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17
molecule inhibitor in the TME. The small molecule inhibitor is encapsulated in cross-linked
multilamellar liposomes, which are covalently conjugated to the surface of CAR-T cells. We
hypothesized that this co-delivery strategy would be able to enhance CAR-T cell functions in the
TME and, consequently, augment CAR-T cell antitumor activities. We demonstrated in this
study that our drug delivery strategy was able to prevent CAR-T cells from becoming
hypofunctional in the TME and improved CAR-T cell antitumor response. Moreover, we showed
that the antitumor function of tumor infiltrated CAR-T cells could be rescued upon interference
of the adenosine pathway using A2a receptor small molecule inhibitors. This study signifies the
effects adenosine has on tumor infiltrating immune cells and demonstrated a strategy in which it
could be overcome, in order to improve the efficacy of CAR-T cell therapy.
The second obstacle we aim to overcome is the PD-1/PD-L1 immune regulatory
pathway. In chapter 3, we engineered CAR-T cells to secrete the PD-1/PD-L1 checkpoint
inhibitor and evaluated the antitumor efficacy in vivo. This strategy was proved to significantly
enhance CAR-T cell effector functions in vivo and was able to completely eradicate established
tumors. We evaluated the effector functions in an ex vivo assay and demonstrated that the
intrinsically secreted PD-1/PD-L1 checkpoint inhibitor was able to prevent CAR-T cell
exhaustion and maintained IFNγ secretion upon restimulation.
Object Description
| Title | Engineered CAR-T cells for treatment of solid cancers |
| Author | Siriwon, Natnaree |
| Author email | siriwon@usc.edu;nsiriwon@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemical Engineering |
| School | Viterbi School of Engineering |
| Date defended/completed | 2018-03-26 |
| Date submitted | 2018-08-05 |
| Date approved | 2018-08-07 |
| Restricted until | 2018-08-07 |
| Date published | 2018-08-07 |
| Advisor (committee chair) | Wang, Pin |
| Advisor (committee member) |
Shing, Katherine Finley, Stacey |
| Abstract | The chimeric antigen receptor T (CAR-T) cell therapy has become a promising cancer immunotherapeutic method, particularly in treating B cell malignancies; however, this therapy is still in the early stages of development for the treatment of solid tumors. One limiting factor of CAR-T cell therapy is the suppressive tumor microenvironment, which inactivates the function of tumor infiltrating lymphocyte (TIL). This thesis work is divided into two major studies that aim to overcome two different immunosuppressive mechanisms in the TME: adenosine up-regulation and PD-1/PD-L1 immune inhibition. In the first study, we surface-engineered CAR-T cells to deliver an A2a receptor small molecule inhibitor in the TME. The small molecule inhibitor is encapsulated in cross- linked multilamellar liposomes, which are covalently conjugated to the surface of CAR-T cells. We hypothesized that this co-delivery strategy would be able to enhance CAR-T cell functions in the TME and, consequently, augment CAR-T cell antitumor activities. We demonstrated in this study that our drug delivery strategy was able to prevent CAR-T cells from becoming hypofunctional in the TME and improved CAR-T cell antitumor response. Moreover, we showed that the antitumor function of tumor infiltrated CAR-T cells could be rescued upon interference of the adenosine pathway using A2a receptor small molecule inhibitors. This study signifies the effects adenosine has on tumor infiltrating immune cells and demonstrated a strategy in which it could be overcome, in order to improve the efficacy of CAR-T cell therapy. The second obstacle we aim to overcome is the PD-1/PD-L1 immune regulatory pathway. In the second study, we engineered CAR-T cells to secrete the PD-1/PD-L1 checkpoint inhibitor and evaluated the antitumor efficacy in vivo. This strategy was proved to significantly enhance CAR-T cell effector functions in vivo and was able to completely eradicate established tumors. We evaluated the effector functions in an ex vivo assay and demonstrated that the intrinsically secreted PD-1/PD-L1 checkpoint inhibitor was able to prevent CAR-T cell exhaustion and maintained IFNγ secretion upon restimulation. |
| Keyword | immunotheray; cancer; CAR-T cells |
| Language | English |
| Format (imt) | application/pdf |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Siriwon, Natnaree |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-SiriwonNat-6685.pdf |
| Archival file | Volume3/etd-SiriwonNat-6685.pdf |
Description
| Title | Page 25 |
| Full text | 17 molecule inhibitor in the TME. The small molecule inhibitor is encapsulated in cross-linked multilamellar liposomes, which are covalently conjugated to the surface of CAR-T cells. We hypothesized that this co-delivery strategy would be able to enhance CAR-T cell functions in the TME and, consequently, augment CAR-T cell antitumor activities. We demonstrated in this study that our drug delivery strategy was able to prevent CAR-T cells from becoming hypofunctional in the TME and improved CAR-T cell antitumor response. Moreover, we showed that the antitumor function of tumor infiltrated CAR-T cells could be rescued upon interference of the adenosine pathway using A2a receptor small molecule inhibitors. This study signifies the effects adenosine has on tumor infiltrating immune cells and demonstrated a strategy in which it could be overcome, in order to improve the efficacy of CAR-T cell therapy. The second obstacle we aim to overcome is the PD-1/PD-L1 immune regulatory pathway. In chapter 3, we engineered CAR-T cells to secrete the PD-1/PD-L1 checkpoint inhibitor and evaluated the antitumor efficacy in vivo. This strategy was proved to significantly enhance CAR-T cell effector functions in vivo and was able to completely eradicate established tumors. We evaluated the effector functions in an ex vivo assay and demonstrated that the intrinsically secreted PD-1/PD-L1 checkpoint inhibitor was able to prevent CAR-T cell exhaustion and maintained IFNγ secretion upon restimulation. |
