Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers.
Purpose:CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate "on-target, off-tumor" toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70.Experimental Design:Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different costimulatory domains from CD28 and/or 41BB were constructed.In vitrofunctionality of these receptors was compared andin vivotreatment efficacy was evaluated in a xenograft mouse model. A homologous, all murine anti-CD70 CAR model was also used to assess treatment-related toxicities.Results:The CAR consisting of the extracellular binding portion of CD27 fused with 41BB and CD3-zeta (trCD27-41BB-zeta) conferred the highest IFNγ production against CD70-expressing tumorsin vitro, and NSG mice bearing established CD70-expressing human tumors could be cured by human lymphocytes transduced with this CAR. In the murine CD27-CD3-zeta CAR model, significant reduction of established tumors and prolonged survival were achieved using CAR-transduced splenocytes in a dose-dependent manner. Host preirradiation enhanced treatment efficacy but increased treatment-related toxicities such as transient weight loss and hematopoetic suppression. The treatment did not appear to block adaptive host immune responses.Conclusions:Preclinical testing supports the safety and efficacy of a CD27-containing CAR targeting CD70-expressing tumors.Clin Cancer Res; 23(9); 2267-76. ©2016 AACR.
Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. qiongwang@mail.nih.gov James_Yang@nih.gov.
Qiong J
QJ
Wang
Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Zhiya
Z
Yu
Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Ken-Ichi
KI
Hanada
Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Krishna
K
Patel
Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
David
D
Kleiner
Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Nicholas P
NP
Restifo
Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. qiongwang@mail.nih.gov James_Yang@nih.gov.
James C
JC
Yang
D000818:Animals; D053282:CD27 Ligand / Q000235:genetics* / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D053282:CD27 Ligand; D018106:CD28 Antigens; D017252:CD3 Complex; C505771:CD70 protein, human; D011948:Receptors, Antigen, T-Cell; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7