NEW ORLEANS – With the annual American Association for Cancer Research (AACR) meeting kicking off over the weekend, there has been no shortage of cutting edge research addressed by an array of international investigators. Some of the most impressive results were provided by a team of scientists from the University College of London (UCL) Cancer Institute.
The UCL team utilized the gene-editing tool TALEN—short for transcription activator-like effector nuclease—to inactivate PD-1–mediated immunosuppression and enhance the efficacy adoptive T-cell transfer immunotherapy against solid tumors.
“TALEN, like CRISPR, is a gene-editing technology that allows cutting specific sequences of DNA that code for the expression of a specific protein,'” explained co-senior study author Sergiov Quezada, Ph.D., group leader of the Immune Regulation and Cancer Immunotherapy Lab at UCL Cancer Institute. “Gene-editing technologies have potential clinical utility, and in cancer research, they have many applications, including enabling the study of proteins that play a role in the development of the disease and the identification of drug targets.”
“In this study, we engineered the TALEN enzyme to cut the region in the DNA that codes for the expression of the immune-inhibitory protein PD-1,” Dr. Quezada added.
The findings from this study were published recently in Cancer Research, an AACR journal, in an article entitled “TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors.”
Immunotherapies such as adoptive cell transfer have been gaining steam over the past several years due to some promising results. The technology involves the collection of tumor-reactive T cells, culturing and expanding those cells in vitro, and transferring cells back into a patient with cancer. However, a limitation of this approach is the immune-suppressive nature of the tumor microenvironment.
“Whilst the modified T cells are very active in a petri dish, once they reach the tumor microenvironment, the tumor often defends itself by expressing immune-regulatory mediators able to silence the activity of the T cells,” Dr. Quezada noted. “We wanted to generate tumor-targeting T cells that are resistant to one of the mechanisms of immunosuppression used by tumor cells, one in which they deliver inhibitory signals to the T cells through the inhibitory receptor PD-1.”
To generate and test the efficacy of T cells refractory to PD-1 signaling, the researchers began isolating tumor-reactive T cells from mice harboring melanoma tumors. The scientists proceeded to culture the T cells in the presence of a TALEN that targets the PD-1 gene. Using electroporation, the UCL team was able to get the TALEN into T cells, which were subsequently transferred back into the melanoma mice to determine if the transfected T cells could eliminate the tumors.
Amazingly, the researchers found that inactivating PD-1 using TALEN increased the persistence of the T cells at the tumor site and were effective in eliminating the tumors.
Furthermore, when the mice were once again injected with tumor cells, the tumors did not grow, to which Dr. Quezada suggested “that an immunological memory was established, meaning the immune system could now remember what the tumor looked like and attack it when it came back.”
“Our study is one of the first proof-of-concept demonstration that we can establish protocols for gene-editing of immune checkpoints in tumor-reactive T cells,” Dr. Quezada remarked.
However, Dr. Quezada cautioned that “these are promising results, but there is still a long way to go. We need more research and more time to start testing this, first with human T cells in a petri dish, and then in more mouse models, after which we can start considering potential incorporation into clinical trials.”