| 1. |
- Donia, M., et al.
(författare)
-
Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN gamma Signaling
- 2017
-
Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 77:17, s. 4562-4566
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFN gamma signaling, led to impaired recognition by tumor-specific CD8(+) T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFN gamma signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.
|
|
| 2. |
- Donia, Marco, et al.
(författare)
-
Acquired immune resistance follows complete tumor regression without loss of target antigens or IFNγ signaling
- 2017
-
Ingår i: Cancer Research. - 0008-5472. ; 77:17, s. 4562-4566
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8þ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.
|
|
| 3. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
-
A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma
- 2018
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8
-
Tidskriftsartikel (refereegranskat)abstract
- Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
|
|
| 4. |
- Forsberg, Elin, et al.
(författare)
-
HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy-Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice
- 2019
-
Ingår i: Cancer Research. - 0008-5472. ; 79:5, s. 899-904
-
Tidskriftsartikel (refereegranskat)abstract
- Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T-cell receptors when bound to a cell surface target. CAR-expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), for example, by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo. Curative effects in vivo were only observed in xenografts grown in a NOD/SCID IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR-T cells were also able to kill melanoma cells from patients resistant to adoptive T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. Significance: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
|
|
| 5. |
- Hutchinson, B., et al.
(författare)
-
Microstructures and hardness of as-quenched martensites (0.1-0.5%C)
- 2011
-
Ingår i: Acta Materialia. - : Elsevier BV. - 1359-6454 .- 1873-2453. ; 59:14, s. 5845-5858
-
Tidskriftsartikel (refereegranskat)abstract
- Four commercial steels with carbon contents in the range 0.1-0.5 wt.% have been examined in the as-quenched condition using electron microscopy, X-ray diffraction and atom probe tomography. The austenite had been deformed 0%, 10% and 30% prior to brine quenching. No influence of this deformation was evident on the martensite hardness or in any of the microstructure measurements. Increasing carbon content showed a well-known marked effect on the hardness but resulted in little refinement in the grain structure of the martensite. All crystal structures were cubic; no evidence of tetragonality was seen even at the highest carbon level but some systematic changes in grain boundary misorientations existed. The content of carbon in true interstitial solid solution deduced from X-ray line shifts was small (similar to 0.02 wt.%), and was independent of the total carbon content in the steel. Atom probe tomography showed that carbon was almost completely segregated to lath boundaries and dislocations but with an increasing density of segregates in the higher carbon steels. Calculations of diffusion distances confirmed that the segregation patterns were compatible with autotempering of the martensite during quenching. Analysis of different possible contributions to strength leads to the conclusion that segregated carbon atoms at defects behave similarly to carbon in true solid solution and that this is the largest single factor controlling the strength of as-quenched martensite. (C) 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
|
|
| 6. |
- Jespersen, Henrik, et al.
(författare)
-
Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model.
- 2017
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 7. |
- Muralidharan, Somsundar Veppil, et al.
(författare)
-
BET bromodomain inhibitors synergize with ATR inhibitors in melanoma in melanoma.
- 2017
-
Ingår i: Cell Death & Disease. - 2041-4889. ; 8:8, s. 1-7
-
Tidskriftsartikel (refereegranskat)abstract
- Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.
|
|
| 8. |
- Muralidharan, Somsundar Veppil, et al.
(författare)
-
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
- 2020
-
Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 3:8
-
Tidskriftsartikel (refereegranskat)abstract
- 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. Indeed, 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 associate with the induction of DNA damage and reduction of Chk1 protein levels. Most studies of Chk1 function have 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 germ line. We find that this mouse is overtly normal and does not have problems with erythropoiesis with aging 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 kinase-dead Chk1 mouse with a conditional allele, we are able to demonstrate that expression of only one kinase-dead allele, but no wild-type allele, of Chek1 is lethal for Myc-induced 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.
|
|
| 9. |
- Sah, Vasu R., et al.
(författare)
-
Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma
- 2022
-
Ingår i: Melanoma Research. - : Ovid Technologies (Wolters Kluwer Health). - 0960-8931. ; 32:4, s. 241-248
-
Tidskriftsartikel (refereegranskat)abstract
- Targeted therapy and immunotherapy have revolutionized the treatment of metastatic skin melanoma but around half of all patients develop resistance early or late during treatment. The situation is even worse for patients with metastatic uveal melanoma (UM). Here we hypothesized that the immunotherapy of therapy-resistant skin melanoma or UM can be enhanced by epigenetic inhibitors. Cultured B16F10 cells and human UM cells were treated with the histone deacetylase inhibitor (HDACi) entinostat or BETi JQ1. Entinostat-induced HLA expression and PD-L1, but JQ1 did not. A syngeneic mouse model carrying B16-F10 melanoma cells was treated with PD-1 and CTLA4 inhibitors, which was curative. Co-treatment with the bioavailable BETi iBET726 impaired the immunotherapy effect. Monotherapy of a B16-F10 mouse model with anti-PD-1 resulted in a moderate therapeutic effect that could be enhanced by entinostat. Mice carrying PD-L1 knockout B16-F10 cells were also sensitive to entinostat. This suggests HDAC inhibition and immunotherapy could work in concert. Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted.
|
|
| 10. |
- Soreskog, E., et al.
(författare)
-
Cost-effectiveness of romosozumab for the treatment of postmenopausal women with severe osteoporosis at high risk of fracture in Sweden
- 2021
-
Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 32, s. 585-594
-
Tidskriftsartikel (refereegranskat)abstract
- Romosozumab is a novel bone-building drug that reduces fracture risk. This health economic analysis indicates that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture. Purpose To estimate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate ("romosozumab-to-alendronate") compared with alendronate alone in patients with severe osteoporosis at high risk of fracture in Sweden. Methods A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), for women treated with romosozumab-to-alendronate or alendronate alone. Patients aged 74 years with a recent major osteoporotic fracture (MOF) were followed from the start of treatment until the age of 100 years or death. Treatment with romosozumab for 12 months was followed by alendronate for up to 48 months or alendronate alone with a maximum treatment duration of 60 months. The analysis had a societal perspective. Efficacy of romosozumab and alendronate were derived from phase III randomized controlled trials. Resource use and unit costs were collected from the literature. Cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) with QALYs as effectiveness measures. Results The base case analysis showed that sequential romosozumab-to-alendronate treatment was associated with 0.089 additional QALYs at an additional cost of euro3002 compared to alendronate alone, resulting in an ICER of euro33,732. At a Swedish reference willingness-to-pay per QALY of euro60,000, romosozumab-to-alendronate had a 97.9% probability of being cost-effective against alendronate alone. The results were most sensitive to time horizon, persistence assumptions, patient age, and treatment efficacy. Conclusion The results of this study indicate that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture.
|
|
