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Treatment with Anti...
Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
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- Forsberg, Elin (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology
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- Riise, Rebecca E, 1987 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology
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- Saellström, Sara (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences
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- Karlsson, Joakim (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology
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- Alsén, Samuel (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology
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- Bucher, Valentina, 1996 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Centrum för Cancerforskning (SCCR),Institute of Clinical Sciences, Department of Oncology,Sahlgrenska Center for Cancer Research (SCCR)
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Hemminki, A. E. (author)
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- Olofsson Bagge, Roger, 1978 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Centrum för Cancerforskning (SCCR),Institute of Clinical Sciences, Department of Oncology,Sahlgrenska Center for Cancer Research (SCCR)
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- Ny, Lars, 1967 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology
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- Nilsson, Lisa M, 1976 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Centrum för Cancerforskning (SCCR),Institute of Clinical Sciences, Department of Oncology,Sahlgrenska Center for Cancer Research (SCCR)
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- Rönnberg, Henrik (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences
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- Nilsson, Jonas A, 1971 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Centrum för Cancerforskning (SCCR),Institute of Clinical Sciences, Department of Oncology,Sahlgrenska Center for Cancer Research (SCCR)
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(creator_code:org_t)
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- 2023-01-20
- 2023
- English.
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In: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- LANTBRUKSVETENSKAPER -- Veterinärmedicin -- Klinisk vetenskap (hsv//swe)
- AGRICULTURAL SCIENCES -- Veterinary Science -- Clinical Science (hsv//eng)
Keyword
- metastatic melanoma
- uveal melanoma
- patient-derived xenograft mouse
- model
- adoptive T cell therapy
- chimeric antigen receptor T cells
- immunotherapy
- canine
- companion dog
- comparative oncology
- HER2
Publication and Content Type
- ref (subject category)
- art (subject category)
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Forsberg, Elin
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Riise, Rebecca E ...
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Saellström, Sara
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Karlsson, Joakim
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Alsén, Samuel
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Bucher, Valentin ...
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Hemminki, A. E.
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Olofsson Bagge, ...
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Ny, Lars, 1967
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Nilsson, Lisa M, ...
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Rönnberg, Henrik
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Nilsson, Jonas A ...
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Cancers
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University of Gothenburg
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Swedish University of Agricultural Sciences