Viral platform helps CAR T cells combat solid tumors in mice

Reuters Health - 09/09/2020 - An oncolytic virus (OV19t) engineered to express a non-signaling, truncated CD19 (CD19t) protein can help expedite tumor-selective chimeric antigen receptor (CAR) T cell therapy for solid tumors, according to preclinical proof-of-concept studies.

"This therapeutic platform using oncolytic viruses to redirect CD19-CAR T cells to target and eradicate solid tumors has broad implications for cancer immunotherapy," Dr. Saul J. Priceman of City of Hope, in Duarte, California, told Reuters Health by email.

The approach, he added, "potentially expands the clinical utility of the well-known CD19-CAR T cell for the treatment of patients with any solid tumor and it elucidates novel mechanisms by which the combination of oncolytic viruses and CAR T cells can rewire the microenvironment in tumors to allow for durable anti-tumor immunity."

CD19 is an ideal target for CAR T cells against hematological malignancies and has been approved for use in B cell lymphomas and acute lymphoblastic leukemia, Dr. Priceman and colleagues note in Science Translational Medicine. However, solid tumors lack amenable tumor antigens for CAR T cell development, they add.

The team found that OV19t could effectively deliver the truncated CD19-CAR target to solid tumors, making them susceptible to CD19-CAR T cell-mediated tumor destruction. This was achieved successfully in the triple-negative breast-cancer cell line MDA-MB-468 and in pancreatic, prostate, ovarian other tumor cells.

In therapeutic studies of human xenograft tumors in mice, the combination of OV19t and CD19-CAR T cells resulted in marked tumor regression. These results in mice with subcutaneous MDA-MB-468 tumors were confirmed in mice with gliomas (U251T).

CAR T cell-mediated tumor killing, say the researchers, "also induced release of virus from dying tumor cells, which propagated tumor expression of CD19t."

"While we cured over 50% of mice treated with this combination therapy," the team adds, "some mice either transiently (responded) or did not respond."

The researchers also found "tumor-specific immune memory in cured mice that were protected from subsequent tumor rechallenge."

Dr. Priceman concluded that "while the study utilizes CD19 as a proof-of-concept target, in theory this platform can be adapted to use any CAR target, with any oncolytic virus strain and CAR T cell combination."

Dr. Sonia Guedan, who studies gene and cell-based therapies at the Pi I Sunyer Biomedical Research Institute, in Barcelona, Spain, told Reuters Health by email, "CD19-CAR T cells are generating unprecedented clinical responses in patients with blood cancers."

Dr. Guedan, who was not involved in the new work, said the authors "are presenting a creative and promising idea to expand the use of CD19-CAR T cells to the treatment of solid tumors. This may address a key obstacle for the use of CAR T cells in solid tumors: the lack of tumor-restricted antigens."

The study had no commercial funding, but the researchers are inventors on a patent related to the technology.

By David Douglas

SOURCE: https://bit.ly/2QVbANQ Science Translational Medicine, online September 2, 2020



Posted on 9 September 202016 September 2020