Targeting telomerase: T-cell friendly fire

Telomerase is a reverse transcriptase enzyme that elongates and maintains telomeres, the very ends of linear chromosomes. As DNA polymerase is unable to fully replicate the extremities of the linear DNA molecule during mitosis, telomeres become a little shorter after every cell division, eventually becoming too short to allow cell division and thus provoking cell senescence and apoptosis. Telomerase prevents telomere erosion and consequent cell senescence in highly proliferative cells.

The vast majority of cancers (> 90%) express telomerase to maintain their telomeres and their ability to proliferative indefinitely, making telomerase a good target candidate in treatment of cancer: it is present in many different types of cancers and is essential for unlimited proliferative capacity of most cancers. Different strategies to hit telomerase have been developed: telomerase inhibitors, telomere-disrupting agents, and telomerase vaccines.²  There are several clinical trials currently evaluating these approaches, but the results are not yet known. Ugel and colleagues used a different approach to target telomerase. They developed an adoptive cell therapy by expanding high-avidity T cells reactive against telomerase epitopes that, when injected back into transgenic mice, were able to hamper adenocarcinoma progression. The results also were impressive against human cancer. Using the mouse model, T cells specific against human telomerase abrogated tumor growth of several human cancer cell lines. Because the use of adoptive cell therapy has been effective in the clinic only for patients with melanoma, these results are promising and suggest that using the right targets, adoptive cell therapy may go far beyond melanoma.

However, the injection of T cells reactive against telomerase induced a severe depletion of B cells in peripheral blood, lymph nodes, and spleen. B-cell lymphopenia happened because telomerase expression is not specific to cancer cells. Normal tissues also express telomerase, especially cells with high proliferative requirements. B cells express telomerase and hence are potential targets for transferred reactive T cells. These findings raise important issues on the use of telomerase as a target for the immune therapy of cancer. In humans, telomerase is expressed by T and B cells, as well as by hematopoietic stem and progenitor cells, which could be targeted by transferred T cells reactive against telomerase, inducing clinically relevant cytopenias. Deficient telomerase due to genetic mutations are associated with bone marrow failure syndromes, such as aplastic anemia and dyskeratosis congenita. It is not surprising that using telomerase as the target epitope may eventually cause destruction of lymphocytes or even hematopoietic progenitors in the bone marrow. In fact, a major toxic effect of telomerase inhibitors in current clinical trials appears to be hematologic. Taken together, the results available so far suggest that targeting telomerase may further suppress hematopoiesis, deepening myelosuppression caused by chemotherapy. The findings by Ugel and colleagues suggest that the use of telomerase as a target for adoptive cell therapy against cancer has to be conducted with caution and hematologic toxicity has to be monitored carefully.

National Institutes of Health