TY - JOUR

T1 - Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model

AU - Jespersen, Henrik

AU - Lindberg, Mattias F

AU - Donia, Marco

AU - Söderberg, Elin M V

AU - Andersen, Rikke

AU - Keller, Ulrich

AU - Ny, Lars

AU - Svane, Inge Marie

AU - Nilsson, Lisa M

AU - Nilsson, Jonas A

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies, Monoclonal, Humanized/therapeutic use

KW - Antineoplastic Agents/therapeutic use

KW - Cell Line, Tumor

KW - Humans

KW - Immunotherapy, Adoptive

KW - Interleukin Receptor Common gamma Subunit/genetics

KW - Interleukin-2/genetics

KW - Lymphocytes, Tumor-Infiltrating/immunology

KW - Melanoma/immunology

KW - Mice, Knockout

KW - Neoplasm Metastasis

KW - Skin Neoplasms/immunology

KW - T-Lymphocytes/immunology

U2 - 10.1038/s41467-017-00786-z

DO - 10.1038/s41467-017-00786-z

M3 - Journal article

C2 - 28955032

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 707

ER -