Novel Immunotherapy for Cancer Takes Cue From Transplant Rejection

By Marilynn Larkin

December 16, 2021

NEW YORK (Reuters Health) - A novel immunotherapy treatment works by triggering genetically modified T cells to reject cancer, much as they would a transplanted organ, researchers say.

The approach was effective in mouse models and in leukemia cells from patients.

"Our results show that it is possible to identify therapeutic T-cell receptors (TCRs) that can efficiently 'see' targets inside cancer cells that the immune system normally tolerates, by exploiting the mechanism of transplant rejection," Dr. Johanna Olweus of Oslo University Hospital Radiumhospitalet and the University of Oslo told Reuters Health by email. "This opens the possibility to develop efficient gene therapies for many other cancer types."

"By targeting molecules inside the cell that are unique to the cell type, many more targets become accessible as compared with the limited number of molecules that are available on the outside of the cancer cell," she explained.

As reported in Nature Biology, Dr. Olweus and colleagues genetically modified T cells to express TCRs specific for peptides from the intracellular lymphoid-specific enzyme called terminal deoxynucleotidyl transferase (TdT).

The modified cells eliminated acute lymphoblastic leukemia (ALL) T- and B-cells in vitro, and in three mouse models of disseminated B-ALL.

Notably, the treatment spared normal peripheral T- and B-cells and normal myeloid cells both in vitro and in humanized mice, suggesting that the approach is safe.

The authors state, "TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes."

Dr. Olweus added, "We are currently planning a clinical trial of children and adults with ALL of the T-cell and B-cell type who have failed standard therapies (and) hope to be able to include the first patients in 2023."

"To make the gene-modified immune cells, we need clinical-grade virus, which is used to deliver the therapeutic gene to the immune cells in the laboratory," she said. "This virus is already in production by a commercial provider. In parallel, we are developing the manufacturing protocol for genetic modification of the immune cells. The modified immune cells represent the 'living drug' that will be delivered into the bloodstream of the patient."

Dr. Iannis Aifantis, Chair, Department of Pathology at NYU Langone Health in New York City, commented in an email to Reuters Health, "This is an ingenious use of the immune system and specifically, T cells that are made to recognize specific antigens on ALL cells. The breakthrough was the targeting of TdT, a protein that is specifically expressed during differentiation and on ALL cells."

"TdT is not expressed by mature T and B cells or other cells of the immune system," he said, "(which) minimizes any side effects of the treatment and a negative impact on immune function."

"The identification of 'designed' T cells expressing T-cell receptors that recognize differentiation or cell type-specific antigens like TdT opens the way for the treatment of patients that fail chemotherapy, transplantation or relapse after the use of CAR-T cell therapies," he said. "It also offers a novel therapy option for older patients who are not eligible for CAR-T cell treatments or patients with T-cell ALL, where no targeted therapies or immunotherapies are currently available."

SOURCE: https://go.nature.com/3F1Xwt8 Nature Biotechnology, online December 6, 2021.

processing....