Adoptive immunotherapy with redirected T cells produces CCR7- cells that are trapped in the periphery and benefit from combined CD28-OX40 costimulation.
Adoptive therapy of cancer with genetically redirected T cells showed spectacular efficacy in recent trials. A body of preclinical and clinical data indicate that young effector and central memory T cells perform superior in a primary antitumor response; repetitive antigen engagement, however, drives T-cell maturation to terminally differentiated cells associated with the loss of CCR7, which enables T cells to persist in peripheral tissues. In this work, we explored the antitumor efficacy of CCR7(-) T cells when redirected in an antigen-dependent fashion by a chimeric antigen receptor (CAR) toward tumors in the periphery. CAR-engineered CCR7(-) T cells more efficiently accumulated at the tumor site, secreted more IFN-γ, expressed higher amounts of cytotoxic molecules, and showed superior tumor cell lysis compared to the younger CCR7(+) cells. CCR7(-) T cells, however, were more prone to spontaneous and activation-induced cell death, which could be counteracted by simultaneous CD28 and OX40 (CD134) costimulation. Consequently, the combined CD28-ζ-OX40 signaling CAR rescued CCR7(-) T cells from apoptosis, which then produced more efficient antitumor efficacy than CCR7(+) T cells redirected by the same CAR. Data suggest that T-cell therapy will benefit from combined CD28-ζ-OX40 stimulation in the long-term by rescuing continuously generated CCR7(-) T cells for an antitumor attack.
Center for Molecular Medicine Cologne (CMMC) and Department I Internal Medicine, University of Cologne, Cologne, Germany .
Andreas A
AA
Hombach
Markus
M
Chmielewski
Gunter
G
Rappl
Hinrich
H
Abken
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D010641:Phenotype; D054400:Receptors, CCR7 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053262:Receptors, OX40 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D018106:CD28 Antigens; D054400:Receptors, CCR7; D053262:Receptors, OX40