A number of factors play into the limited success of adoptive cell therapies (ACT)—including chimeric antigen receptor (CAR) T cell therapies—against solid tumors. For one thing, finding CAR-targetable antigens that are stably expressed by cancer cells but not by healthy ones has proved challenging. Another problem is that cancer cells compete for nutrients, including glucose, that are essential to the function and persistence of T cells used for ACT. A pair of studies led by Ludwig Lausanne researchers and published in Frontiers of Immunology addressed each of these challenges. In a September paper, a study led by Ludwig Lausanne Director George Coukos and Hi-TIDe group leader Melita Irving explored whether the enforced expression of the high-affinity glucose transporter GLUT3 by cytotoxic T lymphocytes could improve their efficacy in ACT. The first author of the study, former graduate student Elisabetta Cribioli, showed that T cells so engineered displayed enhanced glucose uptake, improved mitochondrial fitness and better resistance to stress, among other indicators of fitness. Use of the engineered cells in ACT significantly improved the control of tumors and survival in a mouse model of melanoma. Some mice were even cured of the cancer and able to reject subsequent efforts to implant the same melanoma tumors.
The other study, published in August and led by Melita, developed and evaluated three CARs targeting an antigen that is associated with cancer—but not healthy tissues—in humans and expressed in a variety of malignancies, including melanoma, lymphoma and ovarian and breast cancers. The antigen, N-glycoslylated ganglioside monosialic 3 (NGcGM3), is metabolically incorporated onto the cell surface from nutrients derived from nonvegetarian dietary sources. The two lead scientists, Elisabetta and research associate Greta Giordano Attianesse, constructed three CARs using a well-characterized monoclonal antibody against this antigen, 14F7. They showed that T cells bearing those CARs attacked a variety of tumor fragments isolated from patients and could control NGcGM3-expressing ovarian tumors in mice without causing any toxicity, even though the antigen is found in healthy tissues in mice. The researchers suspect this is because antigen levels must reach a certain threshold to elicit CAR-T attack, and those levels were not reached in the mice because they were fed vegetarian diets—a possibility that could have implications for the clinical evaluation of these CAR T cells. Taken together, the studies hold promise for extending the viability of ACT against a broader range of cancers.
Enforcing GLUT3 expression in CD8+ T cells improves fitness and tumor control by promoting glucose uptake and energy storage
Frontiers in Immunology, 2022 September 20
CAR T cells targeting the ganglioside NGcGM3 control ovarian tumors in the absence of toxicity against healthy tissues
Frontiers in Immunology, 2022 August 05