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Manufacturing Chimeric Antigen Receptor CAR T Cells for Adoptive Immunotherapy
Published on: December 17, 2019
T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy
Tori N Yamamoto1,2,3, Ping-Hsien Lee1,2, Suman K Vodnala1,2
1Center for Cancer Research and.
Abstract:
Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.
Insights
Engineered T cells resist tumor-induced apoptosis by blocking Fas-FasL interactions, enhancing adoptive cell transfer (ACT) efficacy. This strategy improves T cell persistence and antitumor activity across various cancers without causing autoimmunity.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- T cell expansion and persistence are crucial for successful adoptive cell transfer (ACT) therapies.
- The tumor microenvironment (TME) can limit T cell durability, impacting treatment outcomes.
- FASLG (Fas Ligand) is overexpressed in many tumors, and its receptor FAS (Fas) is present on therapeutic T cells.
Purpose of the Study:
- To identify ligand-receptor interactions that impair T cell persistence after ACT.
- To investigate the role of the Fas-FasL pathway in limiting T cell function within the TME.
- To develop a genetic strategy to enhance T cell durability and antitumor efficacy.
Main Methods:
- Pan-cancer analysis to identify key ligand-receptor pairs.
- Genetic engineering of Fas variants to create dominant-negative receptors (DNRs).
- Co-engineering T cells with Fas DNR and chimeric antigen receptors (CARs) or T cell receptors (TCRs).
- Assessing T cell persistence, antitumor efficacy, and safety in preclinical cancer models.
Main Results:
- FasL is overexpressed in the TME, and Fas is expressed on ACT T cells, suggesting a potential mechanism for T cell elimination.
- Fas DNR-engineered T cells resisted FasL-induced apoptosis.
- T cells engineered with Fas DNR showed enhanced persistence and superior antitumor efficacy against solid and hematologic cancers.
- Fas DNR-engineered T cells did not exhibit aberrant expansion or cause autoimmunity.
Conclusions:
- Disrupting Fas signaling within T cells is a viable strategy to improve ACT efficacy.
- Genetic engineering of Fas DNR offers a potentially universal approach to enhance T cell persistence and antitumor responses.
- This method holds promise for improving cancer immunotherapy across diverse malignancies.
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