1.
A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer.
Ott, PA, Hu-Lieskovan, S, Chmielowski, B, Govindan, R, Naing, A, Bhardwaj, N, Margolin, K, Awad, MM, Hellmann, MD, Lin, JJ, et al
Cell. 2020;(2):347-362.e24
Abstract
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
2.
Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology.
Ogino, S, Nowak, JA, Hamada, T, Milner, DA, Nishihara, R
Annual review of pathology. 2019;:83-103
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Abstract
Evidence indicates that diet, nutrition, lifestyle, the environment, the microbiome, and other exogenous factors have pathogenic roles and also influence the genome, epigenome, transcriptome, proteome, and metabolome of tumor and nonneoplastic cells, including immune cells. With the need for big-data research, pathology must transform to integrate data science fields, including epidemiology, biostatistics, and bioinformatics. The research framework of molecular pathological epidemiology (MPE) demonstrates the strengths of such an interdisciplinary integration, having been used to study breast, lung, prostate, and colorectal cancers. The MPE research paradigm not only can provide novel insights into interactions among environment, tumor, and host but also opens new research frontiers. New developments-such as computational digital pathology, systems biology, artificial intelligence, and in vivo pathology technologies-will further transform pathology and MPE. Although it is necessary to address the rarity of transdisciplinary education and training programs, MPE provides an exemplary model of integrative scientific approaches and contributes to advancements in precision medicine, therapy, and prevention.
3.
An immunogenic personal neoantigen vaccine for patients with melanoma.
Ott, PA, Hu, Z, Keskin, DB, Shukla, SA, Sun, J, Bozym, DJ, Zhang, W, Luoma, A, Giobbie-Hurder, A, Peter, L, et al
Nature. 2017;(7662):217-221
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Abstract
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.