TY - JOUR
T1 - Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
AU - Forsberg, Elin M.V.
AU - Riise, Rebecca
AU - Saellström, Sara
AU - Karlsson, Joakim
AU - Alsén, Samuel
AU - Bucher, Valentina
AU - Olofsson Bagge, Roger
AU - Ny, Lars
AU - Nilsson, Lisa M.
AU - Rönnberg, Henrik
AU - Nilsson, Jonas A.
N1 - Funding Information:
This work was supported by the Swedish Cancer Society, Swedish Research Council, EU Horizon 2020 (ERA PerMed), Region Västra Götaland (ALF-grant), Knut and Alice Wallenberg Foundation, Sjöberg Foundation, Familjen Erling Persson Foundation, IngaBritt and Arne Lundberg Foundation (to J.A.N.), Assar Gabrielsson Foundation, and Sahlgrenska Universitetssjukhusets stiftelse (Sahlgrenska University Hospital, Gothenburg) (to E.M.V.F.). S.S. and H.R. were supported by the Johansson Family Swedish Boxer Club Cancer Donation, and A.E.H. was supported by the Jane and Aatos Erkko Foundation. J.A.N., L.M.N., and J.K. were supported by the Kirkbride Melanoma Discovery Lab at the Harry Perkins Institute of Medical Research.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
KW - adoptive T cell therapy
KW - canine
KW - chimeric antigen receptor T cells
KW - companion dog
KW - comparative oncology
KW - HER2
KW - immunotherapy
KW - metastatic melanoma
KW - patient-derived xenograft mouse model
KW - uveal melanoma
UR - http://www.scopus.com/inward/record.url?scp=85147877321&partnerID=8YFLogxK
U2 - 10.3390/cancers15030648
DO - 10.3390/cancers15030648
M3 - Article
C2 - 36765608
AN - SCOPUS:85147877321
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 3
M1 - 648
ER -