T Cells for Epithelial Tumors: Malignant tumors harbor genetic alterations. Recently, adoptive T cell therapies have taken advantage of this: T cells specific for mutations in tumors are infused into patients to generate an antitumor immune response. Although therapeutic benefit has been seen for melanomas, effectiveness against more common epithelial tumors is unclear. Using whole-exome sequencing, Tran et al. (p. 641 ) identified tumor-infiltrating CD4+ T cells specific for a mutated antigen expressed by a tumor from a patient with metastatic cholangiocarcinoma. Infusion of this patient with an expanded-population, mutation-specific T cell resulted in tumor regression and stabilization of disease.

We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×10¹¹ HLA-C*08:02–restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.

Identifying tumor-associated T cell epitopes can be laborious. Robbins et al. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies. Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials1,2. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment3. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex–binding algorithm4 for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.

Low mutation rate okay for T cells: Cancers that tend to have high numbers of mutations, such as melanoma and smoking-induced lung cancer, respond well to immunotherapies, whereas those with fewer mutations, such as pancreatic cancer, do not. Tran et al. searched for tumor mutation–reactive T cells in 10 patients with metastatic gastrointestinal cancers, which have relatively low mutation burdens, and discovered that 9 out of 10 harbored such cells. T cells from one patient recognized a mutation common to many types of cancers. Engineering T cells to express this particular mutation-reactive T cell receptor may extend adoptive cell immunotherapy to a larger pool of patients than previously anticipated. Science, this issue p. 1387