Targeting T cells against brain tumors with a bispecific ligand-antibody conjugate

Roy, Edward J.; Cho, Bryan K.; Rund, Laurie A.; Patrick, Todd A.; Kranz, David M.

doi:10.1002/(sici)1097-0215(19980529)76:5<761::aid-ijc23>3.0.co;2-5

Cited by 20 publications

(12 citation statements)

References 18 publications

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“…Because these molecules mediate T-cell activation via binding to CD3 rather than TCR and peptide/MHC interactions, CD3-bispecific antibodies are able to redirect a polyclonal T-cell response to tumor cells independent from tumor-antigen specificity of the T cell. Several reports have demonstrated that treatment of preclinical tumor models with CD3-bispecific antibodies leads to an increase in tumorinfiltrating T cells (1,(7)(8)(9)(10). The mechanism(s) underlying increased T-cell accumulation has yet to be described.…”

Section: Introductionmentioning

confidence: 99%

IFNγ-induced Chemokines Are Required for CXCR3-mediated T-Cell Recruitment and Antitumor Efficacy of Anti-HER2/CD3 Bispecific Antibody

Li¹,

Ybarra²,

Mak³

et al. 2018

Clinical Cancer Research

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The response to cancer immune therapy is dependent on endogenous tumor-reactive T cells. To bypass this requirement, CD3-bispecific antibodies have been developed to induce a polyclonal T-cell response against the tumor. Anti-HER2/CD3 T-cell-dependent bispecific (TDB) antibody is highly efficacious in the treatment of HER2-overexpressing tumors in mice. Efficacy and immunologic effects of anti-HER2/CD3 TDB were investigated in mammary tumor model with very few T cells prior treatment. We further describe the mechanism for TDB-induced T-cell recruitment to tumors. The immunologic effects and the mechanism of CD3-bispecific antibody-induced T-cell recruitment into spontaneous HER2-overexpressing mammary tumors was studied using human HER2 transgenic, immunocompetent mouse models. Anti-HER2/CD3 TDB treatment induced an inflammatory response in tumors converting them from poorly infiltrated to an inflamed, T-cell abundant, phenotype. Multiple mechanisms accounted for the TDB-induced increase in T cells within tumors. TDB treatment induced CD8 T-cell proliferation. T cells were also actively recruited post-TDB treatment by IFNγ-dependent T-cell chemokines mediated via CXCR3. This active T-cell recruitment by TDB-induced chemokine signaling was the dominant mechanism and necessary for the therapeutic activity of anti-HER2/CD3 TDB. In summary, we demonstrate that the activity of anti-HER2/CD3 TDB was not dependent on high-level baseline T-cell infiltration. Our results suggest that anti-HER2/CD3 TDB may be efficacious in patients and indications that respond poorly to checkpoint inhibitors. An active T-cell recruitment mediated by TDB-induced chemokine signaling was the major mechanism for T-cell recruitment.

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Section: Introductionmentioning

confidence: 99%

IFNγ-induced Chemokines Are Required for CXCR3-mediated T-Cell Recruitment and Antitumor Efficacy of Anti-HER2/CD3 Bispecific Antibody

Li¹,

Ybarra²,

Mak³

et al. 2018

Clinical Cancer Research

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“…Alternatively, specific viral proteins can be modified to enhance binding to target cells. Bispecific molecules such as bivalent ScFvs or antibodies covalently conjugated to ligands can alter binding [46, 47], or genetic mutation of viral proteins can provide a permanent change in tropism [48, 49]. …”

Section: Discussionmentioning

confidence: 99%

Mutation of Herpesvirus Saimiri ORF51 Glycoprotein Specifically Targets Infectivity to Hepatocellular Carcinoma Cell Lines

Turrell

Whitehouse

2010

BioMed Research International

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Herpesvirus saimiri (HVS) is a gamma herpesvirus with several properties that make it an amenable gene therapy vector; namely its large packaging capacity, its ability to persist as a nonintegrated episome, and its ability to infect numerous human cell types. We used RecA-mediated recombination to develop an HVS vector with a mutated virion protein. The heparan sulphate-binding region of HVS ORF51 was substituted for a peptide sequence which interacts with somatostatin receptors (SSTRs), overexpressed on hepatocellular carcinoma (HCC) cells. HVS mORF51 showed reduced infectivity in non-HCC human cell lines compared to wild-type virus. Strikingly, HVS mORF51 retained its ability to infect HCC cell lines efficiently. However, neutralisation assays suggest that HVS mORF51 has no enhanced binding to SSTRs. Therefore, mutation of the ORF51 glycoprotein has specifically targeted HVS to HCC cell lines by reducing the infectivity of other cell types; however, the mechanism for this targeting is unknown.

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“…T Ag expression in the choroid plexus begins within 14 days of birth and results in the appearance of microscopic papillomas by 35 days [14]. Tumors progress rapidly beginning at approximately 80 days of age, causing death at a mean age of 105 days [14, 15]. Due to low-level transgene expression in the thymus (unpublished observations), SV11 mice are immunologically tolerant to T Ag and unable to mount a CD8 + T-cell response toward the dominant T Ag determinants, including the immunodominant site IV determinant (residues 404–411) [8].…”

Section: Introductionmentioning

confidence: 99%

Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors

Cozza

Cooper

Budgeon

et al. 2014

Cancer Immunol Immunother

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Adoptive T-cell transfer (ACT) has achieved clinical success in treating established cancer, particularly in combination with lymphodepleting regimens. Our group previously demonstrated that ACT following whole-body irradiation (WBI) promotes high-level T-cell accumulation, regression of established brain tumors, and long-term protection from tumor recurrence in a mouse model of SV40 T antigen-induced choroid plexus tumors. Here we asked whether an approach that can promote strong donor T-cell responses in the absence of WBI might also produce this dramatic and durable tumor elimination following ACT. Agonist anti-CD40 antibody can enhance antigen-specific CD8+ T-cell responses and has shown clinical efficacy as a monotherapy in the setting of cancer. We show that anti-CD40 conditioning promotes rapid accumulation of tumor-specific donor CD8+ T cells in the brain and regression of autochthonous T antigen-induced choroid plexus tumors, similar to WBI. Despite a significant increase in the lifespan, tumors eventually recurred in anti-CD40-conditioned mice coincident with loss of T-cell persistence from both the brain and lymphoid organs. Depletion of CD8+ T cells from the peripheral lymphoid organs of WBI-conditioned recipients failed to promote tumor recurrence, but donor cells persisted in the brains long-term in CD8-depleted mice. These results demonstrate that anti-CD40 conditioning effectively enhances ACT-mediated acute elimination of autochthonous tumors, but suggest that mechanisms associated with WBI conditioning, such as the induction of long-lived T cells, may be critical for protection from tumor recurrence.

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Targeting T cells against brain tumors with a bispecific ligand-antibody conjugate

Cited by 20 publications

References 18 publications

IFNγ-induced Chemokines Are Required for CXCR3-mediated T-Cell Recruitment and Antitumor Efficacy of Anti-HER2/CD3 Bispecific Antibody

IFNγ-induced Chemokines Are Required for CXCR3-mediated T-Cell Recruitment and Antitumor Efficacy of Anti-HER2/CD3 Bispecific Antibody

Mutation of Herpesvirus Saimiri ORF51 Glycoprotein Specifically Targets Infectivity to Hepatocellular Carcinoma Cell Lines

Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors

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