Adoptive T-cell transfer to treat lymphangioleiomyomatosis

F Han, ER Dellacecca, LW Barse… - American journal of …, 2020 - atsjournals.org
F Han, ER Dellacecca, LW Barse, C Cosgrove, SW Henning, CM Ankney, D Jaishankar
American journal of respiratory cell and molecular biology, 2020atsjournals.org
Patients with lymphangioleiomyomatosis (LAM) develop pulmonary cysts associated with
neoplastic, smooth muscle–like cells that feature neuroendocrine cell markers. The disease
preferentially affects premenopausal women. Existing therapeutics do not cure LAM. As
gp100 is a diagnostic marker expressed by LAM lesions, we proposed to target this
immunogenic glycoprotein using TCR transgenic T cells. To reproduce the genetic
mutations underlying LAM, we cultured Tsc2−/− kidney tumor cells from aged Tsc2 …
Patients with lymphangioleiomyomatosis (LAM) develop pulmonary cysts associated with neoplastic, smooth muscle–like cells that feature neuroendocrine cell markers. The disease preferentially affects premenopausal women. Existing therapeutics do not cure LAM. As gp100 is a diagnostic marker expressed by LAM lesions, we proposed to target this immunogenic glycoprotein using TCR transgenic T cells. To reproduce the genetic mutations underlying LAM, we cultured Tsc2−/− kidney tumor cells from aged Tsc2 heterozygous mice and generated a stable gp100-expressing cell line by lentiviral transduction. T cells were isolated from major histocompatibility complex–matched TCR transgenic pmel-1 mice to measure cytotoxicity in vitro, and 80% cytotoxicity was observed within 48 hours. Antigen-specific cytotoxicity was likewise observed using pmel-1 TCR-transduced mouse T cells, suggesting that transgenic T cells may likewise be useful to treat LAM in vivo. On intravenous injection, slow-growing gp100+ LAM-like cells formed lung nodules that were readily detectable in severe combined immunodeficient/beige mice. Adoptive transfer of gp100-reactive but not wild-type T cells into mice significantly shrunk established lung tumors, even in the absence of anti–PD-1 therapy. These results demonstrate the treatment potential of adoptively transferred T cells to eliminate pulmonary lesions in LAM.
ATS Journals