T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model.
For the adoptive transfer of tumor-directed T lymphocytes to prove effective, there will probably need to be a match between the chemokines the tumor produces and the chemokine receptors the effector T cells express. The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tregs) that express the TARC/MDC-specific chemokine receptor CCR4, thus generating an immunosuppressed tumor environment. By contrast, effector CD8(+) T cells lack CCR4, are nonresponsive to these chemokines and are rarely detected at the tumor site. We now show that forced expression of CCR4 by effector T cells enhances their migration to HL cells. Furthermore, T lymphocytes expressing both CCR4 and a chimeric antigen receptor directed to the HL associated antigen CD30 sustain their cytotoxic function and cytokine secretion in vitro, and produce enhanced tumor control when infused intravenously in mice engrafted with human HL. This approach may be of value in patients affected by HL.
Center for Cell and Gene Therapy, Baylor College of Medicine, Methodist Hospital and Texas Children's Hospital, Houston, 77030, USA.
Antonio
A
Di Stasi
Biagio
B
De Angelis
Cliona M
CM
Rooney
Lan
L
Zhang
Aruna
A
Mahendravada
Aaron E
AE
Foster
Helen E
HE
Heslop
Malcolm K
MK
Brenner
Gianpietro
G
Dotti
Barbara
B
Savoldo
D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D054414:Chemokine CCL17 / Q000235:genetics / Q000502:physiology; D054422:Chemokine CCL22 / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D003602:Cytotoxicity, Immunologic; D005822:Genetic Vectors / Q000235:genetics; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D017730:Ki-1 Antigen / Q000502:physiology*; D008213:Lymphocyte Activation; D017728:Lymphoma, Large-Cell, Anaplastic / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D054398:Receptors, CCR4 / Q000235:genetics / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016539:Reed-Sternberg Cells / Q000737:chemistry; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D017730:Ki-1 Antigen; D054398:Receptors, CCR4; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins