료저록
- Dissertations Abstracts International. 85-05B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.