Sir Peter MacCallum Department of Oncology - Research Publications
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ItemEnhancing the antitumor effects of radiotherapy with combinations of immunostimulatory antibodies(LANDES BIOSCIENCE, 2012-12)The development and use of combination immunotherapy-based anticancer regimens is at an early but clearly exciting stage. We now demonstrate that the antibody-based co-targeting of multiple immunostimulatory and/or inhibitory pathways can be used safely and effectively in combination with single dose or fractionated radiotherapy to cure mice bearing established mammary tumors.
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ItemHypoxia-driven immunosuppression contributes to the pre-metastatic niche(TAYLOR & FRANCIS INC, 2013-01)Primary tumor cells create favorable microenvironments in secondary organs, termed pre-metastatic niches, that promote the formation of metastases. Using immune competent syngenic breast cancer mouse models, we have recently demonstrated that factors secreted by hypoxic tumor cells condition pre-metastatic niches by recruiting CD11b+/Ly6Cmed/Ly6G+ myeloid cells and suppressing natural killer cell functions.
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ItemThe combination of histone deacetylase inhibitors with immune-stimulating antibodies has potent anti-cancer effects(LANDES BIOSCIENCE, 2012-05-01)The use of immunotherapy to treat cancer is rapidly gaining momentum. Using pre-clinical mouse models, we have recently demonstrated potent and long lasting tumor regression can be elicited by immune-stimulating monoclonal antibodies (mAbs) when combined with histone deacetylase inhibitors (HDACi) and believe this therapy will have broad application in humans.
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ItemCancer immunoediting by the innate immune system in the absence of adaptive immunity(ROCKEFELLER UNIV PRESS, 2012-09-24)Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2(-/-), and RAG2(-/-)x γc(-/-) mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2(-/-)x γc(-/-) mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting.
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ItemStudying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma(TAYLOR & FRANCIS INC, 2012-11)Recent evidence demonstrates that the efficacy of conventional anticancer therapies including chemotherapy requires a functional immune system. Here, we addressed the possibility that the antitumor effect of a selective Smoothened antagonist and Hedgehog (Hh) pathway inhibitor (LDE225), a promising anticancer drug, might at least partially depend on the immune system. To this aim, we used tumor cell lines derived from a murine model of radiation-induced osteosarcoma. In vitro treatment of osteosarcoma cells with LDE225 resulted in a decreased ability of tumor cells to proliferate, but had no effect on their viability. Flow cytometry analysis demonstrated that LDE225-treatment did not detectably modulate the immunogenicity of tumor cells. Moreover, LDE225 did not display any pro-apoptotic properties on osteosarcoma cells, highlighting that its antitumor profile mainly derives from a cytostatic effect. Furthermore, calreticulin exposure, a key feature of immunogenic cell death, was not provoked by LDE225, neither alone nor combined with recognized immunogenic drugs. Finally, the oral administration of LDE225 to osteosarcoma-bearing mice did significantly delay the tumor growth even in an immunocompromised setting. These data suggest that inhibiting Hh signaling can control osteosarcoma cell proliferation but does not modulate the immunogenic profile of these cells.
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ItemThree agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice(BMC, 2010-04-28)BACKGROUND: Combination immunotherapies can be effective against subcutaneous tumors in mice but the effect against orthotopic malignant disease is less well characterized. In particular, a combination of three agonist antibodies, termed Tri-mAb, consisting of anti-DR5, anti-CD40 and anti-CD137 has previously been demonstrated to eradicate a large proportion of subcutaneous renal cell carcinoma (Renca) tumors (75% long-term survival), but the effect against orthotopic disease is not known. PURPOSE: To determine the relative response of orthotopic tumors, we inoculated Renca into the kidney followed by treatment with Tri-mAb. RESULTS: We found that orthotopic tumors responded much less to treatment (approximately 13% survival), but a significant improvement in survival was achieved through the addition of IL-2 to the treatment regimen (55% survival). All three agonist antibodies and high dose IL-2, 100,000 IU for up to six doses, were required. CD8+ T cells were also required for optimal anti-tumor responses. Coadministration of IL-2 led to enhanced T cell activity as demonstrated by an increased frequency of IFN-gamma-producing T cells in tumor-draining lymph nodes, which may have contributed to the observed improvement of therapy against kidney tumors. IMPLICATIONS: Responses of subcutaneous tumors to immunotherapy do not necessarily reflect how orthotopic tumors respond. The use of combination immunotherapy stimulating multiple facets of immunity and including cytokine support for T cells can induce effective anti-tumor responses against orthotopic and metastatic tumors.
