T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer

By E. Tran, P. Robbins, Yong-Chen Lu, Todd D Prickett, J. Gartner, Li Jia, A. Pasetto, Zhili Zheng, Satyajit Ray, E. Groh and 2 more. 2016

1,181 citations recorded by the source corpus.

Summary 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.

Subfields: Immunology, Oncology

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Citations in the corpus

Macromolecular modeling and design in Rosetta: recent methods and frameworks (2020, methodology): “RosettaTCR permits structural insights into TCRs, for example those targeting cancer neoepitopes 217 , or to identify feature sets of TCRs from high throughput sequencing.”
TCRmodel: high resolution modeling of T cell receptors from sequence (2018, background): “…immune clearance of viruses and pathogens, while TCR autoreac-tivity is associated with a range of autoimmune diseases including diabetes (1) and multiple sclerosis (2), and studies have demonstrated that TCRs have major potential as cell-based (3,4) and soluble therapeutics (5) for cancer.”
Genetics and biology of prostate cancer (2018, background): “…et al. 2000; Sucker et al. 2014); these defects contribute to the lack of T-cell responses observed in patients with primary resistance (Ribas 2015; McGray and Bramson 2017; Sharma et al. 2017) or acquired resistance (D’Urso et al. 1991; Restifo et al. 1996; Tran et al. 2016; Zaretsky et al. 2016).”
Organoid modeling of the tumor immune microenvironment (2018, methodology): “PDOs or analogous methods may also allow cryopreservable biobanks of the human immune TME for research and drug discovery, with potential relevance to adoptive cell transfer TIL-based immunotherapies (Feldman et al., 2015; Forget et al., 2017; Tran et al., 2016).”
Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution (2017, background): “Because the presence of the HLA-C*08:02 allele was required for presentation of the KRAS G12D neoantigen and tumor recognition by T cells, its loss was proposed to directly enable immune evasion.”