| 1. |
- Forsberg, Elin, et al.
(författare)
-
Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
- 2023
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
-
Tidskriftsartikel (refereegranskat)abstract
- Simple Summary CAR-T cells are immune cells equipped with a claw that enable them to bind cancer cells. Usually, CAR-T cells are made using immune cells from blood. Here, we tested the hypothesis that also immune cells that reside in the tumor, so called tumor-infiltrating lymphocytes, can also be modified to carry the claw. This may mean that these cells, called CAR-TILs, will be able to attack cancer cells in two ways, using the claw or binding using its normal protein on the cell surface, the so-called T cell receptor. We show that CAR-TILs can be generated, and that they can kill melanoma cells in cell culture and in mice. Finally, to prepare for clinical trials, we also assess if CAR-TILs can be safe in a human cancer patient-like model, a companion dog suffering from cancer. Our data suggest that CAR-TILs may be a way to treat patients with melanoma but human clinical trials are needed. Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
|
|
| 2. |
- Vladic, Tomislav, et al.
(författare)
-
Sperm competition between alternative reproductive tactics of the Atlantic salmon in vitro
- 2010
-
Ingår i: Aquaculture. - : Elsevier. - 0044-8486 .- 1873-5622. ; 302:3-4, s. 265-269
-
Tidskriftsartikel (refereegranskat)abstract
- The maintenance of brood stock in appropriate conditions is an important requirement for the production of high quality offspring. In this study, we investigated fertility of the two life history forms of Atlantic salmon males, precocious parr, brought up in breeding tanks in the hatchery and anadromous, migratory searanched males, caught when returning to the home river. The sperm quality was assessed by experiments between equal amount of sperm from one adult and one parr male in competition to fertilize eggs of a single female. The paternity was determined by a microsatellite analysis. Parr males achieved greater reproductive success than anadromous males under competition, and anadromous adults had greater fertility in controls as compared to the sperm competition situation. In total, parr males achieved 3.6 times greater fertilization success than anadromous males. Sperm ATP content contributed significantly to male fertility. Our results provide evidence that ejaculates of precociously mature Atlantic salmon parr are of increased quality as an adaptation to high sperm competition intensity due to better maintenance in the fish farm than in the wild.
|
|
