Antitumor Antibodies Can Drive Therapeutic T Cell Responses

Wittrup, K. Dane

doi:10.1016/j.trecan.2017.07.001

Cited by 29 publications

(20 citation statements)

References 30 publications

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“…46 CD8 + T cells are essential for anti-tumor associated antigen (TAA) monoclonal antibody efficacy, Her-2-specific CD8 + T cell responses could eradicate drug-refractory tumors, but the cytotoxicity of antigen-specific CD8 + T cells is blocked by tumor-induced immunosuppression in the tumor microenvironment. 9,45,47 Thus, it would be ideal if the treatment against her-2/neu TAA could generate both antibodies and lasting T cell responses.…”

Section: Discussionmentioning

confidence: 99%

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Zhang

et al. 2020

OncoImmunology

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In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2 D4) was found to enhance IFN-γ-producing-CD8 + T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2 D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2 D4 and antitumor immunity, as evidenced by the reversal of tumor-infiltrating CD8 + T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy.

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Section: Discussionmentioning

confidence: 99%

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Zhang

et al. 2020

OncoImmunology

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“…The development of antibody responses against tumors has been studied in multiple contexts. In recent studies of effective immunotherapy, the development of antibodies to tumor-associated antigens has been associated with a positive response ( 23 , 24 ). However, the importance of antibodies as a component of effective antitumor responses has long been recognized ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Ranitidine Inhibition of Breast Tumor Growth Is B Cell Dependent and Associated With an Enhanced Antitumor Antibody Response

et al. 2018

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BackgroundThe histamine receptor 2 antagonist ranitidine is a commonly used, non-prescription, medication. It limits the development, growth, and metastasis of breast cancers in mouse models of disease. In this study, we examined the role of B cells in this response, the impact of ranitidine on the development of antitumor antibodies and subpopulations of natural killer cells using murine breast cancer models.MethodsPeripheral blood granulocyte populations were assessed in both E0771-GFP and 4T1 orthotopic tumor-bearing mice by evaluation of stained blood smears. Antibody responses were assessed both in terms of the levels of anti-GFP antibodies detected by enzyme-linked immunosorbent assay and also by antibody binding to the surface of tumor cells evaluated by flow cytometry. B cell and NK cell populations were examined in the draining lymph nodes and spleens of tumor-bearing animals, by flow cytometry with and without ranitidine treatment.ResultsOral ranitidine treatment was not associated with changes in peripheral blood granulocyte populations in tumor-bearing mice. However, ranitidine treatment was associated with the development of enhanced antitumor antibody responses. This was not limited to the tumor setting since ranitidine-treated mice immunized with ovalbumin also demonstrated increased IgG antibody responses. Analysis of B cell populations indicated that while B1 cell populations remained unchanged there was a significant decrease in B2 cells in the tumor-draining inguinal lymph nodes. Notably, ranitidine did not significantly inhibit primary tumor growth in B cell-deficient animals. Examination of NK cell populations revealed a significant decrease in the proportion of intermediately functionally mature NK cells populations (CD27+CD11b−) in ranitidine-treated tumor-bearing mice compared with untreated tumor-bearing controls.ConclusionThese data demonstrate an important role for B cells in the enhanced antitumor immune response that occurs in response to ranitidine treatment. Our findings are consistent with a model, whereby ranitidine reduces tumor-associated immune suppression allowing for the development of more effective antitumor responses mediated by B cells which may include the participation of NK cells. These data underline the importance of considering widely used histamine receptor antagonists as modulators of antitumor immunity to breast cancer.

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“…Some monoclonal antibodies can exert anti-tumor effect by recruiting effector cells from the innate and adaptive immune system (57,58).…”

Section: Vaccinal Effectmentioning

confidence: 99%

Nimotuzumab for Patients With Inoperable Cancer of the Head and Neck

et al. 2020

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EGFR activation induces cell proliferation, neoformation of blood vessels, survival, and metastasis of the cancer cells. Nimotuzumab is an engineered, intermediate affinity anti-EGFR antibody, that apart from other drugs in its class, is very safe and does not cause hypomagnesemia or grade 3-4 cutaneous rash. The antibody inhibits cell proliferation and angiogenesis, activates natural killer cells, stimulates dendritic cell maturation, and induces cytotoxic T cells. Nimotuzumab restores MHC-I expression on tumor cells, hindering one of the EGFR immune-escape ways. The antibody has been extensively studied in 7 clinical trials, concurrently with irradiation or irradiation plus chemotherapy in subjects with inoperable head and neck tumors. Nimotuzumab was safe and efficacious in unfit patients receiving irradiation alone and in subjects treated with cisplatin and radiotherapy. In patients with locally advanced squamous cell carcinomas of the head and neck, nimotuzumab in combination with low dose cisplatin and radiotherapy was superior to cisplatin and radiotherapy in progression free survival, disease free survival, and locoregional tumor control.

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Antitumor Antibodies Can Drive Therapeutic T Cell Responses

Cited by 29 publications

References 30 publications

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Ranitidine Inhibition of Breast Tumor Growth Is B Cell Dependent and Associated With an Enhanced Antitumor Antibody Response

Nimotuzumab for Patients With Inoperable Cancer of the Head and Neck

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