Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects

Fransen, Marieke F.; Sluis, Tetje C. van der; Ossendorp, Ferry; Arens, Ramon; Melief, Cornelis J.M.

doi:10.1158/1078-0432.ccr-12-0781

Cited by 175 publications

(153 citation statements)

References 32 publications

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“…with 100 mg of the CD8-depleting monoclonal antibody (mAb) 2.43 on day 7 and then every 6 days onward. mAbs were prepared and purified as described previously (20). Only mice that had a >99% depletion of CD8 T cell, as measured by flow cytometry, were included in the experiment.…”

Section: Tumor Cell Linesmentioning

confidence: 99%

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Sluis

Sluijter

Duikeren

et al. 2015

Cancer Immunology Research

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Abundant macrophage infiltration of solid cancers commonly correlates with poor prognosis. Tumor-promoting functions of macrophages include angiogenesis, metastasis formation, and suppression of Th1-type immune responses. Here, we show that successful treatment of cervical carcinoma in mouse models with synthetic long peptide (SLP) vaccines induced influx of cytokineproducing CD8 T cells that strongly altered the numbers and phenotype of intratumoral macrophages. On the basis of the expression of CD11b, CD11c, F4/80, Ly6C, Ly6G, and MHC II, we identified four myeloid subpopulations that increased in numbers from 2.0-fold to 8.7-fold in regressing tumors. These changes of the intratumoral myeloid composition coincided with macrophage recruitment by chemokines, including CCL2 and CCL5, and were completely dependent on a vaccine-induced influx of tumor-specific CD8 T cells. CD4 T cells were dispensable. Incubation of tumor cells with T cell-derived IFNg and TNFa recapitulated the chemokine profile observed in vivo, confirming the capacity of antitumor CD8 T cells to mediate macrophage infiltration of tumors. Strikingly, complete regressions of large established tumors depended on the tumor-infiltrating macrophages that were induced by this immunotherapy, because a smallmolecule drug inhibitor targeting CSF-1R diminished the number of intratumoral macrophages and abrogated the complete remissions. Survival rates after therapeutic SLP vaccination deteriorated in the presence of CSF-1R blockers. Together, these results show that therapeutic peptide vaccination could induce cytokine-producing T cells with strong macrophage-skewing capacity necessary for tumor shrinkage, and suggest that the development of macrophage-polarizing, rather than macrophage-depleting, agents is warranted.

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Section: Tumor Cell Linesmentioning

confidence: 99%

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Sluis

Sluijter

Duikeren

et al. 2015

Cancer Immunology Research

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“…The concept of generating a systemic immune response with local administration of immunomodulating antibodies has been demonstrated by us and others for CD40 antibodies but also for other targets such as CTLA-4 and CD137 (14,15,(34)(35)(36)(37). In this study, we describe the generation of an optimized CD40 agonistic antibody.…”

Section: Discussionmentioning

confidence: 93%

The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity

Mangsbo

Broos

Fletcher

et al. 2015

Clinical Cancer Research

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Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.Results: Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.Conclusions: Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.

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“…Lately, the focus has shifted toward local administration, through which doses and consequently toxicity can be reduced, but potentially retaining the efficacy of the systemic antitumor effects (20,23,29,(42)(43)(44).…”

Section: -T B + T B -T B + T B -T B + T B -T B + T B -T B + T B -T B mentioning

confidence: 99%

Locally Delivered CD40 Agonist Antibody Accumulates in Secondary Lymphoid Organs and Eradicates Experimental Disseminated Bladder Cancer

Sandin

Orlova

Gustafsson

et al. 2014

Cancer Immunology Research

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Immunotherapy with intratumoral injection of adenoviral vectors expressing CD40L has yielded positive results in experimental and clinical bladder cancer. We therefore hypothesized that anti-CD40 antibody would be effective in this setting. Agonistic CD40 antibodies were developed as vaccine adjuvants but have later been used as treatment of advanced solid tumors and hematologic cancers. Systemic anti-CD40 therapy has been associated with immune-related adverse events, such as cytokine release syndrome and liver toxicity, and local delivery is an attractive approach that could reduce toxicity. Herein, we compared local and systemic anti-CD40 antibody delivery to evaluate efficacy, toxicity, and biodistribution in the experimental MB49 bladder cancer model. Antitumor effects were confirmed in the B16 model. In terms of antitumor efficacy, local anti-CD40 antibody stimulation was superior to systemic therapy at an equivalent dose and CD8 T cells were crucial for tumor growth inhibition. Both administration routes were dependent on host CD40 expression for therapeutic efficacy. In vivo biodistribution studies revealed CD40-specific antibody accumulation in the tumor-draining lymph nodes and the spleen, most likely reflecting organs with frequent target antigen-expressing immune cells. Systemic administration led to higher antibody concentrations in the liver and blood compared with local delivery, and was associated with elevated levels of serum haptoglobin. Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates antitumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic. Cancer Immunol Res; 2(1); 80-90. Ó2013 AACR.

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Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects

Cited by 175 publications

References 32 publications

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity

Locally Delivered CD40 Agonist Antibody Accumulates in Secondary Lymphoid Organs and Eradicates Experimental Disseminated Bladder Cancer

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