Genetically targeted T cells eradicate established breast cancer in syngeneic mice
Hao Wang1, Huafeng Wei, Ruiping Zhang
1International Joint Cancer Institute and Changhai Hospital Cancer Center, The Second Military Medical University, Shanghai, People's Republic of China.
Purpose:
The purpose of the present study was to evaluate the capacity and mechanisms of genetically modified erbB2-specific T cells to eradicate erbB2+ tumors in syngeneic mice.
Experimental Design:
Primary mouse T cells were modified to target the breast tumor-associated antigen erbB2 through retroviral-mediated transfer of a chimeric antigen receptor, termed single-chain antibody (scFv)-CD28-zeta. Antitumor efficacy of scFv-CD28-zeta-modified T cells was analyzed in mice bearing D2F2/E2 breast tumors.
Results:
The scFv-CD28-zeta-modified T cells were shown to specifically secrete T cytotoxic-1 cytokines and lyse erbB2+ breast tumor cells following receptor stimulation in vitro. Treatment with scFv-CD28-zeta-modified T cells was able to lead to long-term, tumor-free survival in mice bearing erbB2+ D2F2/E2 breast tumors. Importantly, the surviving mice developed a host memory response to D2F2/E2 tumor cells, and this host response was able to protect against a rechallenge with erbB2+ D2F2/E2 tumor cells and parental erbB2(-) D2F2 tumor cells. In addition, scFv-CD28-zeta T-cell expression of perforin and interferon-gamma were essential for complete antitumor efficacy.
Conclusions:
Treatment with scFv-CD28-zeta-modified T cells was able to induce a host antitumor immunity in syngeneic mice. Complete tumor elimination by scFv-CD28-zeta-modified T cells required T cell-derived interferon-gamma and perforin, indicating that cytotoxicity and cytokine secretion play a role in the in vivo response.
Insights
Genetically modified T cells targeting erbB2 eradicated tumors in mice, inducing a protective memory response. This immunotherapy required T cell-derived interferon-gamma and perforin for complete tumor elimination.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Engineering
Background:
- Breast cancer often overexpresses the erbB2 antigen.
- T cells are crucial components of the adaptive immune system for tumor surveillance.
- Genetically engineering T cells offers a promising strategy for targeted cancer therapy.
Purpose of the Study:
- To assess the efficacy of genetically modified T cells in eradicating erbB2-expressing tumors.
- To elucidate the mechanisms by which these modified T cells exert antitumor effects.
- To evaluate the potential for inducing a lasting immune memory response.
Main Methods:
- Primary mouse T cells were engineered with a chimeric antigen receptor (scFv-CD28-zeta) to target erbB2.
- Antitumor activity was evaluated in a syngeneic mouse model using D2F2/E2 breast tumors.
- Key effector molecules like perforin and interferon-gamma were assessed for their role in efficacy.
Main Results:
- Modified T cells demonstrated specific lysis of erbB2+ tumor cells and cytokine secretion in vitro.
- Treatment resulted in long-term, tumor-free survival in mice with erbB2+ tumors.
- Surviving mice developed a memory response protecting against tumor rechallenge.
- Perforin and interferon-gamma expression by T cells were critical for complete tumor eradication.
Conclusions:
- Genetically modified T cells can induce host antitumor immunity in vivo.
- Complete tumor elimination relies on T cell cytotoxicity and cytokine secretion, specifically interferon-gamma and perforin.
- This approach holds potential for developing effective immunotherapies against erbB2+ cancers.
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