Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer

Abstract

Limited evidence exists that humans mount a mutation-specific T cell response to epithelial cancers. We used a whole-exomic-sequencing-based approach to demonstrate that tumor-infiltrating lymphocytes (TIL) from a patient with metastatic cholangiocarcinoma contained CD4+ T helper 1 (T(H)1) cells recognizing a mutation in erbb2 interacting protein (ERBB2IP) expressed by the cancer. After adoptive transfer of TIL containing about 25% mutation-specific polyfunctional T(H)1 cells, the patient achieved a decrease in target lesions with prolonged stabilization of disease. Upon disease progression, the patient was retreated with a >95% pure population of mutation-reactive T(H)1 cells and again experienced tumor regression. These results provide evidence that a CD4+ T cell response against a mutated antigen can be harnessed to mediate regression of a metastatic epithelial cancer.

T‐cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death‐ligand 1 expression in patients with soft tissue sarcomas

“…Although well‐differentiated/dedifferentiated (WD/DD) liposarcomas may have a low mutation burden and are driven through overexpression of MDM2 and CDK4, DD liposarcomas can acquire additional mutations, ultimately becoming highly mutated 18. Highly mutated tumors are more genetically heterogeneous and may provide multiple immunogenic mutated protein targets for T cells, which subsequently may be inhibited at checkpoints such as PD‐1 19, 20. Indeed, recently presented provisional data have indicated that treatment with checkpoint inhibitors can result in a benefit in patients with certain sarcoma subtypes such as UPS 21…”

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…A previous study shows that adoptive transfer of HLA-DP4-restricted NY-ESO-1-specific CD4 + T cells results in tumor regression in a metastatic melanoma patient [201]. Indeed, a recent study shows that adoptive transfer of mutation-specific CD4 + T cells results in the regression of metastatic cholangiocarcinoma (an epithelial cancer) in a cancer patient [202], suggesting that tumor-specific CD4 + T cells are capable of mediating tumor regression in epithelial cancers.…”

“…Meanwhile, a single T cell can be isolated and tested for its reactivity against newly identified neoantigens. Neoantigen-specific T cells can be expanded for adoptive T cell therapy, as demonstrated for ERBB2IP (E805G) and KRAS (G12D) [60,202,240], or used to identify neoantigen-specific T cell receptors (TCRs). These neoantigen-specific TCRs are cloned into expression vectors for further engineering of T cells in TCR-based immunotherapy.…”

“…For screening of neoantigens, long peptides that contain a mutated amino acid can be pulsed onto autologous APCs, which are then co-cultured with T cells to determine their reactivity based on cytokine release or upregulation of co-stimulatory molecules. Alternatively, minigenes encoding the mutated peptides are transfected into autologous APCs, and tested for T cell recognition [60,202]. However, neoantigens could not be defined if the patient's T cells fail to recognize candidate neoantigens or if tumor-reactive T cells are not available.…”

“…In a second study, two neoantigens were identified by screening tandem minigenes with CD4 + T cells, using minigene RNA-transduced B cells or DCs [202]. Furthermore, several neoantigens have been identified from human gastrointestinal cancers [60].…”