Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression

Abstract

In this report, we developed a chimeric receptor (N29g 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 N29g 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 N29g 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 N29g T cells was required to mediate regression of advanced 8-day macrometastases. Exogenous administration of interleukin-2 (IL-2) after N29g T-cell transfer was dispensable for treatment of 3-day micrometastases, but was required for mediating regression of wellestablished 8-day macrometastases. Moreover, fractionated CD8 T cells expressing N29g chR suppressed HER2-positive tumor cell growth after adoptive transfer independent of CD4 þ 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.

Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model

“…10 The approach with scFv-CIR can avoid MHC limitations imposed by the use of TCR, thus stable transfectants expressing CIR has shown its therapeutic potentials against several surface tumor antigens. 11,12 Long-term persistency and expansion of gene-modified lymphocytes can be mediated by retroviral or lentiviral transduction. However, regulatory concerns on their potential for insertional mutagenesis and genotoxicity increase the need of alternative method.…”

Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells

“…Lymphocyte depletion [29][30][31] and exogenous IL-2 32 have been shown to enhance the anticancer efficacy of adoptively transferred T cells. We conducted a series of experiments to assess the impact of irradiation before T-cell transfer and IL-2 after T-cell transfer on the antilymphoma efficacy of CAR-transduced T cells targeting the self-antigen CD19.…”

“…23,39 In another type of experimental model, murine T cells expressing CARs that target human tumor-associated antigens have been used to treat mice bearing murine tumor cells that were genetically engineered to express the targeted human tumorassociated antigens. 14,32,40 There are several drawbacks to murine tumor immunology studies that use murine tumor cells expressing foreign antigens, such as human tumor-associated antigens. Mice might be able to generate an endogenous immune response against the human antigens, 41 and autoimmunity cannot be assessed in such models because the targeted human antigens are not expressed by normal murine cells.…”

Modulation of tumor immunity by therapeutic monoclonal antibodies

“…Clinical studies also have revealed the existence of T cell epitopes that can be recognized by CTLs or helper T cells in breast cancer patients following anti-HER-2/Neu mAb (trastuzumab) therapy [80][81][82][83][84][85]. Some of these peptides were used in anti-tumor vaccine approaches that were evaluated in HER-2/Neu + mouse tumor models [86][87][88][89]. In another study, the use of a vaccine approach associated to anti-HER-2/Neu mAb therapy led to optimal therapeutic efficacy in a HER-2/ Neu transgenic mouse tumor model [90].…”