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ItemA role for CCL2 in both tumor progression and immunosurveillance(TAYLOR & FRANCIS INC, 2013-07-01)The chemokine CCL2, which is best known for its chemotactic functions, is expressed not only by immune cells, but also by several types of malignant and stromal cells. CCL2 has been shown to exert both pro- and anti-tumor effects. However, recent results demonstrate a main role for CCL2 in tumor progression and metastasis, suggesting that this chemokine may constitute a therapeutic target for anticancer drugs. Mammary carcinoma models, including models of implantable, transgenic, and chemically-induced tumors, were employed in the setting of Ccl2 or Ccr2 knockout mice or CCL2 neutralization with a monoclonal antibody to further investigate the role of the CCL2/CCR2 signaling axis in tumor progression and metastatic spread. In our implantable tumor models, an anti-CCL2 monoclonal antibody inhibited the growth of primary malignant lesions in a biphasic manner and reduced the number of metastases. However, in Ccl2-/- or Ccr2-/- mice developing implanted or transgenic tumors, the number of pulmonary metastases was increased despite a reduction in the growth rate of primary neoplasms. Transgenic Mtag.Ccl2-/- or Mtag.Ccr2-/- mice also exhibited a significantly earlier of disease onset. In a chemical carcinogenesis model, anti-CCL2 monoclonal antibody inhibited the growth of established lesions but was ineffective in the tumor induction phase. In contrast to previous studies indicating a role for CCL2 in the establishment of metastases, we have demonstrated that the absence of CCL2/CCR2-signaling results in increased metastatic disease. Thus, the CCL2/CCR2 signaling axis appears to play a dual role in mediating early tumor immunosurveillance and sustaining the growth and progression of established neoplasms. Our findings support the use of anti-CCL2 therapies for the treatment of established breast carcinoma, although the complete abrogation of the CCL2 signaling cascade may also limit immunosurveillance and support metastatic spread.
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ItemNon-classical MHC Class I molecules regulating natural killer cell function(TAYLOR & FRANCIS INC, 2013-03-01)Natural killer (NK) cells possess effector and immunoregulatory functions that are controlled by a myriad of receptor-ligand pairs, including human killer inhibitory receptor (KIR) and mouse Ly49-MHC class I interactions. We have recently shown that the NK cell inhibitory molecule Ly49A binds the non-classical MHC molecule H2-M3, thus regulating host innate immune responses to tumor initiation and metastasis.
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ItemType I NKT-cell-mediated TNF-α is a positive regulator of NLRP3 inflammasome priming(WILEY, 2014-07)The NLRP3 inflammasome plays a crucial role in the innate immune response to pathogens and exogenous or endogenous danger signals. Its activity must be precisely and tightly regulated to generate tailored immune responses. However, the immune cell subsets and cytokines controlling NLRP3 inflammasome activity are still poorly understood. Here, we have shown a link between NKT-cell-mediated TNF-α and NLRP3 inflammasome activity. The NLRP3 inflammasome in APCs was critical to potentiate NKT-cell-mediated immune responses, since C57BL/6 NLRP3 inflammasome-deficient mice exhibited reduced responsiveness to α-galactosylceramide. Importantly, NKT cells were found to act as regulators of NLRP3 inflammasome signaling, as NKT-cell-derived TNF-α was required for optimal IL-1β and IL-18 production by myeloid cells in response to α-galactosylceramide, by acting on the NLRP3 inflammasome priming step. Thus, NKT cells play a role in the positive regulation of NLRP3 inflammasome priming by mediating the production of TNF-α, thus demonstrating another means by which NKT cells control early inflammation.
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ItemNo Preview AvailableCombined Anti-CD40 and Anti-IL-23 Monoclonal Antibody Therapy Effectively Suppresses Tumor Growth and Metastases(AMER ASSOC CANCER RESEARCH, 2014-05-01)Tumor-induced immunosuppression remains one of the major obstacles to many potentially effective cancer therapies and vaccines. Host interleukin (IL)-23 suppresses the immune response during tumor initiation, growth, and metastases, and neutralization of IL-23 causes IL-12-dependent antitumor effects. Here, we report that combining agonistic anti-CD40 monoclonal antibodies (mAb) to drive IL-12 production and anti-IL-23 mAbs to counter the tumor promoting effects of IL-23 has greater antitumor activity than either agent alone. This increased antitumor efficacy was observed in several experimental and spontaneous lung metastases models as well as in models of de novo carcinogenesis. The combination effects were dependent on host IL-12, perforin, IFN-γ, natural killer, and/or T cells and independent of host B cells and IFN-αβ sensitivity. Interestingly, in the experimental lung metastases tumor models, we observed that intracellular IL-23 production was specifically restricted to MHC-II(hi)CD11c(+)CD11b(+) cells. Furthermore, an increase in proportion of these IL-23-producing cells was detected only in tumor models where IL-23 neutralization was therapeutic. Overall, these data suggest the clinical potential of using anti-CD40 (push) and anti-IL-23 mAbs (pull) to tip the IL-12/23 balance in established tumors.