Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model

• Published in: Nature communications 2017-09, Vol.8 (1), p.707-10, Article 707
• Main Authors: Jespersen, Henrik, Lindberg, Mattias F., Donia, Marco, Söderberg, Elin M. V., Andersen, Rikke, Keller, Ulrich, Ny, Lars, Svane, Inge Marie, Nilsson, Lisa M., Nilsson, Jonas A.
• Format: Article
• Language: English
• Subjects: 631/67/1059/2325; 631/67/1813/1634; 631/67/580; 631/67/70; Animals; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - therapeutic use; Autografts; Cancer; Cancer and Oncology; Cancer och onkologi; Cell interactions; Cell Line, Tumor; Cell survival; Diabetes mellitus; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immunotherapy; Immunotherapy, Adoptive; Interleukin 2; Interleukin Receptor Common gamma Subunit - genetics; Interleukin-2 - genetics; Kirurgi; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Lymphocytes, Tumor-Infiltrating - transplantation; Melanoma; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Mice, Knockout; multidisciplinary; Neoplasm Metastasis; Patients; Science; Science (multidisciplinary); Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Surgery; T-Lymphocytes - immunology; T-Lymphocytes - pathology; T-Lymphocytes - transplantation; Tumor cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00786-z

Immune checkpoint inhibitors and adoptive cell transfer (ACT) of autologous tumor-infiltrating T cells have shown durable responses in patients with melanoma. To study ACT and immunotherapies in a humanized model, we have developed PDXv2.0 — a melanoma PDX model where tumor cells and tumor-infiltrating T cells from the same patient are transplanted sequentially in non-obese diabetic/severe combined immune-deficient/common gamma chain (NOG/NSG) knockout mouse. Key to T-cell survival/effect in this model is the continuous presence of interleukin-2 (IL-2). Tumors that grow in PDXv2.0 are eradicated if the autologous tumor cells and T cells come from a patient that exhibited an objective response to ACT in the clinic. However, T cells from patients that are non-responders to ACT cannot kill tumor cells in PDXv2.0. Taken together, PDXv2.0 provides the potential framework to further model genetically diverse human cancers for assessing the efficacy of immunotherapies as well as combination therapies. Combining different types of immune therapies might benefit certain patients. Here, the authors develop an autologous immune-humanized melanoma mouse model that allows the preclinical assessment of cancer cell–T cell interactions from each individual patient and the benefits of immunotherapies combinations.