Editors' ChoiceImmunotherapy

The Long-Awaited Marriage of Cancer Genomics and Immunotherapy Bears Fruit

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Science Translational Medicine  21 May 2014:
Vol. 6, Issue 237, pp. 237ec89
DOI: 10.1126/scitranslmed.3009312

For decades now, the majority of cancer therapies have spawned from a combination of understanding the human genome, the cancer genome, and aberrant signaling proteins in cancer cells. However, exciting new developments in immunotherapy revolve around T cells, including antibodies that relieve T cell checkpoints and genetic modification and transfer of T cells. Even though T cells are naturally poised to recognize cancer mutations, the field of immunotherapy for cancer has progressed in quiet parallel to the field of cancer genetics. Now, Tran and colleagues have merged T cell therapy with tumor exome sequencing and show a proof of concept that T cells recognize tumor-specific mutations and that merely culturing and expanding these T cells and transferring them back to the patient is enough to mediate tumor regression.

Here, resected lung metastases from a patient with metastatic cholangiocarcinoma were used as a source of tumor and T cells. After identification of 26 nonsynonymous mutations, a CD4+ T cell population that specifically recognized a mutant epitope from erbb2-interacting protein (ERBB2IP) was identified, expanded, and cloned; the T cell receptor was sequenced; and its specificity confirmed. The patient received two infusions of cultured and expanded tumor-infiltrating lymphocytes; conditioning chemotherapy and cytokine support were administered to improve engraftment of the cells. The patient experienced a marked tumor regression after each infusion.

The wedding of cancer genomics with T cell immunotherapy is exciting and raises scientific and practical questions; Could this dormant T cell population have mediated tumor regression with checkpoint blockade? The patient was not cured; what if the specific T cell receptor had been genetically introduced into circulating T cells? Could these have a better functional profile than the ones isolated from tumor? What is the implication of the fact that these were CD4+ T cells, which are not expected to recognize intracellular epitopes by the classical immunologic pathways? The process of identifying mutations and generating specific T cells for each patient is probably too slow and expensive to treat all patients, but one can imagine beginning to build a library of T cell receptors that recognize common tumor mutations in multiple tumor types and, in the future, combining personalized tumor diagnostics with personalized cell therapy.

E. Tran et al., Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014). [Abstract]

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