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

Jespersen, Henrik; Lindberg, Mattias F.; Donia, Marco; Söderberg, Elin; Andersen, Rikke; Keller, Ulrich; Ny, Lars; Svane, Inge Marie; Nilsson, Lisa M.; Nilsson, Jonas A.

doi:10.1038/s41467-017-00786-z

Cited by 143 publications

(157 citation statements)

References 51 publications

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“…Already in the 1950's medical oncologists performed studies on the correlation between drug responses of cancer patients in vivo with that of corresponding tumor biopsies in tissue culture models . Over the years many more approaches to personalized medicine have been established, ranging from purely sequencing‐based methods to the use of patient‐derived xenograft mouse models that can be used as avatars to test different treatment options . However, so far only very few approaches have made it into routine clinical use.…”

Section: Discussionmentioning

confidence: 99%

Microfluidics as an Enabling Technology for Personalized Cancer Therapy

Mathur

Ballinger

Utharala

et al. 2019

Small

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Tailoring patient‐specific treatments for cancer is necessary in order to achieve optimal results but requires new diagnostic approaches at affordable prices. Microfluidics has immense potential to provide solutions for this, as it enables the processing of samples that are not available in large quantities (e.g., cells from patient biopsies), is cost efficient, provides a high level of automation, and allows the set‐up of complex models for cancer studies. In this review, individual solutions in the fields of genetics, circulating tumor cell monitoring, biomarker analysis, phenotypic drug sensitivity tests, and systems providing controlled environments for disease modeling are discussed. An overview on how these early stage achievements can be combined or developed further is showcased, and the required translational steps before microfluidics becomes a routine tool for clinical applications are critically discussed.

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Section: Discussionmentioning

confidence: 99%

Microfluidics as an Enabling Technology for Personalized Cancer Therapy

Mathur

Ballinger

Utharala

et al. 2019

Small

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“…GDC-0575 is an orally available Chk1 inhibitor under clinical development. To test if the inhibitor is compatible with immunotherapy we used a recently developed model, the PDXv2 model (32), where human melanoma is grown in an immunocompromised mouse transgenic for human IL-2 (hIL2-NOG mice). Infusion of autologous T cells into this mouse model can be used to assess quality of the patient's TILs and responses in these mice mimic the responses to adoptive T cell transfer in the same patients from which the PDXv2 model is developed.…”

Section: Anti-tumoral Immunity Mediated By T Cells Is Not Impaired Bymentioning

confidence: 99%

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

Muralidharan

Nilsson

Lindberg

et al. 2020

Preprint

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Chk1 kinase is downstream of the ATR kinase in the sensing of improper replication. Previous cell culture studies have demonstrated that Chk1 is essential for replication and Chk1 inhibitors are efficacious against tumors with high-level replication stress such as Myc-induced lymphoma cells. Treatment with Chk1 inhibitors also combines well with certain chemotherapeutic drugs and effects associates with induction of DNA damage and reduction of Chk1 protein levels. Most studies of Chk1 function has relied on the use of inhibitors. Whether or not a mouse or cancer cells could survive if a kinase-dead form of Chk1 is expressed has not been investigated before. Here we generate a mouse model that expresses a kinase-dead (D130A) allele in the mouse germline. We find that this mouse is overtly normal and does not have problems with erythropoiesis with ageing as previously been shown for a mouse expressing one null allele. However, similar to a null allele, homozygous kinase-dead mice cannot be generated and timed pregnancies of heterozygous mice suggest lethality of homozygous blastocysts at around the time of implantation. By breeding the kinasedead Chk1 mouse with a conditional allele we are able to demonstrate that expression of only one kinase-dead allele, but no wildtype allele, of Chek1 is lethal for Mycinduced cancer cells. Finally, treatment of melanoma cells with tumor-infiltrating T cells or CAR-T cells is effective even if Chk1 is inhibited, suggesting that Chk1 inhibitors can be safely administered in patients where immunotherapy is an essential component of the arsenal against cancer.

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“…Among them, HLA class I transgenic mice evoked antigen-specific cytotoxic T-cell response against HSV virion protein peptide [128] or WT1 peptide [129]. The success of the reconstitution of human cellular immune response was followed by an adoptive transfer therapy model using the humanized-mouse system [130]. Consequently, the established patient-derived xenograft (PDX) system, which transplants a patient's cancer tissues (minimal standard was reported by Meehan et al [131]), combined with a patient's T cells, is widely accepted.…”

Section: Humanized Mice For Reconstitution Of the Human Immune Systemmentioning

confidence: 99%

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

Kametani

Ohno

Ohshima

et al. 2019

IJMS

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Peptide vaccination was developed for the prevention and therapy of acute and chronic infectious diseases and cancer. However, vaccine development is challenging, because the patient immune system requires the appropriate human leukocyte antigen (HLA) recognition with the peptide. Moreover, antigens sometimes induce a low response, even if the peptide is presented by antigen-presenting cells and T cells recognize it. This is because the patient immunity is dampened or restricted by environmental factors. Even if the immune system responds appropriately, newly-developed immune checkpoint inhibitors (ICIs), which are used to increase the immune response against cancer, make the immune environment more complex. The ICIs may activate T cells, although the ratio of responsive patients is not high. However, the vaccine may induce some immune adverse effects in the presence of ICIs. Therefore, a system is needed to predict such risks. Humanized mouse systems possessing human immune cells have been developed to examine human immunity in vivo. One of the systems which uses transplanted human peripheral blood mononuclear cells (PBMCs) may become a new diagnosis strategy. Various humanized mouse systems are being developed and will become good tools for the prediction of antibody response and immune adverse effects.

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

Cited by 143 publications

References 51 publications

Microfluidics as an Enabling Technology for Personalized Cancer Therapy

Microfluidics as an Enabling Technology for Personalized Cancer Therapy

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

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