Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression.
In this report, we developed a chimeric receptor (N29gamma chR) involving the single chain Fv (scFv) derived from N29 monoclonal antibody (mAb) specific for p185HER2 and characterized the therapeutic efficacy of primary T cells engineered to express N29gamma chR in two histologically distinct murine tumor models. Murine breast (MT901) and fibrosarcoma (MCA207) cancer cell lines were engineered to express human HER2 as targets. Administration of N29gamma chR-expressing T cells eliminated 3-day pulmonary micrometastases of MT901/HER2 and MCA207/HER2 but not parental tumor cells. A 5 to 8-fold increased dose of N29gamma T cells was required to mediate regression of advanced 8-day macrometastases. Exogenous administration of interleukin-2 (IL-2) after N29gamma T-cell transfer was dispensable for treatment of 3-day micrometastases, but was required for mediating regression of well-established 8-day macrometastases. Moreover, fractionated CD8 T cells expressing N29gamma chR suppressed HER2-positive tumor cell growth after adoptive transfer independent of CD4(+) cells. These data indicate that genetically modified T cells expressing a HER2-targeting chimeric receptor can mediate antigen-specific regression of preestablished metastatic cancers in a cell dose-dependent fashion. Systemic administration of IL-2 augments the therapeutic efficacy of these genetically engineered T cells in advanced diseases. These results are relevant to the implication of genetically redirected T cells in clinical cancer immunotherapy.
Li
S
S
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0666, USA.
Yang
J
J
Urban
F A
FA
MacGregor
J N
JN
Hughes
D P M
DP
Chang
A E
AE
McDonagh
K T
KT
Li
Q
Q
D000818:Animals; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D005434:Flow Cytometry; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation
D007128:Immunoglobulin Fragments; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C055966:immunoglobulin Fv; C524056:Erbb2 protein, mouse